65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"Effects of peroxisome proliferator - activated receptor - alpha and - gamma agonist , DB04971 , on diabetic complications in Zucker diabetic fatty rats . This study has investigated the effects of DB04971 , a peroxisome proliferator - activated receptor ( Q07869 ) - alpha and P37231 agonist , on the pathogenesis of diabetic complications in the Zucker diabetic fatty ( ZDF ) rats , a model of type 2 diabetes . Comparison is made with troglitazone , a P37231 agonist . The ZDF rats exhibited hyperglycaemia and hyperlipidaemia , and developed diabetic complications such as cataract , nephropathy , and neuropathy . Treatment with DB04971 from the prediabetic stage controlled glycaemia and lipidaemia , and prevented the development of diabetic complications . DB00197 was less effective in controlling serum cholesterol and neuropathy . ZDF rats developed diabetic osteopenia with reduced bone turnover , and this was prevented by DB04971 and troglitazone , possibly mediated by increased bone turnover and bone formation . Since DB04971 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications , it is suggested that treatment with DB04971 , which activates both Q07869 and P37231 , could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes .\",\n \"Reduced P25874 - 1 content in in vitro differentiated beige / brite adipocytes derived from preadipocytes of human subcutaneous white adipose tissues in obesity . INTRODUCTION : Brown adipose tissue ( Q14032 ) is a potential therapeutic target to reverse obesity . The purpose of this study was to determine whether primary precursor cells isolated from human adult subcutaneous white adipose tissue ( WAT ) can be induced to differentiate in - vitro into adipocytes that express key markers of brown or beige adipose , and whether the expression level of such markers differs between lean and obese young adult males . METHODS : Adipogenic precursor cells were isolated from lean and obese individuals from subcutaneous abdominal WAT biopsies . Cells were grown to confluence , differentiated for 2 . 5 weeks then harvested for measurement of gene expression and P25874 protein . RESULTS : There was no difference between groups with respect to differentiation into adipocytes , as indicated by oil red - O staining , rates of lipolysis , and expression of adipogenic genes ( P15090 , P37231 ) . WAT genes ( P31274 , P06400 ) were expressed equally in the two groups . Post differentiation , the beige adipose specific genes Q99966 and Q07011 were significantly increased in both groups , but classic Q14032 markers Q15915 and Q68G74 decreased significantly . Cell lines from both groups also equally increased post - differentiation expression of the thermogenic - responsive gene Q9UBK2 ( P20142 - 1α ) . P25874 gene expression was undetectable prior to differentiation , however after differentiation both gene expression and protein content were increased in both groups and were significantly greater in cultures from lean compared with obese individuals ( p < 0 . 05 ) . CONCLUSION : Human subcutaneous WAT cells can be induced to attain Q14032 characteristics , but this capacity is reduced in WAT cells from obese individuals .\",\n \"P01308 signaling inhibits the P28335 receptor in choroid plexus via Q96HU1 kinase . BACKGROUND : G protein - coupled receptors ( GPCRs ) interact with heterotrimeric GTP - binding proteins ( G proteins ) to modulate acute changes in intracellular messenger levels and ion channel activity . In contrast , long - term changes in cellular growth , proliferation and differentiation are often mediated by tyrosine kinase receptors and certain GPCRs by activation of mitogen - activated protein ( Q96HU1 ) kinases . Complex interactions occur between these signaling pathways , but the specific mechanisms of such regulatory events are not well - understood . In particular it is not clear whether GPCRs are modulated by tyrosine kinase receptor - Q96HU1 kinase pathways . RESULTS : Here we describe tyrosine kinase receptor regulation of a GPCR via Q96HU1 kinase . P01308 reduced the activity of the P28335 receptor in choroid plexus cells which was blocked by the Q96HU1 kinase kinase ( MEK ) inhibitor , PD 098059 . We demonstrate that the inhibitory effect of insulin and insulin - like growth factor type 1 ( DB01277 ) on the P28335 receptor is dependent on tyrosine kinase , DB01367 and Q96HU1 kinase . The effect may be receptor - specific : insulin had no effect on another GPCR that shares the same G protein signaling pathway as the P28335 receptor . This effect is also direct : activated Q96HU1 kinase mimicked the effect of insulin , and removing a putative Q96HU1 kinase site from the P28335 receptor abolished the effect of insulin . CONCLUSION : These results show that insulin signaling can inhibit P28335 receptor activity and suggest that Q96HU1 kinase may play a direct role in regulating the function of a specific GPCR .\",\n \"P37231 ligands modulate effects of LPS in stimulated rat synovial fibroblasts . This work demonstrated the constitutive expression of peroxisome proliferator - activated receptor ( Q07869 ) - gamma and Q07869 in rat synovial fibroblasts at both mRNA and protein levels . A decrease in P37231 expression induced by 10 microg / ml lipopolysaccharide ( LPS ) was observed , whereas Q07869 mRNA expression was not modified . 15 - Deoxy - Delta ( 12 , 14 )- prostaglandin J ( 2 ) ( 15d - PGJ ( 2 ) ) dose - dependently decreased LPS - induced cyclooxygenase ( P36551 ) - 2 ( - 80 % ) and inducible nitric oxide synthase ( P35228 ) mRNA expression ( - 80 % ) , whereas troglitazone ( 10 microM ) only inhibited P35228 mRNA expression ( - 50 % ) . 15d - PGJ ( 2 ) decreased LPS - induced interleukin ( IL ) - 1 beta ( - 25 % ) and tumor necrosis factor ( P01375 ) - alpha ( - 40 % ) expression . Interestingly , troglitazone strongly decreased P01375 expression ( - 50 % ) but had no significant effect on P01584 expression . 15d - PGJ ( 2 ) was able to inhibit DNA - binding activity of both nuclear factor ( NF ) - kappa B and AP - 1 . DB00197 had no effect on NF - kappa B activation and was shown to increase LPS - induced AP - 1 activation . 15d - PGJ ( 2 ) and troglitazone modulated the expression of LPS - induced P35228 , P35354 , and proinflammatory cytokines differently . Indeed , troglitazone seems to specifically target P01375 and P35228 pathways . These results offer new insights in regard to the anti - inflammatory potential of the P37231 ligands and underline different mechanisms of action of 15d - PGJ ( 2 ) and troglitazone in synovial fibroblasts .\",\n \"Effects of C - phycocyanin and Spirulina on salicylate - induced tinnitus , expression of DB01221 receptor and inflammatory genes . Effects of C - phycocyanin ( C - PC ) , the active component of Spirulina platensis water extract on the expressions of N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , tumor necrosis factor - α ( P01375 - α ) , interleukin - 1β ( IL - 1β ) , and cyclooxygenase type 2 ( P35354 ) genes in the cochlea and inferior colliculus ( IC ) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate . The results showed that 4 - day salicylate treatment ( unlike 4 - day saline treatment ) caused a significant increase in Q13224 , P01375 - α , and IL - 1β mRNAs expression in the cochlea and IC . On the other hand , dietary supplementation with C - PC or Spirulina platensis water extract significantly reduced the salicylate - induced tinnitus and down - regulated the mRNAs expression of Q13224 , P01375 - α , IL - 1β mRNAs , and P35354 genes in the cochlea and IC of mice . The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes .\",\n \"Further insight on the hypoglycemic and nonhypoglycemic effects of troglitazone 400 or 600 mg / d : effects on the very - low - density and high - density lipoprotein particle distribution . The effects of troglitazone 400 or 600 mg / d on the glycemic control , very - low - density lipoprotein ( VLDL ) , and high - density lipoprotein ( HDL ) subclass concentrations and plasminogen - activator inhibitor 1 ( P05121 ) levels were assessed in patients with type 2 diabetes that had not been controlled with dietary treatment . This was a multicenter , open - label , parallel - groups study . It included a run - in 4 - week diet period and a 24 - week randomized treatment . Fifty one patients received 400 mg / d and 55 patients 600 mg . The mean HbA ( 1c ) concentration at the end of the study was similar for both doses . DB00197 , regardless of dose , significantly improved insulin sensitivity assessed by the homeostasis model ( HOMA ) . P05121 levels were significantly decreased in both groups by 13 % . Higher HDL cholesterol concentrations and lower triglycerides levels were observed at the end of treatment . Triglyceride contents were reduced only in the lighter VLDL1 . The change in HDL cholesterol concentration resulted from a combination of increased HDL3 cholesterol and lower HDL2 cholesterol levels . No differences were found in the effects of both treatment groups on the evaluated parameters . Our data provide new information about the actions of the drug on the lipid profile . DB00197 reduces triglyceride levels by lowering the triglycerides content of the VLDL1 particles and increases HDL cholesterol concentrations by increasing HDL3 cholesterol levels .\",\n \"P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .\",\n \"Mediator subunit Gal11p / Q96RN5 is required for fatty acid - dependent gene activation by yeast transcription factor Oaf1p . The yeast zinc cluster transcription factor Oaf1p activates transcription of target genes in response to direct binding of fatty acids in a manner analogous to the vertebrate nuclear receptor peroxisome proliferator - activated receptoralpha ( PPARalpha ) . PPARs and other metazoan nuclear receptors productively engage several distinct LXXLL motif - containing co - activators , including P52701 family members and the Q15648 / MED1 subunit of the Mediator co - activator , to promote ligand - dependent gene activation . Yeast , however , does not appear to harbor LXXLL motif co - activators , and the mechanism of fatty acid - dependent gene activation by the yeast PPARalpha analog Oaf1p is unknown . Here we show that the yeast Mediator subunit Gal11p / Q96RN5 and its activator - targeted KIX domain plays a critical role in fatty acid - dependent transcriptional regulation of fatty acid beta - oxidation and peroxisomal genes by Oaf1p and for the ability of yeast to utilize fatty acids as a sole carbon source . Moreover , structural studies by NMR spectroscopy reveal that the Oaf1p activation domain interacts with the Gal11p / Q96RN5 KIX domain in a manner similar to the yeast zinc cluster family member and xenobiotic receptor Pdr1p , revealing that the Gal11p / Q96RN5 KIX domain is a key target of several ligand - dependent transcription factors in yeast . Together with previous work showing that the Caenorhabditis elegans Gal11p / Q96RN5 homolog MDT - 15 plays a critical role in regulation of fatty acid metabolism by the nematode Q07869 - like nuclear receptor NHR - 49 , the findings presented here provide evidence for an ancient and essential role of a Mediator co - activator subunit in regulation of fatty acid metabolism by nuclear receptor - like transcription factors in eukaryotes .\",\n \"Discrete roles for peroxisome proliferator - activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators . P37231 ( PPARgamma ) plays a major role in adipogenesis . PPARgamma binds to DNA as a heterodimer with retinoid X receptor ( RXR ) , and PPARgamma - RXR can be activated by ligands specific for either receptor ; the presence of both ligands can result in a cooperative effect on the transactivation of target genes . How these ligands mediate transactivation , however , remains unclear . PPARgamma is known to interact with both the P52701 / Q15788 family of coactivators and the distinct , multisubunit coactivator complex called DRIP . A single DRIP subunit , Q15648 ( Q15648 , PBP ) , binds directly to PPARgamma . Here we report that PPARgamma and RXR selectively interacted with Q15648 and P52701 proteins in a ligand - dependent manner . At physiological concentrations , RXR - specific ligands only induced P52701 binding to RXR , and PPARgamma - specific ligands exclusively recruited Q15648 but not P52701 coactivators to PPARgamma . This selectivity was not observed in interaction assays off DNA , implying that the specificity of coactivator binding in response to ligand is strongly influenced by the allosteric effects of DNA - bound heterodimers . These coactivator - selective effects were also observed in transient - transfection assays in the presence of overexpressed P52701 or DRIP coactivators . The results suggest that the cooperative effects of PPARgamma - and RXR - specific ligands may occur at the level of selective coactivator recruitment .\",\n \"Regulation of angiotensin II receptors beyond the classical pathway . The DB01367 ( renin - angiotensin system ) plays a role not only in the cardiovascular system , including blood pressure regulation , but also in the central nervous system . AngII ( angiotensin II ) binds two major receptors : the AT ( 1 ) receptor ( AngII type 1 receptor ) and AT ( 2 ) receptor ( AngII type 2 receptor ) . It has been recognized that AT ( 2 ) receptor activation not only opposes AT ( 1 ) receptor actions , but also has unique effects beyond inhibitory cross - talk with AT ( 1 ) receptor signalling . Novel pathways beyond the classical actions of DB01367 , the P12821 ( angiotensin - converting enzyme ) / AngII / AT ( 1 ) receptor axis , have been highlighted : the Q9BYF1 / Ang -( 1 - 7 ) [ angiotensin -( 1 - 7 ) ] / Mas receptor axis as a new opposing axis against the P12821 / AngII / AT ( 1 ) receptor axis , novel AngII - receptor - interacting proteins and various AngII - receptor - activation mechanisms including dimer formation . Q6RW13 ( AT ( 1 )- receptor - associated protein ) and Q9ULD2 ( AT ( 2 )- receptor - interacting protein ) are well - characterized AngII - receptor - associated proteins . These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states . Moreover , the possible cross - talk between Q07869 ( peroxisome - proliferator - activated receptor ) - γ and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of DB01367 in the metabolic syndrome , and interestingly some ARBs ( AT ( 1 )- receptor blockers ) have been reported to have an AT ( 1 )- receptor - blocking action with a partial Q07869 - γ agonistic effect . These emerging concepts concerning the regulation of AngII receptors are discussed in the present review .\",\n \"___MASK57___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK57___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .\",\n \"P37231 regulates P12830 expression and inhibits growth and invasion of prostate cancer . P37231 ( PPARgamma ) might not be permissive to ligand activation in prostate cancer cells . Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma ligands in a recent randomized clinical trial . Using cells and prostate cancer xenograft mouse models , we demonstrate in this study that a combination treatment using the PPARgamma agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy . We show that the combination treatment impairs the bone - invasive potential of prostate cancer cells in mice . In addition , we demonstrate that expression of P12830 , a protein involved in the control of cell migration and invasion , is highly up - regulated in the presence of valproic acid and pioglitazone . We show that P12830 expression responds only to the combination treatment and not to single PPARgamma agonists , defining a new class of PPARgamma target genes . These results open up new therapeutic perspectives in the treatment of prostate cancer .\",\n \"Disruption of ERalpha signalling pathway by PPARgamma agonists : evidences of PPARgamma - independent events in two hormone - dependent breast cancer cell lines . P37231 ( PPARgamma ) is a nuclear receptor that can be activated by natural ligands such as 15 - deoxy - delta ( 12 , 14 )- prostaglandin J2 ( 15d - PGJ ( 2 ) ) as well as synthetic drugs such as thiazolidinediones . The treatment of human breast cancer cell lines with PPARgamma agonists is known to have antiproliferative effects but the role of PPARgamma activation in the process remains unclear . In the present study , we investigated the effects of four PPARgamma agonists , Rosiglitazone ( RGZ ) , DB09201 ( CGZ ) , DB00197 ( Q96PF1 ) and the natural agonist 15d - PGJ ( 2 ) , on estrogen receptor alpha ( ERalpha ) signalling pathway in two hormone - dependent breast cancer cell lines , MCF - 7 and ZR - 75 - 1 . In both of them , Q96PF1 , CGZ and 15d - PGJ ( 2 ) induced an inhibition of ERalpha signalling associated with the proteasomal degradation of ERalpha . ZR - 75 - 1 cells were more sensitive than MCF - 7 cells to these compounds . Treatments that induced ERalpha degradation inhibited cell proliferation after 24 h . In contrast , 24 h exposure to RGZ , the most potent activator of PPARgamma disrupted neither ERalpha signalling nor cell proliferation . 9 - cis retinoic acid never potentiated the proteasomal degradation of ERalpha . PPARgamma antagonists ( T0070907 , BADGE and GW 9662 ) did not block the proteolysis of ERalpha in MCF - 7 and ZR - 75 - 1 cells treated with Q96PF1 . ERalpha proteolysis still occurred in case of PPARgamma silencing as well as in case of treatment with the PPARgamma - inactive compound Delta2 - Q96PF1 , demonstrating a PPARgamma - independent mechanism . The use of thiazolidinedione derivatives able to trigger ERalpha degradation by a PPARgamma - independent pathway could be an interesting tool for breast cancer therapy .\",\n \"Ligands of peroxisome proliferator - activated receptor - gamma induce apoptosis in AR42J cells . INTRODUCTION : Peroxisome proliferator - activated receptor - gamma ( P37231 ) is a ligand - activated transcription factor that controls growth , differentiation , and inflammation in different tissues . Roles of P37231 activation in pancreatic acinar cells are poorly characterized . AIMS : To examine the effects of P37231 activation on the induction of apoptosis in rat pancreatic AR42J cells . METHODOLOGY : AR42J cells were treated with ligands of P37231 , and induction of apoptosis was evaluated by cell viability , DNA - fragmentation , and flow cytometry . RESULTS : Treatment of the cells with ligands of P37231 ( 15 - deoxy - open triangle12 , 14 - prostaglandin J2 or troglitazone ) induced apoptosis in a dose - dependent manner . DB00197 - induced apoptosis was not blocked by inhibitors of caspases ( acetyl - DEVD - aldehyde and benzoyloxycarbonyl - VAD - fluoromethylketone ) . DB00197 induced the expression of pancreatitis - associated protein - 1 and clusterin mRNAs . DB00197 activated c - Jun NH2 - terminal kinase / stress - activated protein kinase , but inhibited the activation of extracellular signal - regulated kinases 1 / 2 . DB00197 did not activate NF - kappaB , suggesting a role of NF - kappaB - independent pathways . In AR42J cells and isolated pancreatic acini , P37231 gene and protein were detected . In addition , troglitazone increased the Q07869 - dependent transcriptional activity , suggesting that P37231 is functional in AR42J cells . CONCLUSION : These results indicate that activation of P37231 induces apoptosis in AR42J cells and imply that P37231 may be a potential therapeutic target of pancreatic inflammation , because of its anti - inflammatory effects in addition to its proapoptotic effects .\",\n \"Cdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N - methyl - D - aspartate receptor subunit 2A . P12004 - dependent kinase 5 ( Cdk5 ) is a member of the small proline - directed serine / threonine kinase family . Cdk5 is not involved in cell cycle regulation , but is implicated in neurodegenerative disorders . However , the role of Cdk5 in neuropathic pain remains unclear . This study aimed to evaluate the possibility that Cdk5 is involved in neuropathic pain in the dorsal root ganglia ( Q86YR7 ) . We injected intrathecally Cdk5 inhibitor roscovitine in rat model of chronic compression of dorsal root ganglion and examined pain behaviors and the expression of N - methyl - d - aspartate receptor subunit 2A ( Q12879 ) but not Q13224 or Q9UHB4 in Q86YR7 . We found that roscovitine alleviated neuropathic pain , causing decline in paw withdrawal mechanical threshold and paw withdrawal thermal latency . Furthermore , roscovitine inhibited Q12879 expression in Q86YR7 . These data suggest that Cdk5 - Q12879 pathway regulates neuropathic pain in Q86YR7 , and intrathecal injection of roscovitine could alleviate neuropathic pain . Our findings provide new insight into the analgesic effects of Roscovitine and identify Cdk5 - Q12879 pathway as a potential target for effective treatment of neuropathic pain .\",\n \"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .\",\n \"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK57___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK57___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK57___ or Enalapril .\",\n \"P01308 resistance , oxidative stress , and podocyte injury : role of rosuvastatin modulation of filtration barrier injury . BACKGROUND / AIM : There is an emerging relationship between insulin resistance / hyperinsulinemia , oxidative stress , and glomerular injury manifesting as albuminuria . P04035 inhibitors ( statins ) have been shown to reduce oxidative stress in the vasculature as well as albuminuria in animal models and in human studies . The glomerular filtration barrier is emerging as a critical determinant of albumin filtration . We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier . METHOD : Young Zucker obese and Zucker lean rats ( 6 - 7 weeks old ) were treated with the P04035 inhibitor rosuvastatin ( 10 mg / kg / day ) or placebo for 21 days . RESULTS : In the Zucker obese rats , homeostasis model assessment - insulin resistance index , oxidative markers ( NADPH oxidase activity , reactive oxygen species , and urine isoprostane formation ) , podocyte foot process effacement , and albuminuria were increased as compared with Zucker lean controls , independent of increases in systolic blood pressure . Albuminuria correlated with podocyte foot process effacement ( r ( 2 ) = 0 . 61 ) and insulin level ( r ( 2 ) = 0 . 69 ) . ___MASK57___ treatment improved albuminuria , filtration barrier indices , and oxidative stress via copper / zinc superoxide dismutase . CONCLUSIONS : These data indicate that hyperinsulinemia together with insulin resistance is associated with podocyte injury and albuminuria independent of the systolic blood pressure . Further , rosuvastatin modulates filtration barrier injury and albuminuria and improves oxidative stress measures via copper / zinc superoxide dismutase .\",\n \"Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice . Peroxisome proliferator - activated receptor ( Q07869 ) - gamma controls growth , differentiation , and inflammation . P37231 agonists exert anti - inflammatory effects in vitro and inhibit the activation of pancreas stellate cells , implicated in the formation and progression of fibrosis . We determined the influence of troglitazone , a ligand for P37231 , on pancreatic damage and fibrosis in experimental chronic pancreatitis . Mice received six hourly intraperitoneal injections with 50 microg / kg of cerulein or saline , three times a week for 6 weeks . One week after the last injection all mice were sacrificed . Untreated mice were compared with mice treated with troglitazone either during weeks 1 to 6 or weeks 4 to 6 . All mice that received cerulein injections displayed histopathological signs of chronic pancreatitis at week 7 . DB00197 treatment improved all markers for severity of pancreatitis . Moreover , early and postponed troglitazone treatments were equally effective in diminishing intrapancreatic fibrosis as quantified by Sirius red staining , hydroxyproline content , and laminin staining as well as the increased number of pancreatic stellate cells and pancreas levels of transforming growth factor - beta . Thus , troglitazone attenuated pancreatic damage and inflammation in experimental chronic pancreatitis and remained beneficial in a therapeutic setting when given after initial damage had been established .\",\n \"Knockdown of receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) affects EMT - associated gene expression in human hepatoma cells . BACKGROUND : Receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) has been reported to be an important regulator of tumor proliferation , differentiation and wound repair . We investigated the effects of O43353 knockdown in human hepatoma cells on epithelial - to - mesenchymal transition ( EMT ) - associated gene expression . MATERIALS AND METHODS : HepG2 cells stably expressing O43353 - shRNA ( HepG2 - shRIPK2 ) were generated after puromycin selection . Total RNAs from HepG2 - shRIPK2 and from HepG2 - shcontrol cells were isolated and PCR - based arrays were performed to compare the 84 EMT - associated gene expressions . RESULTS : We observed that knockdown of O43353 down - regulated mRNA expression of jagged 1 ( P78504 ) ; plasminogen activator inhibitor - 1 ( P05121 ) ; regulator of G - protein signalling 2 , 24 kDa ( P41220 ) ; P12830 ( CDH1 ) ; fibroblast growth factor binding protein 1 ( Q14512 ) ; snail homolog 2 ( O43623 ) ; protein tyrosine phosphatase type IVA , member 1 ( Q93096 ) ; keratin 19 ( P08727 ) ; vimentin ( P08670 ) ; and survival of motor neuron protein - interacting protein 1 ( SIP1 ) . CONCLUSION : We found that knockdown of O43353 down - regulated nuclear factor kappa B ( NF - κB ) - dependent P05121 and P08670 gene expressions . O43353 might play an important role in hepatic cell migration . These findings could shed new light on carcinogenesis and on liver regeneration .\",\n \"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK2___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK2___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK2___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK2___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .\",\n \"DB00142 reverses Pb2 +- induced reductions of DB01221 receptor subunits in vitro . The objective of this study is to determine the effects of Pb2 + on N - methyl - d - aspartate receptor ( NMDAR ) subunits -- Q07869 , Q12879 and Q13224 in primary cultured neuronal cells . We hypothesize that L - glutamic acid ( GA ) reverses Pb2 +- induced NMDAR damage . Neuronal cells were isolated from the fetus brain at 18 - 20th day of gestation of pregnant Sprague Dawley ( SD ) rats . All experiments were included three independent cell preparations ( N = 3 ) . The neuronal cells were exposed to Pb2 + ( 10 (- 10 ) , 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) M ) for 24 h . Neurons were pretreated with NMDAR agonist -- L - glutamic acid ( GA ) ( 200 microM ) and antagonists dizocipine ( MK - 801 , 50 nM ) for 1h and then exposed to 10 (- 7 ) M of Pb2 + for 24 h . Finally , GA at 2 , 0 . 2 and 0 . 02 mM was incubated with neurons prior to Pb2 + exposure . Aliquots of Q9UHB4 , Q12879 and Q13224 proteins from cell homogenate were immunoprecipitated with protein A agarose and detected by Western blotting . The addition of GA unconventionally reversed the reductions of NMDAR by Pb at protein levels , whereas MK - 801 exacerbated Pb2 +- induced damage . The protection by GA against Pb2 +- induced reduction of NMDAR was dose - dependent . These findings suggest that the administration of GA may be a potential approach to intervene the Pb2 +- induced NMDAR alterations .\",\n \"Gene expression analysis of troglitazone reveals its impact on multiple pathways in cell culture : a case for in vitro platforms combined with gene expression analysis for early ( idiosyncratic ) toxicity screening . P37231 ( PPARgamma ) agonists of the thiazolidinedione family are used for the treatment of type 2 diabetes mellitus due to their ability to reduce glucose and lipid levels in patients with this disease . Three thiazolidinediones that were approved for treatment are Rezulin ( troglitazone ) , Avandia ( rosiglitazone ) , and Actos ( pioglitazone ) . DB00197 was withdrawn from the market due to idiosyncratic drug toxicity . Rosiglitazone and pioglitazone are still on the market for the treatment of type 2 diabetes . The authors present data from a gene expression screen that compares the impact these three compounds have in rats , in rat hepatocytes , and in the clone 9 rat liver cell line . The authors monitored the changes in expression in multiple genes , including those related to xenobiotic metabolism , proliferation , DNA damage , oxidative stress , apoptosis , and inflammation . Compared to the other two compounds , troglitazone had a significant impact on many of the pathways monitored in vitro although no major perturbation was detected in vivo . The changes detected predict not only general toxicity but potential mechanisms of toxicity . Based on gene expression analysis , the authors propose there is not just one but multiple ways troglitazone could be toxic , depending on a patient ' s environment and genetic makeup , including immune response - related toxicity .\",\n \"Sequence variation in P37231 may underlie differential response to troglitazone . Thiazolidinediones ( TZDs ) are peroxisome proliferator - activated receptor - gamma ( P37231 ) agonists used to treat type 2 diabetes . TZDs can also be used to reduce rates of type 2 diabetes in at - risk individuals . However , a large fraction of TZD - treated patients ( 30 - 40 % ) do not respond to TZD treatment with an improvement in insulin sensitivity ( Si ) . We hypothesized that variation within the gene encoding P37231 may underlie this differential response to TZD therapy . We screened approximately 40 kb of P37231 in 93 nondiabetic Hispanic women ( 63 responders and 30 nonresponders ) with previous gestational diabetes who had participated in the DB00197 In the Prevention Of Diabetes study . TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment . Baseline demographic and clinical measures were not different between responders and nonresponders . We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion - deletion polymorphisms . Linkage disequilibrium analysis identified five haplotype blocks . Eight variants were associated with TZD response ( P < 0 . 05 ) . Three variants were also associated with changes in Si as a continuous variable . Our results suggest that P37231 variation may underlie response to TZD therapy in women at risk for type 2 diabetes .\",\n \"Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK93___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .\",\n \"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK25___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .\",\n \"DB00197 inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo . P37231 ( PPARgamma ) has been implicated in the differentiation and growth inhibition of cancer cells . We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma ( HCC ) cell growth , proliferation , and apoptosis in vitro and in vivo . We also studied relationships between PPARgamma activation and cyclooxygenase - 2 ( P35354 ) expression . Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone . Cell growth was determined via WST - 1 assay , proliferation by cell cycle analysis and proliferating cell nuclear antigen ( P12004 ) Western blotting , and apoptosis by flow cytometry and TUNEL . Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored , and the effects of treatment with troglitazone were determined . In resected HCCs , PPARgamma expression was less compared with the histologically normal surrounding liver . In cultures of Hep3B and Huh7 cells , basal expression of PPARgamma was relatively low , but troglitazone caused dose - dependent induction of PPARgamma expression . Cell cycle analysis revealed a decreased proportion of cells in S phase , with arrest at G0 / P55008 . Concomitant downregulation of P12004 and an increase in TUNEL staining , cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone . DB00197 - mediated PPARgamma activation also suppressed P35354 expression and induced p27 in HCC cells . Administration of troglitazone to Huh7 tumor - bearing mice significantly reduced tumor growth and caused tumor regression . In conclusion , collectively , these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC . PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth .\",\n \"P37231 ligand prevents the development of chronic pancreatitis through modulating NF - kappaB - dependent proinflammatory cytokine production and pancreatic stellate cell activation . PURPOSE : Thiazolidinedione derivatives ( TZDs ) are known to be ligands of peroxisome proliferator - activated receptor gamma ( PPARgamma ) . In this study , we investigated the effect of a TZD , troglitazone , on inflammation and fibrogenesis in the pancreas of an experimental model of chronic pancreatitis . MATERIAL AND METHODS : Male WBN / Kob rats with spontaneous chronic pancreatitis were fed rat chow containing 0 . 2 % troglitazone from 1 to 4 months of age . Immunohistochemical studies of rat pancreas were carried out with monoclonal mouse antibody against human alpha - smooth muscle actin ( alpha - SMA ) or rabbit polyclonal antibody against collagen type I , collagen type III , or fibronectin . Cytokine production was measured by enzyme - linked immunosorbent assay . The inhibitory action of troglitazone on nuclear factor - kappaB ( NF - kappaB ) binding activity in activated macrophages was also investigated . RESULTS : Long - term administration of troglitazone reduced inflammatory cell infiltration and fibrosis in the pancreas of WBN / Kob rats , and expression of alpha - SMA , procollagen I , III , and fibronectin was significantly reduced by troglitazone . The increase in P01375 production by activated macrophages was significantly decreased by troglitazone . Peritoneal macrophages isolated from WBN / Kob rats produced a large amount of P01375 , whereas those from troglitazone - treated WBN / Kob rats produced only a marginal amount of P01375 . Lipopolysaccharide - induced NF - kappaB binding activity in peritoneal macrophages was also significantly reduced by troglitazone . CONCLUSIONS : DB00197 prevented the progression of chronic pancreatitis via inhibition of Q13201 synthesis and proinflammatory cytokine production mediated by the inhibition of NF - kappaB activity .\",\n \"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK83___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .\",\n \"DB00197 , a P37231 activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by P01375 . BACKGROUND : Cytokine mediated induction of the mucosal addressin cell adhesion molecule - 1 ( Q13477 ) expression is associated with the onset and progression of inflammatory bowel disease ( Q9UKU7 ) . RESULTS : Using western blotting and cell - based ELISA , we show in this study that troglitazone , an activator of the peroxisome proliferator - activated receptor - gamma ( P37231 ) , widely used in the treatment of diabetes , has as well recently been highlighted as protective in models of inflammation and cancer . We found that troglitazone ( 10 - 40 microM ) , significantly reduced the P01375 ( 1 ng / ml ) mediated induction of endothelial Q13477 in a dose - dependent manner , achieving a 34 . 7 % to 98 . 4 % reduction in induced Q13477 . Trogliazone ( 20 microM ) reduced P01375 induced P19320 , P05362 and P16581 expression . Moreover , troglitazone significantly reduced alpha4beta7 - integrin dependent lymphocyte adhesion to P01375 cultured endothelial cells . CONCLUSIONS : These results suggest that P37231 agonists like troglitazone may be useful in the clinical treatment of Q9UKU7 .\",\n \"Novel function of androgen receptor - associated protein 55 / O43294 as a negative regulator of P84022 signaling . P10275 - associated protein 55 ( O43294 / O43294 ) belongs to the LIM protein superfamily and is featured by three or four N - terminal LD motifs and four C - terminal zinc finger - like LIM domains . Both LD motifs and LIM domains can serve as protein - protein interaction interfaces . Recently , we found that enforced expression of O43294 inhibits transforming growth factor - beta - mediated up - regulation of Smad binding element - luciferase reporter activity in NRP - 154 and NRP - 152 rat prostate and LNCaP human prostate cell lines . Moreover , O43294 also inhibits the induction of Smad - binding element 4 - luciferase and 3TP - luciferase ( a plasminogen activator inhibitor - 1 ( P05121 ) promoter construct ) reporters by constitutively active ( CA ) - P84022 in these cell lines . Co - immunoprecipitation studies suggest an interaction between O43294 and either CA - P84022 or wild - type P84022 in HEK293 cells that occurs through the MH2 domain of P84022 and the C terminus of O43294 with wild - type P84022 having stronger affinity than CA - P84022 to O43294 . O60760 pull - down assays demonstrate that this interaction can occur in a cell - free system . These results are consistent with the luciferase data showing that the C terminus of O43294 is critical for suppression of P84022 activity . Furthermore , using a mammalian two - hybrid system , we confirmed that O43294 interacts with the MH2 domain of P84022 and suppresses CA - P84022 - induced transcriptional responses . In conclusion , these results support that O43294 selectively intercepts transforming growth factor - beta signaling through an interaction of the LIM domain of O43294 with the MH2 domain of P84022 .\",\n \"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .\",\n \"Coadministration of acetaminophen and troglitazone : pharmacokinetics and safety . DB00197 , a P37231 agonist , enhances the actions of insulin on muscle and liver . It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite . Acetaminophen also undergoes metabolism by conjugation . This three - way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa . No statistically or clinically relevant differences in area under the concentration - time curve extrapolated to infinity ( AUCinfinity ) were observed for troglitazone , its quinone metabolite , or acetaminophen . A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant . No statistically or clinically relevant differences were observed in maximum concentration ( Cmax ) , time to Cmax ( tmax ) , or elimination half - life of troglitazone , its two main metabolites , and acetaminophen or in acetaminophen urinary sulfate excretion , although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone . Adverse events were minor and similar between treatments . These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences .\",\n \"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK51___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .\",\n \"Influence of labor on neonatal neutrophil apoptosis , and inflammatory activity . Neutrophil apoptosis is impaired in neonates , and this contributes to prolonged inflammation and tissue injury in infants after infection or trauma . In the present studies , we investigated whether labor generates mediators that further suppress apoptosis . We found that neutrophil apoptosis was reduced in neonates exposed to labor , when compared with infants delivered by cesarean section before labor . This was not due to alterations in caspase - 3 or inhibitor of apoptosis protein - 2 ( IAP - 2 ) . In contrast , labor primed neutrophils to express tumor necrosis factor alpha ( P01375 ) , suggesting that proinflammatory mediators contribute to reduced apoptosis after labor . Eicosanoids generated via cyclooxygenase - 2 ( Cox - 2 ) and lipoxygenase ( Lox ) also regulate neutrophil apoptosis . 15 - Lox , which generates proapoptotic lipoxins , but not Cox - 2 , was greater in neutrophils before labor , relative to cells exposed to labor . Anti - inflammatory eicosanoids exert their effects in part via peroxisome proliferator - activated receptor gamma ( P37231 ) . Expression of gelatinase - associated lipocalin and catalase , two markers of P37231 activity , were increased in neonatal neutrophils before labor , relative to cells exposed to labor . These findings suggest that the anti - inflammatory environment is maintained before labor , in part , by eicosanoids . Although increased neutrophil longevity after labor is important for host defense in the immediate newborn period , it may contribute to inflammatory or oxidative injury in susceptible infants .\",\n \"Effects of the PPARgamma agonist troglitazone on endothelial cells in vivo and in vitro : differences between human and mouse . P37231 ( PPARgamma ) agonists and PPARgamma / alpha dual agonists have been or are being developed for clinical use in the treatment of type 2 diabetes mellitus and hyperlipidemias . A common tumor finding in rodent carcinogenicity studies for these agonists is hemangioma / hemangiosarcoma in mice but not in rats . We hypothesized that increased endothelial cell proliferation may be involved in the mechanism of Q07869 agonist - induced vascular tumors in mice , and we investigated the effects on endothelial cells utilizing troglitazone , the first clinically used PPARgamma agonist , in vivo and in vitro . DB00197 ( 400 and 800 mg / kg / day ) induced hemangiosarcomas in mice in a 2 - year bioassay . We showed that troglitazone increased endothelial cell proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses after 4 weeks of treatment . DB00197 was cytotoxic both to human dermal microvascular endothelial cells ( HMEC1 ) and mouse mammary fat pad microvascular endothelial cells ( MFP MVEC ) at high concentrations . However , MFP MVEC were more resistant to the cytotoxic effects of troglitazone based on the much lower LC ( 50 ) in HMEC1 ( 17 . 4 muM ) compared to MFP MVEC ( 92 . 2 muM ) . DB00197 increased the proliferation and survival of MFP MVEC but not HMEC1 in growth factor reduced conditions . Our data demonstrate that troglitazone may induce hemangiosarcomas in mice , at least in part , through enhancement of survival and proliferation of microvascular endothelial cells . Such an effect does not occur with human cells , suggesting that human may react differently to exposure to Q07869 agonists compared with mice .\",\n \"Cardioprotective mechanism of telmisartan via P37231 - P29474 pathway in dahl salt - sensitive hypertensive rats . BACKGROUND : Recently , some investigators have shown that telmisartan , an angiotensin II ( Ang II ) - receptor blocker ( ARB ) , is a partial agonist of the peroxisome proliferator - activated receptor - gamma ( P37231 ) . We investigate whether telmisartan improves cardiovascular remodeling associated with the production of endothelial nitric oxide synthase ( P29474 ) through P37231 , inhibits the Rho - kinase pathway , and suppresses oxidative stress in Dahl salt - sensitive ( DS ) hypertensive rats . METHODS : Telmisartan ( 1 mg / kg per day ) or telmisartan plus P37231 inhibitor , GW9662 ( 1 mg / kg per day ) was administered from the age of 6 - 11 weeks . Age - matched male Dahl salt - resistant ( DR ) rats served as a control group . RESULTS : The levels of P29474 and P37231 expression , and P29474 phosphorylation were significantly lower in DS rats than in DR rats . Chronic telmisartan treatment in DS rats significantly increased these parameters , but not telmisartan plus GW9662 . Telmisartan effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis , but not telmisartan plus GW9662 . Moreover , upregulated RhoA protein , Rho - kinase mRNA , and myosin light - chain phosphorylation in DS rats was decreased by telmisartan to a similar degree as observed after treatment with Y - 27632 , a selective Rho - kinase inhibitor . In addition , NAD ( P ) H oxidase P13498 , p47phox , gp91phox expression , and mitogen - activated protein kinase and its downstream effector P08133 S6 kinase phosphorylation in DS rats was also inhibited by telmisartan . CONCLUSIONS : These results suggest that the cardioprotective mechanism of telmisartan may be partly due to improvement of endothelial function associated with P37231 - P29474 , oxidative stress , and Rho - kinase pathway .\",\n \"Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK20___","___MASK25___","___MASK2___","___MASK36___","___MASK37___","___MASK51___","___MASK57___","___MASK83___","___MASK93___"],"string":"[\n \"___MASK20___\",\n \"___MASK25___\",\n \"___MASK2___\",\n \"___MASK36___\",\n \"___MASK37___\",\n \"___MASK51___\",\n \"___MASK57___\",\n \"___MASK83___\",\n \"___MASK93___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK37___"},"id":{"kind":"string","value":"MH_train_78"}}},{"rowIdx":79,"cells":{"query":{"kind":"string","value":"interacts_with DB00169?"},"supports":{"kind":"list like","value":["The effect of 1 , 25 - dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma . 1 , 25 ( OH ) 2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system . alpha - Calcidol which is metabolised to 1 , 25 ( OH ) 2D3 has been shown to produce tumour regression in follicular low grade non - Hodgkin ' s lymphoma ( Q9NZ71 ) and the dose limiting toxicity is hypercalcaemia . The cellular action of 1 , 25 ( OH ) 2D3 is mediated by binding to an intracellular protein , the vitamin D receptor ( P11473 ) . We have evaluated the activity of 1 , 25 ( OH ) 2D3 and its non - calcaemogenic analogue MC903 in the SU - DHL4 and SU - DUL5 B cell lines which carry the 14 ; 18 translocation characteristic of follicular Q9NZ71 , and also the expression of the P11473 in a range of B cell NHLs . Both agents induced differentiation and had an antiproliferative effect on the SU - DHL4 and SU - DUL5 cell lines . However this occurred at a relatively high concentration ( 10 (- 7 ) M ) which exceeds the physiological concentration of 1 , 25 ( OH ) 2D3 by approximately 10 ( 3 )- 10 ( 4 )- fold . Expression of the P11473 was low in each cell line and in the low grade lymphoma tumour samples . To account for the observed clinical response to 1 alpha OHD3 ( alpha - calcidol ) in follicular Q9NZ71 a network is suggested whereby 1 , 25 ( OH ) 2D3 modulates the activity of P01730 + T cells which have previously been shown to promote follicle centre cell proliferation . DB00169 analogues may enable serum levels to be achieved which produce a direct action on follicular lymphoma cells without disturbing calcium metabolism .","HIV entry inhibitors : mechanisms of action and resistance pathways . Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection . Several compounds which block the attachment of HIV gp120 to either the P01730 T cell receptor or the P51681 / P61073 co - receptors are currently in clinical development . Most of these compounds have different molecular structures and specific mechanisms of action . These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors . For enfuvirtide , the first and , so far , only entry inhibitor approved for clinical use , the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36 - 45 within the Q96GN5 region of gp41 . For other entry inhibitors , multiple changes in different gp120 domains ( V1 , V2 , V3 , P06681 and C4 ) have been associated with loss of susceptibility to these agents , although in most cases with limited cross - resistance .","Ca2 +/ calmodulin - dependent kinase II signalling cascade mediates Q99572 receptor - dependent inhibition of neuritogenesis in neuroblastoma cells . DB00171 , via purinergic P2X receptors , acts as a neurotransmitter and modulator in both the central and peripheral nervous systems , and is also involved in many biological processes , including cell proliferation , differentiation and apoptosis . Previously , we have reported that Q99572 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons . In this article , we demonstrate that the Q99572 receptor negatively regulates neurite formation in mouse Neuro - 2a neuroblastoma cells through a Ca2 +/ calmodulin - dependent kinase II - related mechanism . Using both molecular and immunocytochemical techniques , we characterized the presence of endogenous P51575 , P56373 , Q99571 and Q99572 subunits in these cells . Of these , the Q99572 receptor was the only functional receptor , as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures , exhibiting pharmacological properties characteristic of homomeric Q99572 receptors . Patch - clamp experiments were also conducted to fully demonstrate that ionotropic Q99572 receptors mediate nonselective cation currents in this cell line . Pharmacological inhibition of the Q99572 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum - containing medium , whereas Q99572 overexpression significantly reduced the formation of neurites . Interestingly , Q99572 receptor inhibition also modified the phosphorylation state of focal adhesion kinase , Akt and glycogen synthase kinase 3 , protein kinases that participate in the Ca2 +/ calmodulin - dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth . Taken together , our results provide the first mechanistic insight into Q99572 receptor - triggered signalling pathways that regulate neurite formation in neuroblastoma cells .","Neutrophil apoptosis : selective regulation by different ligands of integrin alphaMbeta2 . Neutrophils undergo spontaneous apoptosis , but their survival can be extended during inflammatory responses . alpha ( M ) beta ( 2 ) is reported either to delay or accelerate neutrophil apoptosis , but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood . The abilities of closely related alpha ( M ) beta ( 2 ) ligands , plasminogen and angiostatin , derived from plasminogen , as well as fibrinogen and its two derivative alpha ( M ) beta ( 2 ) recognition peptides , P1 and P2 - C , differed markedly in their effects on neutrophil apoptosis . P00747 , fibrinogen , and P2 - C suppressed apoptosis via activation of Akt and P27361 / 2 kinases , while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis . Using cells transfected with alpha ( M ) beta ( 2 ) or its individual alpha ( M ) or beta ( 2 ) subunits , and purified receptors and its constituent chains , we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response . Hence , engagement of a single integrin by closely related ligands can induce distinct signaling pathways , which can elicit distinct cellular responses .","Vitamin D and phosphate regulate fibroblast growth factor - 23 in K - 562 cells . Fibroblast growth factor - 23 ( Q9GZV9 ) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism . To elucidate the precise physiological regulation of Q9GZV9 , we characterized the mouse Q9GZV9 5 '- flanking region and analyzed its promoter activity . The 5 '- flanking region of the mouse Q9GZV9 gene contained a P20226 site ( TATA box ) and several putative transcription factor binding sites , including P28698 , P15976 and c - Ets - 1 motifs , but it did not contain the typical sequences of the vitamin D response element . Plasmids encoding 554 - bp ( pGL /- 0 . 6 ) , 364 - bp ( pGL /- 0 . 4 ) and 200 - bp ( pGL /- 0 . 13 ) promoter regions containing the P20226 element and + 1 - bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays . We also found that Q9GZV9 mRNA was expressed in K - 562 erythroleukemia cell lines but not in MC3T3 - E1 , Raji , or Hep G2 human carcinoma cells . Treatment with 1 , 25 - dihydroxyvitamin D3 in the presence of high phosphate markedly stimulated pGL /- 0 . 6 activity , but calcium had no effect . In addition , the plasma Q9GZV9 levels were affected by the dietary and plasma inorganic phosphate concentrations . Finally , the levels of plasma Q9GZV9 in vitamin D receptor - null mice were significantly lower than in wild - type mice . The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse Q9GZV9 gene .","MAPK inhibition by 1alpha , 25 ( OH ) 2 - DB00169 in breast cancer cells . Evidence on the participation of the P11473 and Src . 1alpha , 25 - Dihydroxyvitamin D ( 3 ) [ 1alpha , 25 ( OH )( 2 ) D ( 3 ) ] , the hormonally active form of Vitamin D ( 3 ) , has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo . 1alpha , 25 ( OH )( 2 ) D ( 3 ) acts through two different mechanisms . In addition to regulating gene transcription via its specific intracellular receptor ( Vitamin D receptor , P11473 ) , 1alpha , 25 ( OH )( 2 ) D ( 3 ) induces , rapid , non - transcriptional responses involving activation of transmembrane signal transduction pathways . The mechanisms that mediate the antiproliferative effects of 1alpha , 25 ( OH )( 2 ) D ( 3 ) in breast cancer cells are not fully understood . Particularly , there is no information about the early non - genomic signal transduction effectors modulated by the hormone . The present study shows that 1alpha , 25 ( OH )( 2 ) D ( 3 ) rapidly inhibits serum induced activation of P27361 and P28482 Q96HU1 kinases . The non - receptor tyrosine kinase Src is involved in the pathway leading to activation of P29323 1 / 2 by serum . Furthermore , 1alpha , 25 ( OH )( 2 ) D ( 3 ) increases the tyrosine - phosphorylated state of Src as well as it inhibits its kinase activity and induces the association of the P11473 with Src . These data suggest that 1alpha , 25 ( OH )( 2 ) D ( 3 ) inhibits MAPK by inactivating Src tyrosine kinase through a so far unknown mechanism that seems to be mediated by the P11473 .","Differential ligand - dependent interactions between the AF - 2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and O15164 . Using a yeast two - hybrid system we report the isolation of a novel mouse protein , mSUG1 , that interacts with retinoic acid receptor alpha ( RAR alpha ) both in yeast cells and in vitro in a ligand - and AF - 2 activating domain ( AF - 2 AD ) - dependent manner and show that it is a structural and functional homologue of the essential yeast protein P62195 . mSUG1 also efficiently interacts with other nuclear receptors , including oestrogen ( ER ) , thyroid hormone ( TR ) , DB00169 ( P11473 ) and retinoid X ( RXR ) receptors . By comparing the interaction properties of these receptors with mSUG1 and O15164 , we demonstrate that : ( i ) RXR alpha efficiently interacts with O15164 , but not with mSUG1 , whereas TR alpha interacts much more efficiently with mSUG1 than with O15164 , and RAR alpha , P11473 and ER efficiently interact with mSUG1 and O15164 ; ( ii ) the amphipathic alpha - helix core of the AF - 2 AD is differentially involved in interactions of RAR alpha with mSUG1 and O15164 ; ( iii ) the AF - 2 AD cores of RAR alpha and ER are similarly involved in their interaction with O15164 , but not with mSUG1 . Thus , the interaction interfaces between the different receptors and either mSUG1 or O15164 may vary depending on the nature of the receptor and the putative mediator of its AF - 2 function . We discuss the possibility that mSUG1 and O15164 may mediate the transcriptional activity of the AF - 2 of nuclear receptors through different mechanisms .","Phosphorylation at serine 208 of the 1alpha , 25 - dihydroxy P11473 modulates the interaction with transcriptional coactivators . Upon ligand binding the 1alpha , 25 - dihydroxy P11473 ( P11473 ) undergoes a conformational change that allows interaction with coactivator proteins including P52701 / P12931 family members and the multimeric DRIP complex through the Q15648 subunit . Casein kinase II ( CKII ) phosphorylates P11473 both in vitro and in vivo at serine 208 within the hinge domain . This phosphorylation does not affect the ability of P11473 to bind DNA , but increases its ability to transactivate target promoters . Here , we have analyzed whether phosphorylation of P11473 by CKII modulates the ability of P11473 to interact with coactivators in vitro . We find that both mutation of serine 208 to aspartic acid ( VDRS208D ) or phosphorylation of P11473 by CKII enhance the interaction of P11473 with Q15648 in the presence of 1alpha , 25 - dihydroxy DB00169 . We also find that the mutation VDRS208D neither affects the ability of this protein to bind DNA nor to interact with Q15788 and RXRalpha . Together , our results indicate that phosphorylation of P11473 at serine 208 contributes to modulate the affinity of P11473 for the DRIP complex and therefore may have a role in vivo regulating P11473 - mediated transcriptional enhancement .","P22681 mutation - related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors . Recurrent homozygous P22681 - inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates P12931 family kinases ( SFK ) and receptor tyrosine kinases ( RTK ) . However , the most important SFK and RTK affected by these mutations , and hence , the most important therapeutic targets , have not been clearly characterized . We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation ( GDM - 1 ) , heterozygous deletion ( MOLM13 ) and wild - type ( WT ) P22681 ( THP1 , U937 ) . As expected with P22681 loss , GDM - 1 displayed high P10721 expression and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) hypersensitivity . Ectopic expression of WT P22681 decreased GDM - 1 proliferation but not cell lines with WT P22681 . GDM - 1 , but not the other cell lines , was highly sensitive to growth inhibition by dasatinib ( dual SFK and RTK inhibitor , LD50 50 nM ) ; there was less or no selective inhibition of GDM - 1 growth by sunitinib ( RTK inhibitor ) , imatinib ( P00519 , P10721 inhibitor ) , or Q99463 ( SFK inhibitor ) . Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM - 1 , including a number of proteins in the P10721 and GM - P04141 receptor pathways ( for example , P10721 Tyr721 , P40763 Tyr705 ) . In conclusion , the promiscuous effects of P22681 loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition .","Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .","DNA methylation - related vitamin D receptor insensitivity in breast cancer . Calcitriol ( 1α , 25 ( OH )( 2 )- DB00169 ) binds to the vitamin D receptor ( P11473 ) and regulates differentiation of the normal mammary gland , and may therefore be useful in breast cancer treatment or prevention . Many breast cancer cells are , however , resistant to Calcitriol . In this study , we investigated the resistance mechanism and the role of epigenetic silencing of P11473 by promoter hypermethylation . Bisulfite sequencing of the P11473 promoter region revealed methylated CpG islands at - 700 base pairs ( bp ) upstream and near the transcription start site . P11473 CpG islands were demethylated by 5 ' deoxy - azacytidine treatment , and this was accompanied by a parallel increase in P11473 mRNA levels in breast cancer cell lines . Quantitative methylation - specific PCR analyses confirmed hypermethylation of these CpG islands in primary tumors , and its absence in normal breast tissue . P11473 transcripts detected in breast cancers were predominantly 5 '- truncated , while normal breast tissue expressed full - length transcripts . Consistent with this observation , genes containing the P11473 - responsive element ( VDRE ) , such as cytochrome p450 hydroxylases , P38936 or C / EBP were underexpressed in breast cancers compared to normal breast samples . Expression of the active longer transcripts of P11473 was restored with 5 ' deoxy - DB00928 ( AZA ) treatment , with a concurrent increase in expression of VDRE - containing genes . Thus , promoter methylation - mediated silencing of expression of the functional variants of P11473 may contribute to reduced expression of downstream effectors of the P11473 pathway and subsequent Calcitriol insensitivity in breast cancer . These data suggest that pharmacological reversal of P11473 methylation may re - establish breast cancer cell susceptibility to differentiation therapy using Calcitriol .","DB00169 and its nuclear receptor increase the expression and activity of the human proton - coupled folate transporter . Folates are essential for nucleic acid synthesis and are particularly required in rapidly proliferating tissues , such as intestinal epithelium and hemopoietic cells . Availability of dietary folates is determined by their absorption across the intestinal epithelium , mediated by the proton - coupled folate transporter ( Q96NT5 ) at the apical enterocyte membranes . Whereas transport properties of Q96NT5 are well characterized , regulation of Q96NT5 gene expression remains less elucidated . We have studied the mechanisms that regulate Q96NT5 promoter activity and expression in intestine - derived cells . Q96NT5 mRNA levels are increased in Caco - 2 cells treated with 1 , 25 - dihydroxyvitamin D ( 3 ) ( vitamin D ( 3 ) ) in a dose - dependent fashion , and the duodenal rat Pcft mRNA expression is induced by vitamin D ( 3 ) ex vivo . The Q96NT5 promoter region is transactivated by the vitamin D receptor ( P11473 ) and its heterodimeric partner retinoid X receptor - alpha ( RXRalpha ) in the presence of vitamin D ( 3 ) . In silico analyses predicted a P11473 response element ( VDRE ) in the Q96NT5 promoter region - 1694 /- 1680 . DNA binding assays showed direct and specific binding of the P11473 : RXRalpha heterodimer to the Q96NT5 (- 1694 /- 1680 ) , and chromatin immunoprecipitations verified that this interaction occurs within living cells . Mutational promoter analyses confirmed that the Q96NT5 (- 1694 /- 1680 ) motif mediates a transcriptional response to vitamin D ( 3 ) . In functional support of this regulatory mechanism , treatment with vitamin D ( 3 ) significantly increased the uptake of [( 3 ) H ] folic acid into Caco - 2 cells at pH 5 . 5 . In conclusion , vitamin D ( 3 ) and P11473 increase intestinal Q96NT5 expression , resulting in enhanced cellular folate uptake . Pharmacological treatment of patients with vitamin D ( 3 ) may have the added therapeutic benefit of enhancing the intestinal absorption of folates .","Dysregulation of vitamin D3 synthesis leads to enhanced cholangiocarcinoma growth . BACKGROUND : Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies . Vitamin ( 1 , 25 ( OH ) 2D ) has anti - proliferative effects on several cancers . DB00169 is synthesized by the enzyme , O15528 , and signals via the nuclear vitamin D3 receptor . The enzyme , Q07973 , degrades vitamin D3 . AIMS : ( i ) Measure the expression of O15528 , Q07973 , and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples ; and ( ii ) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth . METHODS : In vitro studies were performed in malignant and nonmalignant cholangiocytes . P11473 , Q07973 and Q02318 expression was measured in cell lines and biopsy samples . Cell lines were stimulated with vehicle or vitamin D3 from 30min to 48h . Cell viability was assessed by MTS assays and BrdU incorporation . P11473 , Q07973 and O15528 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3 . RESULTS : In cholangiocarcinoma lines and biopsy samples , vitamin D3 receptor and Q07973 expression increased compared to controls , whereas O15528 expression was decreased or unchanged . DB00169 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth . CONCLUSION : Treatment with vitamin D3 decreased Q07973 , whereas O15528 expression increased . Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma .","Changes in circulating biomarkers during a single hemodialysis session . The hemodialysis ( HD ) procedure induces an inflammatory response potentially contributing to cardiovascular disease . Here we investigated the acute impact of HD on circulating biomarkers . Circulating biomarkers ( small solutes , middle molecular - sized peptides , and proteins ) related to inflammation , oxidative stress , and vascular calcification ( VC ) were measured before and after a single session of HD in 45 clinically stable patients . Concentrations were corrected for ultrafiltration - induced hemoconcentration . Among vascular calcification - related biomarkers , osteoprotegerin and fetuin - A remained unchanged while fibroblast growth factor - 23 ( Q9GZV9 ) decreased by - 19 % . Changes of Q9GZV9 and changes of phosphate correlated ( ρ = 0 . 61 , P < 0 . 001 ) . While P02741 did not change , interleukin - 6 ( P05231 ) increased by 14 % and pentraxin 3 ( PTX3 ) increased by 45 % . P05231 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response . VC - related markers were in general not affected by the single HD session ; however , the observed correlation between acute changes of Q9GZV9 and phosphate during HD warrants further studies .","Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .","DB00169 derivatives with adamantane or lactone ring side chains are cell type - selective vitamin D receptor modulators . The vitamin D receptor ( P11473 ) mediates the biological actions of 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] , the active form of vitamin D , which regulates calcium homeostasis , immunity , cellular differentiation , and other physiological processes . We investigated the effects of three 1 , 25 ( OH )( 2 ) D ( 3 ) derivatives on P11473 function . AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position . These vitamin D derivatives bind to P11473 but do not stabilize an active cofactor conformation . In a P11473 transfection assay , AD47 and LAC67b act as partial agonists and all three compounds inhibit P11473 activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . The derivatives enhanced the heterodimerization of P11473 with the retinoid X receptor , an effect unrelated to agonist / antagonist activity . AD47 and LAC67b weakly induced recruitment of the Q15788 cofactor to P11473 , and all three derivatives inhibited the recruitment of P52701 family cofactors to P11473 induced by 1 , 25 ( OH )( 2 ) D ( 3 ) . It is noteworthy that AD47 induced Q15648 recruitment as effectively as 1 , 25 ( OH )( 2 ) D ( 3 ) , whereas LAC67a and LAC67b were not effective . We examined the expression of endogenous P11473 target genes and the nuclear protein levels of P11473 and cofactors in several cell lines , including cells derived from intestine , bone , and monocytes , and found that the vitamin D ( 3 ) derivatives act as cell type - selective P11473 modulators . The data indicate that side chain modification is useful in the development of P11473 antagonists and tissue - selective modulators . Further elucidation of the molecular mechanisms of action of selective P11473 modulators will be essential for their clinical application .","Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( DB00755 ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and DB00755 .","Synthesis and biological evaluation of 2 - , 3 - , and 4 - acylaminocinnamyl - N - hydroxyamides as novel synthetic HDAC inhibitors . A new series of 2 - , 3 - , and 4 - acylaminocinnamyl - N - hydroxyamides 1 - 3 have been prepared , and their anti - HDAC ( against maize Q92769 , HD1 - B , and HD1 - A enzymes ) activities have been assessed . Cinnamyl - hydroxyamides bearing acylamino substituents at the P06681 position of the benzene ring ( compounds 1a - g ) showed very low HDAC inhibiting activities , with IC ( 50 ) values in the high micromolar range . By shifting the same acylamino groups from P06681 to P01024 ( compounds 2a - g ) as well as C4 ( compounds 3a - f ) position of the benzene ring , a number of highly potent HDAC inhibitors have been obtained . In the anti - Q92769 assay 3c ( IC ( 50 ) = 11 nM ) was the most potent compound , being > 11600 - , 4 . 5 - , and 10 - fold more potent than sodium valproate , DB02546 , and HC - toxin , respectively , and showing the same activity as trapoxin . HD1 - B and HD1 - A assays have been performed to screen the inhibitory action of 1 - 3 against mammalian class I ( HD1 - B ) and class II ( HD1 - A ) HDAC homologous enzymes . From the corresponding IC ( 50 ) data , a selectivity ratio has been calculated . In general , compounds 1 - 3 showed no or little selectivity towards the class II homologue HD1 - A , the most selective being 2a with class II selectivity ratio = 4 . 3 . About the inhibitory potency , the 4 -( 2 - naphthoylamino ) cinnamyl - N - hydroxyamide 3f showed the highest inhibiting effect against the two enzymes ( IC ( 50 - HD1 - B ) = 36 nM ; IC ( 50 - HD1 - A ) = 42 nM ) . Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL - 60 cells .","Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .","Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation .","P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .","Synergy between vitamin D ( 3 ) and Toll - like receptor agonists regulates human dendritic cell response during maturation . Human dendritic cells ( DC ) can be differentiated from blood monocytes in the presence of GM - P04141 and P05112 and matured by lipopolysaccharide ( LPS ) . DB00169 inhibits the maturation of human DC measured by changes in surface expression of HLA - DR , P08571 , P25942 , P33681 , Q01151 , and P42081 . We here examine the function of vitamin D3 during DC maturation . One of the earliest changes to LPS - induced maturation was an increase in Q01151 expression . DB00169 inhibited the increase in expression of HLA - DR , P25942 , P33681 , Q01151 , and P42081 and the decrease in expression of P08571 , which was paralleled morphologically by vitamin D3 - induced inhibition of dendritic cell differentiation . DB00169 acted in synergy with the TLR agonists LPS and peptidoglycan ( Q9UQ90 ) in inducing P05231 , P10145 , and P22301 , whereas vitamin D3 completely inhibited LPS - induced secretion of IL - 12 . The synergy occurred at concentrations where neither vitamin D3 nor the TLR agonists alone induced measurable cytokine secretion . Both LPS and Q9UQ90 enhanced the level of the vitamin D3 receptor ( P11473 ) . Taken together , these data demonstrated that vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti - inflammatory environment .","P01148 antagonist DB00050 reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia . BACKGROUND : Recent findings suggest that BPH has an inflammatory component . Clinical trials have documented that therapy with P01148 antagonist DB00050 causes a marked and prolonged improvement in LUTS in men with symptomatic BPH . We investigated the mechanism of action and effect of DB00050 in a rat model of BPH . METHODS : Adult male Wistar rats were used . BPH was induced in rats by subcutaneous injections of TE 2 mg / day for 4 weeks . Control animals received injections of corn oil . After induction of BPH , rats received depot DB00050 pamoate at the doses of 0 . 625 , 1 . 25 , and 12 . 5 mg / kg on days 1 and 22 and TE - control rats received vehicle injections . Whole prostates were weighed and processed for RNA and protein . Real - time RT - PCR assays for numerous inflammatory cytokines and growth factors were performed . Quantitative analyses of prostatic P01148 receptor , P01148 , androgen receptor ( AR ) and 5α - reductase 2 were done by real - time RT - PCR and immunoblotting ; serum DB02901 , LH , PSA , and DB01277 by immunoassays . RESULTS : mRNA levels for inflammatory cytokines IFN - γ , P08700 , P05112 , P05113 , P05231 , P10145 , P35225 , P40933 , and Q16552 and for growth factors P01133 , P09038 , FGF - 7 , P55075 , Q92915 , TGF - β1 , and P15692 were significantly reduced by DB00050 0 . 625 mg / kg ( P < 0 . 05 ) . Prostate weights were also significantly lowered by any dose of DB00050 . CONCLUSIONS : This study suggests that DB00050 reduces various inflammatory cytokines and growth factors in rat prostate and , at doses which do not induce castration levels of testosterone , can lower prostate weights . Our findings shed light on the mechanism of action of P01148 antagonists in BPH .","Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .","Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK81___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .","Retinoic acid - induced modulation of P60568 mRNA production and P60568 receptor expression on T cells . BACKGROUND : Retinoic acid ( RA ) has important immune - modulating effects on both T and B cell function . Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin ( Ig ) response . Investigating cytokines known to affect B cell differentiation , we have recently shown that P05231 production is augmented by RA . In the present study we have examined the immune modulating effects of RA on P60568 mRNA , another important cytokine for B cell immunoglobulin production , the expression of P60568 receptors on T cells , and the RA nuclear receptors . METHODS : Purified T cells were obtained from adenoidal tissues , and incubated with RA ( 10 (- 7 ) M ) or DB01093 solvent / media control for 0 , 6 - 8 , and 24 h . Total mRNA was extracted from T cells , and using RT - PCR , changes in the production of P60568 and RA receptors ( RAR ) - alpha , beta , gamma mRNA were determined . The effects of RA on P60568 - alpha receptor expression was determined by flow cytometry on T cells . CONCLUSION : These studies suggest that RA can augment P60568 mRNA production by T cells with a possible paracrine effect on IL - 2R - alpha expression . These changes appear to be mediated by P10276 . Thus , P60568 may be another important cytokine modulated by RA in the immune response .","Q13507 - like protein and vitamin D receptor mediate DB00136 - induced Q5T124 influx in muscle cells . 1alpha , 25 - Dihydroxy - Vitamin - D3 ( 1alpha , 25 ( OH ) 2 - DB00169 ) stimulates in skeletal muscle cells Ca2 + release from inner stores and influx through both voltage - dependent and store - operated Ca2 + ( Q5T124 , CCE ) channels . We investigated the involvement of TRPC proteins and Vitamin D receptor ( P11473 ) in CCE induced by DB00136 in chick muscle cells . Two fragments were amplified by RT - PCR , exhibiting approximately 80 % sequence homology with mammalian Q13507 / 6 / 7 . Northern and Western blots employing a Q13507 - probe and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein of 140 kDa . Spectrofluorimetric measurements in Fura - 2 loaded cells showed reduced CCE and Mn2 + entry in response to either thapsigargin or DB00136 upon transfection with anti - Q13507 / 6 / 7 antisense oligodeoxynucleotides ( ODNs ) . Transfection with anti - P11473 antisense ODNs diminished DB00136 - dependent Ca2 + and Mn2 + influx . Co - immunoprecipitation of Q13507 - like protein and P11473 under non - denaturating conditions was observed . We propose that endogenous Q13507 - like proteins and the P11473 participate in the modulation of CCE by DB00136 in muscle cells , which could be mediated by an interaction between these proteins .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","DB00169 down - regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen - associated molecular patterns . Toll - like receptors ( TLR ) represent an ancient front - line defence system that enables the host organism to sense the presence of microbial components within minutes . As inducers of inflammation , TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation . We report here that vitamin D3 [ 1alpha , 25 - dihydroxycholecalciferol , 1 , 25 ( OH )( 2 ) D3 ] suppresses the expression of O60603 and O00206 protein and mRNA in human monocytes in a time - and dose - dependent fashion . Despite 1 , 25 ( OH )( 2 ) D3 - induced up - regulation of P08571 , challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired P01375 and procoagulatory tissue factor ( CD142 ) production , emphasizing the critical role of TLR in the induction of inflammation . Moreover , reduced TLR levels in 1 , 25 ( OH )( 2 ) D3 - treated phagocytes were accompanied by impaired NF - kappaB / RelA translocation to the nucleus and by reduced p38 and Q8NFH3 / 44 ( extracellular signal - regulated kinase 1 / 2 ) phosphorylation upon TLR - ligand engagement . Both TLR down - regulation and P08571 up - regulation were substantially inhibited by the vitamin D receptor ( P11473 ) antagonist ZK 159222 , indicating that the immunomodulatory effect of 1 , 25 ( OH )( 2 ) D3 on innate immunity receptors requires P11473 transcription factor activation . Our data provide strong evidence that 1 , 25 ( OH )( 2 ) D3 primes monocytes to respond less effectively to bacterial cell wall components in a P11473 - dependent mechanism , most likely due to decreased levels of O60603 and O00206 .","Attenuation of fever at near term : is interleukin - 6 - P40763 signalling altered ? Pregnant rats in late gestation show a reduced fever response after stimulation with lipopolysaccharide ( LPS ) . This can result from either an increased action of endogenous antipyretics or a reduction in the production or action of endogenous pyrogens . Nonpregnant rats given LPS release interleukin ( IL ) - 6 , which causes nuclear translocation of the signal transducer and activator of transcription 3 ( P40763 ) in the vascular organ of the lamina terminalis ( OVLT ) , followed by a significant increase in core body temperature . The present study investigated whether the reduced fever response in near - term pregnant rats is associated with a reduced nuclear P40763 response . Rats at gestation day 15 ( Q99943 ) , gestation day 21 ( Q96NT5 , near term ) and at lactation day 5 ( Q15004 ) were injected with LPS ( 50 microg / kg , i . p . ) or vehicle . Only near - term pregnant rats responded with an attenuated body temperature during the fever response . Immunohistological analysis indicated no significant difference in nuclear P40763 in the OVLT of the different animal groups 2 h after LPS . Measurement of total and phosphorylated P40763 protein in the OVLT with semiquantitative western blot revealed no significant differences of this protein among these immune challenged animal groups . P05231 concentrations were also similar at Q99943 , Q96NT5 and Q15004 2 h after injection of LPS . These results lead to the conclusion that the attenuation of the fever response at near - term pregnancy is not associated with a reduced amount of nuclear P40763 in the OVLT , indicating a maintained P05231 - P40763 signalling pathway in the OVLT .","Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model . Reduced derivatives of folic acid ( folates ) play a critical role in the development , function and repair of the CNS . However , the molecular systems regulating folate uptake and homeostasis in the central nervous system remain incompletely defined . Choroid plexus epithelial cells express high levels of folate receptor alpha ( FRalpha ) suggesting that the choroid plays an important role in CNS folate trafficking and maintenance of P04141 folate levels . We have characterized 5 - methyltetrahydrofolate ( 5 - MTHF ) uptake and metabolism by primary rat choroid plexus epithelial cells in vitro . Two distinct processes are apparent ; one that is FRalpha dependent and one that is independent of the receptor . FRalpha binds 5 - MTHF with high affinity and facilitates efficient uptake of 5 - MTHF at low extracellular folate concentrations ; a lower affinity FRalpha independent system accounts for increased folate uptake at higher concentrations . Cellular metabolism of 5 - MTHF depends on the route of folate entry into the cell . 5 - MTHF taken up via a non - FRalpha - mediated process is rapidly metabolized to folylpolyglutamates , whereas 5 - MTHF that accumulates via FRalpha remains non - metabolized , supporting the hypothesis that FRalpha may be part of a pathway for transcellular movement of the vitamin . The proton - coupled folate transporter , proton - coupled folate transporter ( Q96NT5 ) , mRNA was also shown to be expressed in choroid plexus epithelial cells . This is consistent with the role we have proposed for proton - coupled folate transporter in FRalpha - mediated transport as the mechanism of export of folates from the endocytic compartment containing FRalpha .","The 1alpha , 25 - dihydroxy P11473 preferentially recruits the coactivator Q15788 during up - regulation of the osteocalcin gene . Binding of 1alpha , 25 - dihydroxy DB00169 to the C - terminal domain ( LBD ) of its receptor ( P11473 ) , induces a conformational change that enables interaction of P11473 with transcriptional coactivators such as the members of the P52701 / P12931 family or the DRIP ( Vitamin D interacting complex ) / Mediator complex . These interactions are critical for P11473 - mediated transcriptional enhancement of target genes . Recent reports indicate that nuclear receptors , including P11473 , interact with P52701 / P12931 members and the DRIP / Mediator complex in a sequential , cyclical , and mutually exclusive manner when bound to a target promoter , exhibiting also a high exchange rate . Here , we present an overview of how these coactivators are recruited to the bone - specific osteocalcin ( OC ) gene in response to short and long exposures to 1alpha , 25 - dihydroxy DB00169 . We find that in intact osteoblastic cells P11473 and Q15788 rapidly bind to the OC promoter in response to the ligand . This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter . In contrast , binding of the Q15648 subunit , which anchors the DRIP / Mediator complex to the P11473 , is detected at the OC promoter after several hours of incubation with 1alpha , 25 - dihydroxy DB00169 . Together , our results indicate that P11473 preferentially recruits Q15788 to enhance basal bone - specific OC gene transcription . We propose a model where specific protein - DNA and protein - protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the P11473 - Q15788 complex .","Replication of genetic association studies in aortic stenosis in adults . Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis ( AS ) . The goal of this study was to validate genes previously associated with AS . Seven genes were assessed : P04114 , P02649 , P29279 , P22301 , PTH , P01137 , and P11473 . Each gene was tested for a comprehensive set of single - nucleotide polymorphisms ( SNPs ) . SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement , and allele frequencies were compared to 3 , 294 controls . A missense mutation in the P04114 gene was significantly associated with AS ( rs1042031 , E4181K , p = 0 . 00001 ) . A second SNP located 5 . 6 kilobases downstream of the P04114 stop codon was also associated with the disease ( rs6725189 , p = 0 . 000013 ) . Six SNPs surrounding the P22301 locus were strongly associated with AS ( 0 . 02 > p > 6 . 2 × 10 ⁻ ¹¹ ) . The most compelling association for P22301 was found with a promoter polymorphism ( rs1800872 ) well known to regulate the production of the encoded anti - inflammatory cytokine . The frequency of the low - producing allele was greater in cases compared to controls ( 30 % vs 20 % , p = 6 . 2 × 10 ⁻ ¹¹ ) . SNPs in PTH , P01137 , and P11473 had nominal p values < 0 . 05 but did not resist Bonferroni correction . In conclusion , this study suggests that subjects carrying specific polymorphisms in the P22301 and P04114 genes are at higher risk for developing AS .","Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Regulation of the human P38936 ( waf1 / cip1 ) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor . The main regulator of the human tumor suppresser gene P38936 ( waf1 / cip1 ) is the transcription factor p53 , but more recently it has been suggested to be a primary anti - proliferative target for the nuclear receptor P11473 in the presence of its ligand 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . To identify P11473 responding regions , we analyzed 20 overlapping regions covering the first 7 . 1 kb of the P38936 ( waf1 / cip1 ) promoter in MCF - 7 human breast cancer cells using chromatin immuno - precipitation assays ( ChIP ) with antibodies against p53 and P11473 . We confirmed two known p53 binding regions at approximate positions - 1400 and - 2300 and identified a novel site at position - 4500 . In addition , we found three P11473 - associated promoter regions at positions - 2300 , - 4500 and - 6900 , i . e . two regions showed binding for both p53 and P11473 . In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53 - positive promoter regions and also five DB00136 response elements within the three P11473 - positive regions . Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5 - fluorouracil and DB00136 . Moreover , re - ChIP assays confirmed the functionality of the three DB00136 - reponsive promoter regions by monitoring simultaneous occupancy of P11473 with the co - activator proteins CBP , Q15788 and Q15648 . Taken together , we demonstrated that the human P38936 ( ( waf1 / cip1 ) ) gene is a primary DB00136 - responding gene with at least three P11473 binding promoter regions , in two of which also p53 co - localizes .","Apoptosis induction by 1alpha , 25 - dihydroxyvitamin D3 in prostate cancer . Calcitriol [ 1alpha , 25 - dihydroxyvitamin D3 ] is the natural ligand of the vitamin D receptor ( P11473 ) . Using cultured prostate cancer ( PC ) cell lines , LN - CaP and ALVA - 31 , we studied the effects of 1alpha , 25 ( OH ) 2 - DB00169 ( VD3 ) on expression of several apoptosis - regulating proteins including : ( a ) Bcl - 2 family proteins ( Bcl - 2 , Bcl - X ( L ) , Mcl - 1 , Bax , and Bak ) ; ( b ) the heat shock protein 70 - binding protein BAG1L ; and ( c ) IAP family proteins ( P98170 , cIAP1 , and cIAP2 ) . VD3 induced decreases in levels of antiapoptotic proteins Bcl - 2 , Bcl - X ( L ) , and Mcl - 1 , BAG1L , P98170 , cIAP1 , and cIAP2 ( without altering proapoptotic Bax and Bak ) in association with increases in apoptosis . In contrast to P11473 - expressing LN - CaP and ALVA - 31 cells , P11473 - deficient prostate cancer line Du - 145 demonstrated no changes in apoptosis protein expression after treatment with VD3 . In sensitive PC cell lines , VD3 activates downstream effector protease , caspase - 3 , and upstream initiator protease caspase - 9 , the apical protease in the mitochondrial ( \" intrinsic \" ) pathway for apoptosis , but not caspase - 8 , an initiator caspase linked to an alternative ( \" extrinsic \" ) apoptosis pathway triggered by cytokine receptors . VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase - independent mechanism . Moreover , apoptosis induction by VD3 was suppressed by overexpressing Bcl - 2 , a known blocker of cytochrome c release , whereas the caspase - 8 suppressor CrmA afforded little protection . Thus , VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in P11473 - expressing prostate cancer cells , leading to activation of the mitochondrial pathway for apoptosis .","The potential role of PD0332991 ( ___MASK66___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK66___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .","Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK53___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .","Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .","___MASK64___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK98___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .","Wogonin has multiple anti - cancer effects by regulating c - Myc / Q13309 / Fbw7α and Q13547 / Q92769 pathways and inducing apoptosis in human lung adenocarcinoma cell line A549 . Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and / or induce apoptosis in various tumors . The present study examined the apoptosis - inducing activity and underlying mechanism of action of wogonin in A549 cells . The results showed that wogonin was a potent inhibitor of the viability of A549 cells . Apoptotic protein changes detected after exposure to wogonin included decreased P98170 and Mcl - 1 expression , increased cleaved - PARP expression and increased release of O95831 and cytochrome C . Western blot analysis showed that the activity of c - Myc / Skp2 and Q13547 / Q92769 pathways , which play important roles in tumor progress , was decreased . Quantitative PCR identified increased levels of c - Myc mRNA and decreased levels of its protein . Protein levels of Fbw7α , GSK3β and Thr58 - Myc , which are involved in c - Myc ubiquitin - dependent degradation , were also analyzed . After exposure to wogonin , Fbw7α and GSK3β expression decreased and Thr58 - Myc expression increased . However , MG132 was unable to prevent c - Myc degradation . The present results suggest that wogonin has multiple anti - cancer effects associated with degradation of c - Myc , Q13309 , Q13547 and Q92769 . Its ability to induce apoptosis independently of Fbw7α suggests a possible use in drug - resistance cancer related to Fbw7 deficiency . Further studies are needed to determine which pathways are related to c - Myc and Fbw7α reversal and whether Thr58 phosphorylation of c - Myc is dependent on GSK3β .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK91___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","Retinoid receptors and acute promyelocytic leukaemia . While a great deal has been learned about APL over the last few years , many important questions remain unanswered . It has become clear that the P29590 / P10276 fusion protein is expressed in most cases of APL , and this protein presumably contributes to leukaemia initiation and / or progression . P29590 / P10276 appears to specifically block the further differentiation of myeloid progenitor cells , although the mechanism of its action is not known . It may inhibit the transcription of RAR - or P29590 - regulated genes , in which case expression must be restored in the presence of therapeutic RA concentrations . However , the possibility remains that P29590 / P10276 may have a novel function . In order to elucidate the molecular pathogenesis of APL , several important questions remain to be answered . These include whether P29590 is a transcription factor ; the identification of its target genes and response elements , and the role of P29590 / P10276 and RA in their regulation . Also whether the expression of P29590 / P10276 in bone marrow cells ( either by itself or in combination with other oncogenes ) alters their tumourigenicity or differentiation potential . It is also important to determine the function ( s ) of Q05516 and Q05516 / P10276 , and determine whether other APL patients with mutations involving P29590 or P10276 ( but not both ) respond to therapy with all - trans - RA . Finally , it is important both for the understanding of the molecular biology of APL and its therapy , to determine the effects of other regulatory factors involved in the control of myeloid cell differentiation such as granulocyte colony stimulation factor ( DB00099 ) and granulocyte macrophage colony stimulating factor ( GM - P04141 ) on APL cells in vitro and in vivo , both at presentation and in the RA - resistant patients in relapse .","Role of transient receptor potential P01024 in P01375 - enhanced calcium influx in human airway myocytes . Previous studies have suggested that the proinflammatory cytokine , P01375 , contributes to airway hyperresponsivness by altering airway smooth muscle ( P17405 ) Ca ( 2 +) responses to agonist stimulation . The present study examined the effects of P01375 on Ca ( 2 +) influx pathways in cultured human P17405 cells ( HASMCs ) . Proteins encoded by the transient receptor potential ( TRP ) gene family function as channels through which receptor - operated and store - operated Ca ( 2 +) entry ( SOCE ) occur . In the present study , the presence of P48995 , Q13507 , Q9UBN4 , Q9UL62 , and Q9Y210 mRNA and protein expression was confirmed in cultured HASMCs using RT - PCR and Western blot analysis . P01375 treatment significantly increased Q13507 mRNA and protein levels in HASMCs as well as SOCE . P01375 treatment also increased both the peak and plateau intracellular Ca ( 2 +) concentration responses in HASMCs elicited by acetylcholine and bradykinin . The effects of P01375 treatment on SOCE and agonist - induced intracellular Ca ( 2 +) concentration responses were attenuated using small interfering RNA transfection , which knocked down Q13507 expression . Thus , in inflammatory airway diseases , P01375 treatment may result in increased myocyte activation due to altered Ca ( 2 +) influx pathways . These results suggest that Q13507 may be an important therapeutic target in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease .","Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis . Endometriosis displays some features that resemble malignant processes , including invasive growth , resistance to apoptosis and distant implantation . The objective of this study was to investigate whether gene alterations that are frequent in endometrial and / or ovarian cancers contribute to the pathogenesis of endometriosis . Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score stage 1 ( n = 1 ) , 2 ( n = 10 ) , 3 ( n = 11 ) or 4 ( n = 1 ) endometriosis . Six genes ( P25054 , CDKN2A , Q9ULZ3 , P10826 , Q9NS23 and P03372 ) were analyzed for promoter hypermethylation using methylation - specific melting curve analysis , and 9 genes ( P15056 , P01112 , P01111 , P35222 , P11802 , P22607 , P42336 , P04637 and P60484 ) were analyzed for mutations using denaturing gradient gel electrophoresis and direct sequencing . An oncogenic mutation in P01116 ( c . 34G > T ; p . G12C ) was detected in a single lesion . No gene alterations were found in the remaining samples . Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis . However , other proto - oncogenes and tumor suppressor genes should be tested for alterations in order to identify the molecular basis of the susceptibility of endometriosis to malignant transformation .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Essential role of Ret for defining non - peptidergic nociceptor phenotypes and functions in the adult mouse . Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons . A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non - peptidergic nociceptors around birth . In this process , peptidergic neurons maintain TrkA expression , while non - peptidergic neurons downregulate TrkA and upregulate the common glial - derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 ( IB4 ) . Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons , its role is not fully understood . Here we have deleted Ret in small - and medium - size sensory neurons , bypassing the early lethality of the full Ret knockout . We identify that Ret is expressed in two distinct populations of small - medium sized non - peptidergic neurons , an IB4 (+) and an IB4 (-) population . In these neurons , Ret is a critical regulator of several ion channels and receptors , including Nav1 . 8 , Nav1 . 9 , ASIC2a , P56373 , Q13507 , TrpM8 , TrpA1 , delta opioid receptor , MrgD , MrgA1 and MrgB4 . Ret - deficient mice fail to respond to mustard oil - induced neurogenic inflammation , have elevated basal responses and a failure to terminate injury - induced sensitization to cold stimuli , hypersensitivity to basal but not injury - induced mechanical stimuli , while heat sensation is largely intact . We propose that elevated pain responses could be contributed by Q9HC97 , which is dysregulated in adult Ret - deficient mice . Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli , resulting in altered physiology following Ret deficiency .","Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand - binding domain . DB00169 is metabolized into the hormonally active form , 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) , via 25 - hydroxyvitamin D3 ( 2 ) which is the most abundant circulating metabolite . Introduction of the 1alpha - hydroxyl group into 25 - hydroxyvitamin D3 ( 2 ) to produce 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) increases the P11473 binding affinity by approximately 1000 - fold . The X - ray crystal structure of human P11473 in complex with 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) shows that , together with DB00133 - 237 , the 1alpha - hydroxyl group of 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) makes hydrogen bonds with DB00125 - 274 , single mutation of which results in impaired ligand recognition . In 2002 , lithocholic acid , which possesses a carboxyl group at position C24 , was demonstrated to be a weak P11473 ligand . We speculated that the carboxylic acid of lithocholic acid could be recognized by DB00125 - 274 in the ligand - binding domain of P11473 . In view of the significance of DB00125 - 274 to direct the 1alpha - hydroxyl group , as well as the results with lithocholic acid and its derivatives , we designed the P06681 modified analogues of 25 - hydroxylvitamin D3 ( 2 ) having a carboxyl group , instead of the 1 - hydroxyl group , for better electrostatic interaction to the guanidinium side - chain of arginine .","TIF1delta , a novel P59665 - interacting member of the transcriptional intermediary factor 1 ( O15164 ) family expressed by elongating spermatids . O15164 ( transcriptional intermediary factor 1 ) proteins are encoded by an expanding family of developmental and physiological control genes that are conserved from flies to man . These proteins are characterized by an N - terminal RING - B box - coiled - coil ( Q9Y577 ) motif and a C - terminal P20941 finger / bromodomain unit , and have been implicated in epigenetic mechanisms of transcriptional repression involving histone modifiers and heterochromatin - binding proteins . We describe here the isolation and functional characterization of a fourth murine O15164 gene , TIF1delta . The predicted TIF1delta protein displays all the structural hallmarks of a bona fide O15164 family member and resembles the other TIF1s in that it can exert a deacetylase - dependent silencing effect when tethered to a promoter region . Moreover , like TIF1alpha and TIF1beta , TIF1delta can homodimerize and contains a PXVXL motif necessary and sufficient for P59665 ( heterochromatin protein 1 ) binding . Although TIF1alpha and TIF1beta also bind nuclear receptors and Kruppel - associated boxes specifically and respectively , TIF1delta appears to lack nuclear receptor - and Kruppel - associated box binding activity . Furthermore , TIF1delta is unique among the O15164 family proteins in that its expression is largely restricted to the testis and confined to haploid elongating spermatids , where it associates preferentially with P59665 isotype gamma ( HP1gamma ) and forms discrete foci dispersed within the centromeric chromocenter and the surrounding nucleoplasm . Collectively , these data are consistent with specific , nonredundant functions for the O15164 family members in vivo and suggest a role for TIF1delta in heterochromatin - mediated gene silencing during postmeiotic phases of spermatogenesis .","P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK27___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .","[ Current Topics on Vitamin D . Evolution of animals and vitamin D ] . DB00169 is already found in the early evolution of life , but essentially as inactive products of the photochemical reaction of 7 - dehydrocholesterol . The full vitamin D endocrine system characterized by the specific vitamin D transport protein ( DBP ) , specific vitamin D - metabolizing CYP P450 enzymes , active vitamin D metabolites , 1α , 25 ( OH ) 2D3 , specific vitamin D nuclear receptor ( P11473 ) , and fibroblast growth factor 23 ( Q9GZV9 ) became essential for maintaining calcium and bone homeostasis in terrestrial animals cope with the challenging of higher gravity and calcium - poor environment . The present review describes the story about the evolution of animals and vitamin D .","Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .","Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK13___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .","Discovery of [ 4 - Amino - 2 -( 1 - methanesulfonylpiperidin - 4 - ylamino ) pyrimidin - 5 - yl ] ( 2 , 3 - difluoro - 6 - methoxyphenyl ) methanone ( R547 ) , a potent and selective cyclin - dependent kinase inhibitor with significant in vivo antitumor activity . The cyclin - dependent kinases ( CDKs ) and their cyclin partners are key regulators of the cell cycle . Since deregulation of CDKs is found with high frequency in many human cancer cells , pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer . The 2 , 4 - diamino - 5 - ketopyrimidines 6 reported here represent a novel class of potent and DB00171 - competitive inhibitors that selectively target the cyclin - dependent kinase family . This diaminopyrimidine core with a substituted 4 - piperidine moiety on the P06681 - amino position and 2 - methoxybenzoyl at the P01031 position has been identified as the critical structure responsible for the CDK inhibitory activity . Further optimization has led to a good number of analogues that show potent inhibitory activities against P06493 , P24941 , and P11802 but are inactive against a large panel of serine / threonine and tyrosine kinases ( K ( i ) > 10 microM ) . As one of these representative analogues , compound 39 ( R547 ) has the best CDK inhibitory activities ( K ( i ) = 0 . 001 , 0 . 003 , and 0 . 001 microM for P06493 , P24941 , and P11802 , respectively ) and excellent in vitro cellular potency , inhibiting the growth of various human tumor cell lines including an HCT116 cell line ( IC ( 50 ) = 0 . 08 microM ) . An X - ray crystal structure of 39 bound to P24941 has been determined in this study , revealing a binding mode that is consistent with our SAR . Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95 % tumor growth inhibition . On the basis of its superior overall profile , 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer .","Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .","Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .","P12004 D3 interacts with vitamin D receptor and regulates its transcription activity . D - type cyclins are essential for the progression through the P55008 phase of the cell cycle . Besides serving as cell cycle regulators , D - type cyclins were recently reported to have transcription regulation functions . Here , we report that cyclin D3 is a new interacting partner of vitamin D receptor ( P11473 ) , a member of the superfamily of nuclear receptors for steroid hormones , thyroid hormone , and the fat - soluble vitamins A and D . The interaction was confirmed with methods of yeast two - hybrid system , in vitro binding analysis and in vivo co - immunoprecipitation . P12004 D3 interacted with P11473 in a ligand - independent manner , but treatment of the ligand , 1 , 25 - dihydroxyvitamin D3 , strengthened the interaction . Confocal microscopy analysis showed that ligand - activated P11473 led to an accumulation of cyclin D3 in the nuclear region . P12004 D3 up - regulated transcriptional activity of P11473 and this effect was counteracted by overexpression of P11802 and Q00534 . These findings provide us a new clue to understand the transcription regulation functions of D - type cyclins .","DB00169 suppresses the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells by transcriptional repression of fibroblast growth factor 8 . Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone - related prostate and breast cancers . When various concentrations of 1alpha , 25 - dihydroxyvitamin D3 ( vitamin D3 ) , all - trans - retinoic acid ( DB00755 ) and 9 - cis retinoic acid ( 9 - cis RA ) were examined , the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells was inhibited by vitamin D3 alone in a dose - dependent manner . A flow cytometer analysis showed that vitamin D3 leads SC - 3 cells to relative P55008 - growth arrest after 72 h . Characterization of vitamin D3 - responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold , and 84 genes were downregulated to less than one - third , compared with the testosterone - stimulated SC - 3 cells . Neither cyclin - dependent kinase inhibitors ( CDKIs ) nor the antiapoptotic bcl - 2 gene were induced in vitamin D3 - responsive genes , with the exception of a slight induction of p15 ( INK4B ) . Importantly , fgf8 was markedly repressed in response to vitamin D3 . The exogenous addition of P55075 canceled the growth suppression by vitamin D3 in SC - 3 cells , suggesting that the repression of fgf8 is an indispensable step in vitamin D3 - mediated growth inhibition . In reporter assays using the ARE - containing artificial construct and the natural androgen - regulated PSA promoter , co - transfection of the vitamin D receptor ( P11473 ) and androgen receptor ( AR ) suppressed AR - stimulated promoter activity . In addition , vitamin D3 also suppressed androgen - stimulated promoter activity in the stably transfected SC - 3 cells . Moreover , P11473 repressed the core promoter activity of fgf8 in COS1 cells and in the SC - 3 cells . All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen - related and fgf8 transcriptions .","Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .","Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK56___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK56___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK56___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK56___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK56___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .","Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .","P98170 regulates human interleukin - 6 in umbilical vein endothelial cells via stimulation of the nuclear factor - kappaB and Q96HU1 kinase signaling pathways . X - linked inhibitior of apoptosis ( P98170 ) is known as a potent inhibitor of apoptosis , but more recently has been shown to also act as a modulator of the nuclear factor kB ( NF - kappaB ) signaling pathway . To investigate whether P98170 also affects other signalling pathways , we studied the transcriptional regulation of interleukin 6 ( P05231 ) , a gene that is strongly affected by P98170 , in more detail . The human P05231 gene contains transcription factor binding sites for activator protein 1 ( P05412 ) , enhancer binding protein beta ( C / EBP - beta ) and NF - kappaB . In reporter gene assays , mutation of these binding sites revealed the necessity of functional NF - kappaB and P05412 - sites for its ability to respond to P98170 . In contrast , P05231 promoter activity was slightly increased in the C / EBP deletion mutant . Pharmacologic inhibition of extracellular signal regulated kinase ( P29323 ) kinases ( Q02750 / 2 ) as well as inhibition of the p38 signaling pathway both reduced P98170 - induced P05231 promoter activity . In conclusion , these results suggest that P98170 regulates P05231 transcription via NF - kappaB in cooperation with P05412 and C / EBP - beta ."],"string":"[\n \"The effect of 1 , 25 - dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma . 1 , 25 ( OH ) 2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system . alpha - Calcidol which is metabolised to 1 , 25 ( OH ) 2D3 has been shown to produce tumour regression in follicular low grade non - Hodgkin ' s lymphoma ( Q9NZ71 ) and the dose limiting toxicity is hypercalcaemia . The cellular action of 1 , 25 ( OH ) 2D3 is mediated by binding to an intracellular protein , the vitamin D receptor ( P11473 ) . We have evaluated the activity of 1 , 25 ( OH ) 2D3 and its non - calcaemogenic analogue MC903 in the SU - DHL4 and SU - DUL5 B cell lines which carry the 14 ; 18 translocation characteristic of follicular Q9NZ71 , and also the expression of the P11473 in a range of B cell NHLs . Both agents induced differentiation and had an antiproliferative effect on the SU - DHL4 and SU - DUL5 cell lines . However this occurred at a relatively high concentration ( 10 (- 7 ) M ) which exceeds the physiological concentration of 1 , 25 ( OH ) 2D3 by approximately 10 ( 3 )- 10 ( 4 )- fold . Expression of the P11473 was low in each cell line and in the low grade lymphoma tumour samples . To account for the observed clinical response to 1 alpha OHD3 ( alpha - calcidol ) in follicular Q9NZ71 a network is suggested whereby 1 , 25 ( OH ) 2D3 modulates the activity of P01730 + T cells which have previously been shown to promote follicle centre cell proliferation . DB00169 analogues may enable serum levels to be achieved which produce a direct action on follicular lymphoma cells without disturbing calcium metabolism .\",\n \"HIV entry inhibitors : mechanisms of action and resistance pathways . Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection . Several compounds which block the attachment of HIV gp120 to either the P01730 T cell receptor or the P51681 / P61073 co - receptors are currently in clinical development . Most of these compounds have different molecular structures and specific mechanisms of action . These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors . For enfuvirtide , the first and , so far , only entry inhibitor approved for clinical use , the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36 - 45 within the Q96GN5 region of gp41 . For other entry inhibitors , multiple changes in different gp120 domains ( V1 , V2 , V3 , P06681 and C4 ) have been associated with loss of susceptibility to these agents , although in most cases with limited cross - resistance .\",\n \"Ca2 +/ calmodulin - dependent kinase II signalling cascade mediates Q99572 receptor - dependent inhibition of neuritogenesis in neuroblastoma cells . DB00171 , via purinergic P2X receptors , acts as a neurotransmitter and modulator in both the central and peripheral nervous systems , and is also involved in many biological processes , including cell proliferation , differentiation and apoptosis . Previously , we have reported that Q99572 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons . In this article , we demonstrate that the Q99572 receptor negatively regulates neurite formation in mouse Neuro - 2a neuroblastoma cells through a Ca2 +/ calmodulin - dependent kinase II - related mechanism . Using both molecular and immunocytochemical techniques , we characterized the presence of endogenous P51575 , P56373 , Q99571 and Q99572 subunits in these cells . Of these , the Q99572 receptor was the only functional receptor , as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures , exhibiting pharmacological properties characteristic of homomeric Q99572 receptors . Patch - clamp experiments were also conducted to fully demonstrate that ionotropic Q99572 receptors mediate nonselective cation currents in this cell line . Pharmacological inhibition of the Q99572 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum - containing medium , whereas Q99572 overexpression significantly reduced the formation of neurites . Interestingly , Q99572 receptor inhibition also modified the phosphorylation state of focal adhesion kinase , Akt and glycogen synthase kinase 3 , protein kinases that participate in the Ca2 +/ calmodulin - dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth . Taken together , our results provide the first mechanistic insight into Q99572 receptor - triggered signalling pathways that regulate neurite formation in neuroblastoma cells .\",\n \"Neutrophil apoptosis : selective regulation by different ligands of integrin alphaMbeta2 . Neutrophils undergo spontaneous apoptosis , but their survival can be extended during inflammatory responses . alpha ( M ) beta ( 2 ) is reported either to delay or accelerate neutrophil apoptosis , but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood . The abilities of closely related alpha ( M ) beta ( 2 ) ligands , plasminogen and angiostatin , derived from plasminogen , as well as fibrinogen and its two derivative alpha ( M ) beta ( 2 ) recognition peptides , P1 and P2 - C , differed markedly in their effects on neutrophil apoptosis . P00747 , fibrinogen , and P2 - C suppressed apoptosis via activation of Akt and P27361 / 2 kinases , while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis . Using cells transfected with alpha ( M ) beta ( 2 ) or its individual alpha ( M ) or beta ( 2 ) subunits , and purified receptors and its constituent chains , we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response . Hence , engagement of a single integrin by closely related ligands can induce distinct signaling pathways , which can elicit distinct cellular responses .\",\n \"Vitamin D and phosphate regulate fibroblast growth factor - 23 in K - 562 cells . Fibroblast growth factor - 23 ( Q9GZV9 ) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism . To elucidate the precise physiological regulation of Q9GZV9 , we characterized the mouse Q9GZV9 5 '- flanking region and analyzed its promoter activity . The 5 '- flanking region of the mouse Q9GZV9 gene contained a P20226 site ( TATA box ) and several putative transcription factor binding sites , including P28698 , P15976 and c - Ets - 1 motifs , but it did not contain the typical sequences of the vitamin D response element . Plasmids encoding 554 - bp ( pGL /- 0 . 6 ) , 364 - bp ( pGL /- 0 . 4 ) and 200 - bp ( pGL /- 0 . 13 ) promoter regions containing the P20226 element and + 1 - bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays . We also found that Q9GZV9 mRNA was expressed in K - 562 erythroleukemia cell lines but not in MC3T3 - E1 , Raji , or Hep G2 human carcinoma cells . Treatment with 1 , 25 - dihydroxyvitamin D3 in the presence of high phosphate markedly stimulated pGL /- 0 . 6 activity , but calcium had no effect . In addition , the plasma Q9GZV9 levels were affected by the dietary and plasma inorganic phosphate concentrations . Finally , the levels of plasma Q9GZV9 in vitamin D receptor - null mice were significantly lower than in wild - type mice . The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse Q9GZV9 gene .\",\n \"MAPK inhibition by 1alpha , 25 ( OH ) 2 - DB00169 in breast cancer cells . Evidence on the participation of the P11473 and Src . 1alpha , 25 - Dihydroxyvitamin D ( 3 ) [ 1alpha , 25 ( OH )( 2 ) D ( 3 ) ] , the hormonally active form of Vitamin D ( 3 ) , has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo . 1alpha , 25 ( OH )( 2 ) D ( 3 ) acts through two different mechanisms . In addition to regulating gene transcription via its specific intracellular receptor ( Vitamin D receptor , P11473 ) , 1alpha , 25 ( OH )( 2 ) D ( 3 ) induces , rapid , non - transcriptional responses involving activation of transmembrane signal transduction pathways . The mechanisms that mediate the antiproliferative effects of 1alpha , 25 ( OH )( 2 ) D ( 3 ) in breast cancer cells are not fully understood . Particularly , there is no information about the early non - genomic signal transduction effectors modulated by the hormone . The present study shows that 1alpha , 25 ( OH )( 2 ) D ( 3 ) rapidly inhibits serum induced activation of P27361 and P28482 Q96HU1 kinases . The non - receptor tyrosine kinase Src is involved in the pathway leading to activation of P29323 1 / 2 by serum . Furthermore , 1alpha , 25 ( OH )( 2 ) D ( 3 ) increases the tyrosine - phosphorylated state of Src as well as it inhibits its kinase activity and induces the association of the P11473 with Src . These data suggest that 1alpha , 25 ( OH )( 2 ) D ( 3 ) inhibits MAPK by inactivating Src tyrosine kinase through a so far unknown mechanism that seems to be mediated by the P11473 .\",\n \"Differential ligand - dependent interactions between the AF - 2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and O15164 . Using a yeast two - hybrid system we report the isolation of a novel mouse protein , mSUG1 , that interacts with retinoic acid receptor alpha ( RAR alpha ) both in yeast cells and in vitro in a ligand - and AF - 2 activating domain ( AF - 2 AD ) - dependent manner and show that it is a structural and functional homologue of the essential yeast protein P62195 . mSUG1 also efficiently interacts with other nuclear receptors , including oestrogen ( ER ) , thyroid hormone ( TR ) , DB00169 ( P11473 ) and retinoid X ( RXR ) receptors . By comparing the interaction properties of these receptors with mSUG1 and O15164 , we demonstrate that : ( i ) RXR alpha efficiently interacts with O15164 , but not with mSUG1 , whereas TR alpha interacts much more efficiently with mSUG1 than with O15164 , and RAR alpha , P11473 and ER efficiently interact with mSUG1 and O15164 ; ( ii ) the amphipathic alpha - helix core of the AF - 2 AD is differentially involved in interactions of RAR alpha with mSUG1 and O15164 ; ( iii ) the AF - 2 AD cores of RAR alpha and ER are similarly involved in their interaction with O15164 , but not with mSUG1 . Thus , the interaction interfaces between the different receptors and either mSUG1 or O15164 may vary depending on the nature of the receptor and the putative mediator of its AF - 2 function . We discuss the possibility that mSUG1 and O15164 may mediate the transcriptional activity of the AF - 2 of nuclear receptors through different mechanisms .\",\n \"Phosphorylation at serine 208 of the 1alpha , 25 - dihydroxy P11473 modulates the interaction with transcriptional coactivators . Upon ligand binding the 1alpha , 25 - dihydroxy P11473 ( P11473 ) undergoes a conformational change that allows interaction with coactivator proteins including P52701 / P12931 family members and the multimeric DRIP complex through the Q15648 subunit . Casein kinase II ( CKII ) phosphorylates P11473 both in vitro and in vivo at serine 208 within the hinge domain . This phosphorylation does not affect the ability of P11473 to bind DNA , but increases its ability to transactivate target promoters . Here , we have analyzed whether phosphorylation of P11473 by CKII modulates the ability of P11473 to interact with coactivators in vitro . We find that both mutation of serine 208 to aspartic acid ( VDRS208D ) or phosphorylation of P11473 by CKII enhance the interaction of P11473 with Q15648 in the presence of 1alpha , 25 - dihydroxy DB00169 . We also find that the mutation VDRS208D neither affects the ability of this protein to bind DNA nor to interact with Q15788 and RXRalpha . Together , our results indicate that phosphorylation of P11473 at serine 208 contributes to modulate the affinity of P11473 for the DRIP complex and therefore may have a role in vivo regulating P11473 - mediated transcriptional enhancement .\",\n \"P22681 mutation - related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors . Recurrent homozygous P22681 - inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates P12931 family kinases ( SFK ) and receptor tyrosine kinases ( RTK ) . However , the most important SFK and RTK affected by these mutations , and hence , the most important therapeutic targets , have not been clearly characterized . We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation ( GDM - 1 ) , heterozygous deletion ( MOLM13 ) and wild - type ( WT ) P22681 ( THP1 , U937 ) . As expected with P22681 loss , GDM - 1 displayed high P10721 expression and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) hypersensitivity . Ectopic expression of WT P22681 decreased GDM - 1 proliferation but not cell lines with WT P22681 . GDM - 1 , but not the other cell lines , was highly sensitive to growth inhibition by dasatinib ( dual SFK and RTK inhibitor , LD50 50 nM ) ; there was less or no selective inhibition of GDM - 1 growth by sunitinib ( RTK inhibitor ) , imatinib ( P00519 , P10721 inhibitor ) , or Q99463 ( SFK inhibitor ) . Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM - 1 , including a number of proteins in the P10721 and GM - P04141 receptor pathways ( for example , P10721 Tyr721 , P40763 Tyr705 ) . In conclusion , the promiscuous effects of P22681 loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition .\",\n \"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .\",\n \"DNA methylation - related vitamin D receptor insensitivity in breast cancer . Calcitriol ( 1α , 25 ( OH )( 2 )- DB00169 ) binds to the vitamin D receptor ( P11473 ) and regulates differentiation of the normal mammary gland , and may therefore be useful in breast cancer treatment or prevention . Many breast cancer cells are , however , resistant to Calcitriol . In this study , we investigated the resistance mechanism and the role of epigenetic silencing of P11473 by promoter hypermethylation . Bisulfite sequencing of the P11473 promoter region revealed methylated CpG islands at - 700 base pairs ( bp ) upstream and near the transcription start site . P11473 CpG islands were demethylated by 5 ' deoxy - azacytidine treatment , and this was accompanied by a parallel increase in P11473 mRNA levels in breast cancer cell lines . Quantitative methylation - specific PCR analyses confirmed hypermethylation of these CpG islands in primary tumors , and its absence in normal breast tissue . P11473 transcripts detected in breast cancers were predominantly 5 '- truncated , while normal breast tissue expressed full - length transcripts . Consistent with this observation , genes containing the P11473 - responsive element ( VDRE ) , such as cytochrome p450 hydroxylases , P38936 or C / EBP were underexpressed in breast cancers compared to normal breast samples . Expression of the active longer transcripts of P11473 was restored with 5 ' deoxy - DB00928 ( AZA ) treatment , with a concurrent increase in expression of VDRE - containing genes . Thus , promoter methylation - mediated silencing of expression of the functional variants of P11473 may contribute to reduced expression of downstream effectors of the P11473 pathway and subsequent Calcitriol insensitivity in breast cancer . These data suggest that pharmacological reversal of P11473 methylation may re - establish breast cancer cell susceptibility to differentiation therapy using Calcitriol .\",\n \"DB00169 and its nuclear receptor increase the expression and activity of the human proton - coupled folate transporter . Folates are essential for nucleic acid synthesis and are particularly required in rapidly proliferating tissues , such as intestinal epithelium and hemopoietic cells . Availability of dietary folates is determined by their absorption across the intestinal epithelium , mediated by the proton - coupled folate transporter ( Q96NT5 ) at the apical enterocyte membranes . Whereas transport properties of Q96NT5 are well characterized , regulation of Q96NT5 gene expression remains less elucidated . We have studied the mechanisms that regulate Q96NT5 promoter activity and expression in intestine - derived cells . Q96NT5 mRNA levels are increased in Caco - 2 cells treated with 1 , 25 - dihydroxyvitamin D ( 3 ) ( vitamin D ( 3 ) ) in a dose - dependent fashion , and the duodenal rat Pcft mRNA expression is induced by vitamin D ( 3 ) ex vivo . The Q96NT5 promoter region is transactivated by the vitamin D receptor ( P11473 ) and its heterodimeric partner retinoid X receptor - alpha ( RXRalpha ) in the presence of vitamin D ( 3 ) . In silico analyses predicted a P11473 response element ( VDRE ) in the Q96NT5 promoter region - 1694 /- 1680 . DNA binding assays showed direct and specific binding of the P11473 : RXRalpha heterodimer to the Q96NT5 (- 1694 /- 1680 ) , and chromatin immunoprecipitations verified that this interaction occurs within living cells . Mutational promoter analyses confirmed that the Q96NT5 (- 1694 /- 1680 ) motif mediates a transcriptional response to vitamin D ( 3 ) . In functional support of this regulatory mechanism , treatment with vitamin D ( 3 ) significantly increased the uptake of [( 3 ) H ] folic acid into Caco - 2 cells at pH 5 . 5 . In conclusion , vitamin D ( 3 ) and P11473 increase intestinal Q96NT5 expression , resulting in enhanced cellular folate uptake . Pharmacological treatment of patients with vitamin D ( 3 ) may have the added therapeutic benefit of enhancing the intestinal absorption of folates .\",\n \"Dysregulation of vitamin D3 synthesis leads to enhanced cholangiocarcinoma growth . BACKGROUND : Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies . Vitamin ( 1 , 25 ( OH ) 2D ) has anti - proliferative effects on several cancers . DB00169 is synthesized by the enzyme , O15528 , and signals via the nuclear vitamin D3 receptor . The enzyme , Q07973 , degrades vitamin D3 . AIMS : ( i ) Measure the expression of O15528 , Q07973 , and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples ; and ( ii ) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth . METHODS : In vitro studies were performed in malignant and nonmalignant cholangiocytes . P11473 , Q07973 and Q02318 expression was measured in cell lines and biopsy samples . Cell lines were stimulated with vehicle or vitamin D3 from 30min to 48h . Cell viability was assessed by MTS assays and BrdU incorporation . P11473 , Q07973 and O15528 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3 . RESULTS : In cholangiocarcinoma lines and biopsy samples , vitamin D3 receptor and Q07973 expression increased compared to controls , whereas O15528 expression was decreased or unchanged . DB00169 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth . CONCLUSION : Treatment with vitamin D3 decreased Q07973 , whereas O15528 expression increased . Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma .\",\n \"Changes in circulating biomarkers during a single hemodialysis session . The hemodialysis ( HD ) procedure induces an inflammatory response potentially contributing to cardiovascular disease . Here we investigated the acute impact of HD on circulating biomarkers . Circulating biomarkers ( small solutes , middle molecular - sized peptides , and proteins ) related to inflammation , oxidative stress , and vascular calcification ( VC ) were measured before and after a single session of HD in 45 clinically stable patients . Concentrations were corrected for ultrafiltration - induced hemoconcentration . Among vascular calcification - related biomarkers , osteoprotegerin and fetuin - A remained unchanged while fibroblast growth factor - 23 ( Q9GZV9 ) decreased by - 19 % . Changes of Q9GZV9 and changes of phosphate correlated ( ρ = 0 . 61 , P < 0 . 001 ) . While P02741 did not change , interleukin - 6 ( P05231 ) increased by 14 % and pentraxin 3 ( PTX3 ) increased by 45 % . P05231 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response . VC - related markers were in general not affected by the single HD session ; however , the observed correlation between acute changes of Q9GZV9 and phosphate during HD warrants further studies .\",\n \"Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .\",\n \"DB00169 derivatives with adamantane or lactone ring side chains are cell type - selective vitamin D receptor modulators . The vitamin D receptor ( P11473 ) mediates the biological actions of 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] , the active form of vitamin D , which regulates calcium homeostasis , immunity , cellular differentiation , and other physiological processes . We investigated the effects of three 1 , 25 ( OH )( 2 ) D ( 3 ) derivatives on P11473 function . AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position . These vitamin D derivatives bind to P11473 but do not stabilize an active cofactor conformation . In a P11473 transfection assay , AD47 and LAC67b act as partial agonists and all three compounds inhibit P11473 activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . The derivatives enhanced the heterodimerization of P11473 with the retinoid X receptor , an effect unrelated to agonist / antagonist activity . AD47 and LAC67b weakly induced recruitment of the Q15788 cofactor to P11473 , and all three derivatives inhibited the recruitment of P52701 family cofactors to P11473 induced by 1 , 25 ( OH )( 2 ) D ( 3 ) . It is noteworthy that AD47 induced Q15648 recruitment as effectively as 1 , 25 ( OH )( 2 ) D ( 3 ) , whereas LAC67a and LAC67b were not effective . We examined the expression of endogenous P11473 target genes and the nuclear protein levels of P11473 and cofactors in several cell lines , including cells derived from intestine , bone , and monocytes , and found that the vitamin D ( 3 ) derivatives act as cell type - selective P11473 modulators . The data indicate that side chain modification is useful in the development of P11473 antagonists and tissue - selective modulators . Further elucidation of the molecular mechanisms of action of selective P11473 modulators will be essential for their clinical application .\",\n \"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( DB00755 ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and DB00755 .\",\n \"Synthesis and biological evaluation of 2 - , 3 - , and 4 - acylaminocinnamyl - N - hydroxyamides as novel synthetic HDAC inhibitors . A new series of 2 - , 3 - , and 4 - acylaminocinnamyl - N - hydroxyamides 1 - 3 have been prepared , and their anti - HDAC ( against maize Q92769 , HD1 - B , and HD1 - A enzymes ) activities have been assessed . Cinnamyl - hydroxyamides bearing acylamino substituents at the P06681 position of the benzene ring ( compounds 1a - g ) showed very low HDAC inhibiting activities , with IC ( 50 ) values in the high micromolar range . By shifting the same acylamino groups from P06681 to P01024 ( compounds 2a - g ) as well as C4 ( compounds 3a - f ) position of the benzene ring , a number of highly potent HDAC inhibitors have been obtained . In the anti - Q92769 assay 3c ( IC ( 50 ) = 11 nM ) was the most potent compound , being > 11600 - , 4 . 5 - , and 10 - fold more potent than sodium valproate , DB02546 , and HC - toxin , respectively , and showing the same activity as trapoxin . HD1 - B and HD1 - A assays have been performed to screen the inhibitory action of 1 - 3 against mammalian class I ( HD1 - B ) and class II ( HD1 - A ) HDAC homologous enzymes . From the corresponding IC ( 50 ) data , a selectivity ratio has been calculated . In general , compounds 1 - 3 showed no or little selectivity towards the class II homologue HD1 - A , the most selective being 2a with class II selectivity ratio = 4 . 3 . About the inhibitory potency , the 4 -( 2 - naphthoylamino ) cinnamyl - N - hydroxyamide 3f showed the highest inhibiting effect against the two enzymes ( IC ( 50 - HD1 - B ) = 36 nM ; IC ( 50 - HD1 - A ) = 42 nM ) . Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL - 60 cells .\",\n \"Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .\",\n \"Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation .\",\n \"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .\",\n \"Synergy between vitamin D ( 3 ) and Toll - like receptor agonists regulates human dendritic cell response during maturation . Human dendritic cells ( DC ) can be differentiated from blood monocytes in the presence of GM - P04141 and P05112 and matured by lipopolysaccharide ( LPS ) . DB00169 inhibits the maturation of human DC measured by changes in surface expression of HLA - DR , P08571 , P25942 , P33681 , Q01151 , and P42081 . We here examine the function of vitamin D3 during DC maturation . One of the earliest changes to LPS - induced maturation was an increase in Q01151 expression . DB00169 inhibited the increase in expression of HLA - DR , P25942 , P33681 , Q01151 , and P42081 and the decrease in expression of P08571 , which was paralleled morphologically by vitamin D3 - induced inhibition of dendritic cell differentiation . DB00169 acted in synergy with the TLR agonists LPS and peptidoglycan ( Q9UQ90 ) in inducing P05231 , P10145 , and P22301 , whereas vitamin D3 completely inhibited LPS - induced secretion of IL - 12 . The synergy occurred at concentrations where neither vitamin D3 nor the TLR agonists alone induced measurable cytokine secretion . Both LPS and Q9UQ90 enhanced the level of the vitamin D3 receptor ( P11473 ) . Taken together , these data demonstrated that vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti - inflammatory environment .\",\n \"P01148 antagonist DB00050 reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia . BACKGROUND : Recent findings suggest that BPH has an inflammatory component . Clinical trials have documented that therapy with P01148 antagonist DB00050 causes a marked and prolonged improvement in LUTS in men with symptomatic BPH . We investigated the mechanism of action and effect of DB00050 in a rat model of BPH . METHODS : Adult male Wistar rats were used . BPH was induced in rats by subcutaneous injections of TE 2 mg / day for 4 weeks . Control animals received injections of corn oil . After induction of BPH , rats received depot DB00050 pamoate at the doses of 0 . 625 , 1 . 25 , and 12 . 5 mg / kg on days 1 and 22 and TE - control rats received vehicle injections . Whole prostates were weighed and processed for RNA and protein . Real - time RT - PCR assays for numerous inflammatory cytokines and growth factors were performed . Quantitative analyses of prostatic P01148 receptor , P01148 , androgen receptor ( AR ) and 5α - reductase 2 were done by real - time RT - PCR and immunoblotting ; serum DB02901 , LH , PSA , and DB01277 by immunoassays . RESULTS : mRNA levels for inflammatory cytokines IFN - γ , P08700 , P05112 , P05113 , P05231 , P10145 , P35225 , P40933 , and Q16552 and for growth factors P01133 , P09038 , FGF - 7 , P55075 , Q92915 , TGF - β1 , and P15692 were significantly reduced by DB00050 0 . 625 mg / kg ( P < 0 . 05 ) . Prostate weights were also significantly lowered by any dose of DB00050 . CONCLUSIONS : This study suggests that DB00050 reduces various inflammatory cytokines and growth factors in rat prostate and , at doses which do not induce castration levels of testosterone , can lower prostate weights . Our findings shed light on the mechanism of action of P01148 antagonists in BPH .\",\n \"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .\",\n \"Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK81___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .\",\n \"Retinoic acid - induced modulation of P60568 mRNA production and P60568 receptor expression on T cells . BACKGROUND : Retinoic acid ( RA ) has important immune - modulating effects on both T and B cell function . Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin ( Ig ) response . Investigating cytokines known to affect B cell differentiation , we have recently shown that P05231 production is augmented by RA . In the present study we have examined the immune modulating effects of RA on P60568 mRNA , another important cytokine for B cell immunoglobulin production , the expression of P60568 receptors on T cells , and the RA nuclear receptors . METHODS : Purified T cells were obtained from adenoidal tissues , and incubated with RA ( 10 (- 7 ) M ) or DB01093 solvent / media control for 0 , 6 - 8 , and 24 h . Total mRNA was extracted from T cells , and using RT - PCR , changes in the production of P60568 and RA receptors ( RAR ) - alpha , beta , gamma mRNA were determined . The effects of RA on P60568 - alpha receptor expression was determined by flow cytometry on T cells . CONCLUSION : These studies suggest that RA can augment P60568 mRNA production by T cells with a possible paracrine effect on IL - 2R - alpha expression . These changes appear to be mediated by P10276 . Thus , P60568 may be another important cytokine modulated by RA in the immune response .\",\n \"Q13507 - like protein and vitamin D receptor mediate DB00136 - induced Q5T124 influx in muscle cells . 1alpha , 25 - Dihydroxy - Vitamin - D3 ( 1alpha , 25 ( OH ) 2 - DB00169 ) stimulates in skeletal muscle cells Ca2 + release from inner stores and influx through both voltage - dependent and store - operated Ca2 + ( Q5T124 , CCE ) channels . We investigated the involvement of TRPC proteins and Vitamin D receptor ( P11473 ) in CCE induced by DB00136 in chick muscle cells . Two fragments were amplified by RT - PCR , exhibiting approximately 80 % sequence homology with mammalian Q13507 / 6 / 7 . Northern and Western blots employing a Q13507 - probe and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein of 140 kDa . Spectrofluorimetric measurements in Fura - 2 loaded cells showed reduced CCE and Mn2 + entry in response to either thapsigargin or DB00136 upon transfection with anti - Q13507 / 6 / 7 antisense oligodeoxynucleotides ( ODNs ) . Transfection with anti - P11473 antisense ODNs diminished DB00136 - dependent Ca2 + and Mn2 + influx . Co - immunoprecipitation of Q13507 - like protein and P11473 under non - denaturating conditions was observed . We propose that endogenous Q13507 - like proteins and the P11473 participate in the modulation of CCE by DB00136 in muscle cells , which could be mediated by an interaction between these proteins .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"DB00169 down - regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen - associated molecular patterns . Toll - like receptors ( TLR ) represent an ancient front - line defence system that enables the host organism to sense the presence of microbial components within minutes . As inducers of inflammation , TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation . We report here that vitamin D3 [ 1alpha , 25 - dihydroxycholecalciferol , 1 , 25 ( OH )( 2 ) D3 ] suppresses the expression of O60603 and O00206 protein and mRNA in human monocytes in a time - and dose - dependent fashion . Despite 1 , 25 ( OH )( 2 ) D3 - induced up - regulation of P08571 , challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired P01375 and procoagulatory tissue factor ( CD142 ) production , emphasizing the critical role of TLR in the induction of inflammation . Moreover , reduced TLR levels in 1 , 25 ( OH )( 2 ) D3 - treated phagocytes were accompanied by impaired NF - kappaB / RelA translocation to the nucleus and by reduced p38 and Q8NFH3 / 44 ( extracellular signal - regulated kinase 1 / 2 ) phosphorylation upon TLR - ligand engagement . Both TLR down - regulation and P08571 up - regulation were substantially inhibited by the vitamin D receptor ( P11473 ) antagonist ZK 159222 , indicating that the immunomodulatory effect of 1 , 25 ( OH )( 2 ) D3 on innate immunity receptors requires P11473 transcription factor activation . Our data provide strong evidence that 1 , 25 ( OH )( 2 ) D3 primes monocytes to respond less effectively to bacterial cell wall components in a P11473 - dependent mechanism , most likely due to decreased levels of O60603 and O00206 .\",\n \"Attenuation of fever at near term : is interleukin - 6 - P40763 signalling altered ? Pregnant rats in late gestation show a reduced fever response after stimulation with lipopolysaccharide ( LPS ) . This can result from either an increased action of endogenous antipyretics or a reduction in the production or action of endogenous pyrogens . Nonpregnant rats given LPS release interleukin ( IL ) - 6 , which causes nuclear translocation of the signal transducer and activator of transcription 3 ( P40763 ) in the vascular organ of the lamina terminalis ( OVLT ) , followed by a significant increase in core body temperature . The present study investigated whether the reduced fever response in near - term pregnant rats is associated with a reduced nuclear P40763 response . Rats at gestation day 15 ( Q99943 ) , gestation day 21 ( Q96NT5 , near term ) and at lactation day 5 ( Q15004 ) were injected with LPS ( 50 microg / kg , i . p . ) or vehicle . Only near - term pregnant rats responded with an attenuated body temperature during the fever response . Immunohistological analysis indicated no significant difference in nuclear P40763 in the OVLT of the different animal groups 2 h after LPS . Measurement of total and phosphorylated P40763 protein in the OVLT with semiquantitative western blot revealed no significant differences of this protein among these immune challenged animal groups . P05231 concentrations were also similar at Q99943 , Q96NT5 and Q15004 2 h after injection of LPS . These results lead to the conclusion that the attenuation of the fever response at near - term pregnancy is not associated with a reduced amount of nuclear P40763 in the OVLT , indicating a maintained P05231 - P40763 signalling pathway in the OVLT .\",\n \"Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model . Reduced derivatives of folic acid ( folates ) play a critical role in the development , function and repair of the CNS . However , the molecular systems regulating folate uptake and homeostasis in the central nervous system remain incompletely defined . Choroid plexus epithelial cells express high levels of folate receptor alpha ( FRalpha ) suggesting that the choroid plays an important role in CNS folate trafficking and maintenance of P04141 folate levels . We have characterized 5 - methyltetrahydrofolate ( 5 - MTHF ) uptake and metabolism by primary rat choroid plexus epithelial cells in vitro . Two distinct processes are apparent ; one that is FRalpha dependent and one that is independent of the receptor . FRalpha binds 5 - MTHF with high affinity and facilitates efficient uptake of 5 - MTHF at low extracellular folate concentrations ; a lower affinity FRalpha independent system accounts for increased folate uptake at higher concentrations . Cellular metabolism of 5 - MTHF depends on the route of folate entry into the cell . 5 - MTHF taken up via a non - FRalpha - mediated process is rapidly metabolized to folylpolyglutamates , whereas 5 - MTHF that accumulates via FRalpha remains non - metabolized , supporting the hypothesis that FRalpha may be part of a pathway for transcellular movement of the vitamin . The proton - coupled folate transporter , proton - coupled folate transporter ( Q96NT5 ) , mRNA was also shown to be expressed in choroid plexus epithelial cells . This is consistent with the role we have proposed for proton - coupled folate transporter in FRalpha - mediated transport as the mechanism of export of folates from the endocytic compartment containing FRalpha .\",\n \"The 1alpha , 25 - dihydroxy P11473 preferentially recruits the coactivator Q15788 during up - regulation of the osteocalcin gene . Binding of 1alpha , 25 - dihydroxy DB00169 to the C - terminal domain ( LBD ) of its receptor ( P11473 ) , induces a conformational change that enables interaction of P11473 with transcriptional coactivators such as the members of the P52701 / P12931 family or the DRIP ( Vitamin D interacting complex ) / Mediator complex . These interactions are critical for P11473 - mediated transcriptional enhancement of target genes . Recent reports indicate that nuclear receptors , including P11473 , interact with P52701 / P12931 members and the DRIP / Mediator complex in a sequential , cyclical , and mutually exclusive manner when bound to a target promoter , exhibiting also a high exchange rate . Here , we present an overview of how these coactivators are recruited to the bone - specific osteocalcin ( OC ) gene in response to short and long exposures to 1alpha , 25 - dihydroxy DB00169 . We find that in intact osteoblastic cells P11473 and Q15788 rapidly bind to the OC promoter in response to the ligand . This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter . In contrast , binding of the Q15648 subunit , which anchors the DRIP / Mediator complex to the P11473 , is detected at the OC promoter after several hours of incubation with 1alpha , 25 - dihydroxy DB00169 . Together , our results indicate that P11473 preferentially recruits Q15788 to enhance basal bone - specific OC gene transcription . We propose a model where specific protein - DNA and protein - protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the P11473 - Q15788 complex .\",\n \"Replication of genetic association studies in aortic stenosis in adults . Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis ( AS ) . The goal of this study was to validate genes previously associated with AS . Seven genes were assessed : P04114 , P02649 , P29279 , P22301 , PTH , P01137 , and P11473 . Each gene was tested for a comprehensive set of single - nucleotide polymorphisms ( SNPs ) . SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement , and allele frequencies were compared to 3 , 294 controls . A missense mutation in the P04114 gene was significantly associated with AS ( rs1042031 , E4181K , p = 0 . 00001 ) . A second SNP located 5 . 6 kilobases downstream of the P04114 stop codon was also associated with the disease ( rs6725189 , p = 0 . 000013 ) . Six SNPs surrounding the P22301 locus were strongly associated with AS ( 0 . 02 > p > 6 . 2 × 10 ⁻ ¹¹ ) . The most compelling association for P22301 was found with a promoter polymorphism ( rs1800872 ) well known to regulate the production of the encoded anti - inflammatory cytokine . The frequency of the low - producing allele was greater in cases compared to controls ( 30 % vs 20 % , p = 6 . 2 × 10 ⁻ ¹¹ ) . SNPs in PTH , P01137 , and P11473 had nominal p values < 0 . 05 but did not resist Bonferroni correction . In conclusion , this study suggests that subjects carrying specific polymorphisms in the P22301 and P04114 genes are at higher risk for developing AS .\",\n \"Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Regulation of the human P38936 ( waf1 / cip1 ) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor . The main regulator of the human tumor suppresser gene P38936 ( waf1 / cip1 ) is the transcription factor p53 , but more recently it has been suggested to be a primary anti - proliferative target for the nuclear receptor P11473 in the presence of its ligand 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . To identify P11473 responding regions , we analyzed 20 overlapping regions covering the first 7 . 1 kb of the P38936 ( waf1 / cip1 ) promoter in MCF - 7 human breast cancer cells using chromatin immuno - precipitation assays ( ChIP ) with antibodies against p53 and P11473 . We confirmed two known p53 binding regions at approximate positions - 1400 and - 2300 and identified a novel site at position - 4500 . In addition , we found three P11473 - associated promoter regions at positions - 2300 , - 4500 and - 6900 , i . e . two regions showed binding for both p53 and P11473 . In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53 - positive promoter regions and also five DB00136 response elements within the three P11473 - positive regions . Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5 - fluorouracil and DB00136 . Moreover , re - ChIP assays confirmed the functionality of the three DB00136 - reponsive promoter regions by monitoring simultaneous occupancy of P11473 with the co - activator proteins CBP , Q15788 and Q15648 . Taken together , we demonstrated that the human P38936 ( ( waf1 / cip1 ) ) gene is a primary DB00136 - responding gene with at least three P11473 binding promoter regions , in two of which also p53 co - localizes .\",\n \"Apoptosis induction by 1alpha , 25 - dihydroxyvitamin D3 in prostate cancer . Calcitriol [ 1alpha , 25 - dihydroxyvitamin D3 ] is the natural ligand of the vitamin D receptor ( P11473 ) . Using cultured prostate cancer ( PC ) cell lines , LN - CaP and ALVA - 31 , we studied the effects of 1alpha , 25 ( OH ) 2 - DB00169 ( VD3 ) on expression of several apoptosis - regulating proteins including : ( a ) Bcl - 2 family proteins ( Bcl - 2 , Bcl - X ( L ) , Mcl - 1 , Bax , and Bak ) ; ( b ) the heat shock protein 70 - binding protein BAG1L ; and ( c ) IAP family proteins ( P98170 , cIAP1 , and cIAP2 ) . VD3 induced decreases in levels of antiapoptotic proteins Bcl - 2 , Bcl - X ( L ) , and Mcl - 1 , BAG1L , P98170 , cIAP1 , and cIAP2 ( without altering proapoptotic Bax and Bak ) in association with increases in apoptosis . In contrast to P11473 - expressing LN - CaP and ALVA - 31 cells , P11473 - deficient prostate cancer line Du - 145 demonstrated no changes in apoptosis protein expression after treatment with VD3 . In sensitive PC cell lines , VD3 activates downstream effector protease , caspase - 3 , and upstream initiator protease caspase - 9 , the apical protease in the mitochondrial ( \\\" intrinsic \\\" ) pathway for apoptosis , but not caspase - 8 , an initiator caspase linked to an alternative ( \\\" extrinsic \\\" ) apoptosis pathway triggered by cytokine receptors . VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase - independent mechanism . Moreover , apoptosis induction by VD3 was suppressed by overexpressing Bcl - 2 , a known blocker of cytochrome c release , whereas the caspase - 8 suppressor CrmA afforded little protection . Thus , VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in P11473 - expressing prostate cancer cells , leading to activation of the mitochondrial pathway for apoptosis .\",\n \"The potential role of PD0332991 ( ___MASK66___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK66___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .\",\n \"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK53___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \\\" neurological dose \\\" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .\",\n \"Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .\",\n \"___MASK64___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK98___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .\",\n \"Wogonin has multiple anti - cancer effects by regulating c - Myc / Q13309 / Fbw7α and Q13547 / Q92769 pathways and inducing apoptosis in human lung adenocarcinoma cell line A549 . Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and / or induce apoptosis in various tumors . The present study examined the apoptosis - inducing activity and underlying mechanism of action of wogonin in A549 cells . The results showed that wogonin was a potent inhibitor of the viability of A549 cells . Apoptotic protein changes detected after exposure to wogonin included decreased P98170 and Mcl - 1 expression , increased cleaved - PARP expression and increased release of O95831 and cytochrome C . Western blot analysis showed that the activity of c - Myc / Skp2 and Q13547 / Q92769 pathways , which play important roles in tumor progress , was decreased . Quantitative PCR identified increased levels of c - Myc mRNA and decreased levels of its protein . Protein levels of Fbw7α , GSK3β and Thr58 - Myc , which are involved in c - Myc ubiquitin - dependent degradation , were also analyzed . After exposure to wogonin , Fbw7α and GSK3β expression decreased and Thr58 - Myc expression increased . However , MG132 was unable to prevent c - Myc degradation . The present results suggest that wogonin has multiple anti - cancer effects associated with degradation of c - Myc , Q13309 , Q13547 and Q92769 . Its ability to induce apoptosis independently of Fbw7α suggests a possible use in drug - resistance cancer related to Fbw7 deficiency . Further studies are needed to determine which pathways are related to c - Myc and Fbw7α reversal and whether Thr58 phosphorylation of c - Myc is dependent on GSK3β .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK91___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"Retinoid receptors and acute promyelocytic leukaemia . While a great deal has been learned about APL over the last few years , many important questions remain unanswered . It has become clear that the P29590 / P10276 fusion protein is expressed in most cases of APL , and this protein presumably contributes to leukaemia initiation and / or progression . P29590 / P10276 appears to specifically block the further differentiation of myeloid progenitor cells , although the mechanism of its action is not known . It may inhibit the transcription of RAR - or P29590 - regulated genes , in which case expression must be restored in the presence of therapeutic RA concentrations . However , the possibility remains that P29590 / P10276 may have a novel function . In order to elucidate the molecular pathogenesis of APL , several important questions remain to be answered . These include whether P29590 is a transcription factor ; the identification of its target genes and response elements , and the role of P29590 / P10276 and RA in their regulation . Also whether the expression of P29590 / P10276 in bone marrow cells ( either by itself or in combination with other oncogenes ) alters their tumourigenicity or differentiation potential . It is also important to determine the function ( s ) of Q05516 and Q05516 / P10276 , and determine whether other APL patients with mutations involving P29590 or P10276 ( but not both ) respond to therapy with all - trans - RA . Finally , it is important both for the understanding of the molecular biology of APL and its therapy , to determine the effects of other regulatory factors involved in the control of myeloid cell differentiation such as granulocyte colony stimulation factor ( DB00099 ) and granulocyte macrophage colony stimulating factor ( GM - P04141 ) on APL cells in vitro and in vivo , both at presentation and in the RA - resistant patients in relapse .\",\n \"Role of transient receptor potential P01024 in P01375 - enhanced calcium influx in human airway myocytes . Previous studies have suggested that the proinflammatory cytokine , P01375 , contributes to airway hyperresponsivness by altering airway smooth muscle ( P17405 ) Ca ( 2 +) responses to agonist stimulation . The present study examined the effects of P01375 on Ca ( 2 +) influx pathways in cultured human P17405 cells ( HASMCs ) . Proteins encoded by the transient receptor potential ( TRP ) gene family function as channels through which receptor - operated and store - operated Ca ( 2 +) entry ( SOCE ) occur . In the present study , the presence of P48995 , Q13507 , Q9UBN4 , Q9UL62 , and Q9Y210 mRNA and protein expression was confirmed in cultured HASMCs using RT - PCR and Western blot analysis . P01375 treatment significantly increased Q13507 mRNA and protein levels in HASMCs as well as SOCE . P01375 treatment also increased both the peak and plateau intracellular Ca ( 2 +) concentration responses in HASMCs elicited by acetylcholine and bradykinin . The effects of P01375 treatment on SOCE and agonist - induced intracellular Ca ( 2 +) concentration responses were attenuated using small interfering RNA transfection , which knocked down Q13507 expression . Thus , in inflammatory airway diseases , P01375 treatment may result in increased myocyte activation due to altered Ca ( 2 +) influx pathways . These results suggest that Q13507 may be an important therapeutic target in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease .\",\n \"Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis . Endometriosis displays some features that resemble malignant processes , including invasive growth , resistance to apoptosis and distant implantation . The objective of this study was to investigate whether gene alterations that are frequent in endometrial and / or ovarian cancers contribute to the pathogenesis of endometriosis . Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score stage 1 ( n = 1 ) , 2 ( n = 10 ) , 3 ( n = 11 ) or 4 ( n = 1 ) endometriosis . Six genes ( P25054 , CDKN2A , Q9ULZ3 , P10826 , Q9NS23 and P03372 ) were analyzed for promoter hypermethylation using methylation - specific melting curve analysis , and 9 genes ( P15056 , P01112 , P01111 , P35222 , P11802 , P22607 , P42336 , P04637 and P60484 ) were analyzed for mutations using denaturing gradient gel electrophoresis and direct sequencing . An oncogenic mutation in P01116 ( c . 34G > T ; p . G12C ) was detected in a single lesion . No gene alterations were found in the remaining samples . Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis . However , other proto - oncogenes and tumor suppressor genes should be tested for alterations in order to identify the molecular basis of the susceptibility of endometriosis to malignant transformation .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Essential role of Ret for defining non - peptidergic nociceptor phenotypes and functions in the adult mouse . Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons . A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non - peptidergic nociceptors around birth . In this process , peptidergic neurons maintain TrkA expression , while non - peptidergic neurons downregulate TrkA and upregulate the common glial - derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 ( IB4 ) . Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons , its role is not fully understood . Here we have deleted Ret in small - and medium - size sensory neurons , bypassing the early lethality of the full Ret knockout . We identify that Ret is expressed in two distinct populations of small - medium sized non - peptidergic neurons , an IB4 (+) and an IB4 (-) population . In these neurons , Ret is a critical regulator of several ion channels and receptors , including Nav1 . 8 , Nav1 . 9 , ASIC2a , P56373 , Q13507 , TrpM8 , TrpA1 , delta opioid receptor , MrgD , MrgA1 and MrgB4 . Ret - deficient mice fail to respond to mustard oil - induced neurogenic inflammation , have elevated basal responses and a failure to terminate injury - induced sensitization to cold stimuli , hypersensitivity to basal but not injury - induced mechanical stimuli , while heat sensation is largely intact . We propose that elevated pain responses could be contributed by Q9HC97 , which is dysregulated in adult Ret - deficient mice . Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli , resulting in altered physiology following Ret deficiency .\",\n \"Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand - binding domain . DB00169 is metabolized into the hormonally active form , 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) , via 25 - hydroxyvitamin D3 ( 2 ) which is the most abundant circulating metabolite . Introduction of the 1alpha - hydroxyl group into 25 - hydroxyvitamin D3 ( 2 ) to produce 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) increases the P11473 binding affinity by approximately 1000 - fold . The X - ray crystal structure of human P11473 in complex with 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) shows that , together with DB00133 - 237 , the 1alpha - hydroxyl group of 1alpha , 25 - dihydroxyvitamin D3 ( 1 ) makes hydrogen bonds with DB00125 - 274 , single mutation of which results in impaired ligand recognition . In 2002 , lithocholic acid , which possesses a carboxyl group at position C24 , was demonstrated to be a weak P11473 ligand . We speculated that the carboxylic acid of lithocholic acid could be recognized by DB00125 - 274 in the ligand - binding domain of P11473 . In view of the significance of DB00125 - 274 to direct the 1alpha - hydroxyl group , as well as the results with lithocholic acid and its derivatives , we designed the P06681 modified analogues of 25 - hydroxylvitamin D3 ( 2 ) having a carboxyl group , instead of the 1 - hydroxyl group , for better electrostatic interaction to the guanidinium side - chain of arginine .\",\n \"TIF1delta , a novel P59665 - interacting member of the transcriptional intermediary factor 1 ( O15164 ) family expressed by elongating spermatids . O15164 ( transcriptional intermediary factor 1 ) proteins are encoded by an expanding family of developmental and physiological control genes that are conserved from flies to man . These proteins are characterized by an N - terminal RING - B box - coiled - coil ( Q9Y577 ) motif and a C - terminal P20941 finger / bromodomain unit , and have been implicated in epigenetic mechanisms of transcriptional repression involving histone modifiers and heterochromatin - binding proteins . We describe here the isolation and functional characterization of a fourth murine O15164 gene , TIF1delta . The predicted TIF1delta protein displays all the structural hallmarks of a bona fide O15164 family member and resembles the other TIF1s in that it can exert a deacetylase - dependent silencing effect when tethered to a promoter region . Moreover , like TIF1alpha and TIF1beta , TIF1delta can homodimerize and contains a PXVXL motif necessary and sufficient for P59665 ( heterochromatin protein 1 ) binding . Although TIF1alpha and TIF1beta also bind nuclear receptors and Kruppel - associated boxes specifically and respectively , TIF1delta appears to lack nuclear receptor - and Kruppel - associated box binding activity . Furthermore , TIF1delta is unique among the O15164 family proteins in that its expression is largely restricted to the testis and confined to haploid elongating spermatids , where it associates preferentially with P59665 isotype gamma ( HP1gamma ) and forms discrete foci dispersed within the centromeric chromocenter and the surrounding nucleoplasm . Collectively , these data are consistent with specific , nonredundant functions for the O15164 family members in vivo and suggest a role for TIF1delta in heterochromatin - mediated gene silencing during postmeiotic phases of spermatogenesis .\",\n \"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK27___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .\",\n \"[ Current Topics on Vitamin D . Evolution of animals and vitamin D ] . DB00169 is already found in the early evolution of life , but essentially as inactive products of the photochemical reaction of 7 - dehydrocholesterol . The full vitamin D endocrine system characterized by the specific vitamin D transport protein ( DBP ) , specific vitamin D - metabolizing CYP P450 enzymes , active vitamin D metabolites , 1α , 25 ( OH ) 2D3 , specific vitamin D nuclear receptor ( P11473 ) , and fibroblast growth factor 23 ( Q9GZV9 ) became essential for maintaining calcium and bone homeostasis in terrestrial animals cope with the challenging of higher gravity and calcium - poor environment . The present review describes the story about the evolution of animals and vitamin D .\",\n \"Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .\",\n \"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK13___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .\",\n \"Discovery of [ 4 - Amino - 2 -( 1 - methanesulfonylpiperidin - 4 - ylamino ) pyrimidin - 5 - yl ] ( 2 , 3 - difluoro - 6 - methoxyphenyl ) methanone ( R547 ) , a potent and selective cyclin - dependent kinase inhibitor with significant in vivo antitumor activity . The cyclin - dependent kinases ( CDKs ) and their cyclin partners are key regulators of the cell cycle . Since deregulation of CDKs is found with high frequency in many human cancer cells , pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer . The 2 , 4 - diamino - 5 - ketopyrimidines 6 reported here represent a novel class of potent and DB00171 - competitive inhibitors that selectively target the cyclin - dependent kinase family . This diaminopyrimidine core with a substituted 4 - piperidine moiety on the P06681 - amino position and 2 - methoxybenzoyl at the P01031 position has been identified as the critical structure responsible for the CDK inhibitory activity . Further optimization has led to a good number of analogues that show potent inhibitory activities against P06493 , P24941 , and P11802 but are inactive against a large panel of serine / threonine and tyrosine kinases ( K ( i ) > 10 microM ) . As one of these representative analogues , compound 39 ( R547 ) has the best CDK inhibitory activities ( K ( i ) = 0 . 001 , 0 . 003 , and 0 . 001 microM for P06493 , P24941 , and P11802 , respectively ) and excellent in vitro cellular potency , inhibiting the growth of various human tumor cell lines including an HCT116 cell line ( IC ( 50 ) = 0 . 08 microM ) . An X - ray crystal structure of 39 bound to P24941 has been determined in this study , revealing a binding mode that is consistent with our SAR . Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95 % tumor growth inhibition . On the basis of its superior overall profile , 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer .\",\n \"Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .\",\n \"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .\",\n \"P12004 D3 interacts with vitamin D receptor and regulates its transcription activity . D - type cyclins are essential for the progression through the P55008 phase of the cell cycle . Besides serving as cell cycle regulators , D - type cyclins were recently reported to have transcription regulation functions . Here , we report that cyclin D3 is a new interacting partner of vitamin D receptor ( P11473 ) , a member of the superfamily of nuclear receptors for steroid hormones , thyroid hormone , and the fat - soluble vitamins A and D . The interaction was confirmed with methods of yeast two - hybrid system , in vitro binding analysis and in vivo co - immunoprecipitation . P12004 D3 interacted with P11473 in a ligand - independent manner , but treatment of the ligand , 1 , 25 - dihydroxyvitamin D3 , strengthened the interaction . Confocal microscopy analysis showed that ligand - activated P11473 led to an accumulation of cyclin D3 in the nuclear region . P12004 D3 up - regulated transcriptional activity of P11473 and this effect was counteracted by overexpression of P11802 and Q00534 . These findings provide us a new clue to understand the transcription regulation functions of D - type cyclins .\",\n \"DB00169 suppresses the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells by transcriptional repression of fibroblast growth factor 8 . Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone - related prostate and breast cancers . When various concentrations of 1alpha , 25 - dihydroxyvitamin D3 ( vitamin D3 ) , all - trans - retinoic acid ( DB00755 ) and 9 - cis retinoic acid ( 9 - cis RA ) were examined , the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells was inhibited by vitamin D3 alone in a dose - dependent manner . A flow cytometer analysis showed that vitamin D3 leads SC - 3 cells to relative P55008 - growth arrest after 72 h . Characterization of vitamin D3 - responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold , and 84 genes were downregulated to less than one - third , compared with the testosterone - stimulated SC - 3 cells . Neither cyclin - dependent kinase inhibitors ( CDKIs ) nor the antiapoptotic bcl - 2 gene were induced in vitamin D3 - responsive genes , with the exception of a slight induction of p15 ( INK4B ) . Importantly , fgf8 was markedly repressed in response to vitamin D3 . The exogenous addition of P55075 canceled the growth suppression by vitamin D3 in SC - 3 cells , suggesting that the repression of fgf8 is an indispensable step in vitamin D3 - mediated growth inhibition . In reporter assays using the ARE - containing artificial construct and the natural androgen - regulated PSA promoter , co - transfection of the vitamin D receptor ( P11473 ) and androgen receptor ( AR ) suppressed AR - stimulated promoter activity . In addition , vitamin D3 also suppressed androgen - stimulated promoter activity in the stably transfected SC - 3 cells . Moreover , P11473 repressed the core promoter activity of fgf8 in COS1 cells and in the SC - 3 cells . All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen - related and fgf8 transcriptions .\",\n \"Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .\",\n \"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK56___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK56___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK56___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK56___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK56___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .\",\n \"Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .\",\n \"P98170 regulates human interleukin - 6 in umbilical vein endothelial cells via stimulation of the nuclear factor - kappaB and Q96HU1 kinase signaling pathways . X - linked inhibitior of apoptosis ( P98170 ) is known as a potent inhibitor of apoptosis , but more recently has been shown to also act as a modulator of the nuclear factor kB ( NF - kappaB ) signaling pathway . To investigate whether P98170 also affects other signalling pathways , we studied the transcriptional regulation of interleukin 6 ( P05231 ) , a gene that is strongly affected by P98170 , in more detail . The human P05231 gene contains transcription factor binding sites for activator protein 1 ( P05412 ) , enhancer binding protein beta ( C / EBP - beta ) and NF - kappaB . In reporter gene assays , mutation of these binding sites revealed the necessity of functional NF - kappaB and P05412 - sites for its ability to respond to P98170 . In contrast , P05231 promoter activity was slightly increased in the C / EBP deletion mutant . Pharmacologic inhibition of extracellular signal regulated kinase ( P29323 ) kinases ( Q02750 / 2 ) as well as inhibition of the p38 signaling pathway both reduced P98170 - induced P05231 promoter activity . In conclusion , these results suggest that P98170 regulates P05231 transcription via NF - kappaB in cooperation with P05412 and C / EBP - beta .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK13___","___MASK27___","___MASK53___","___MASK56___","___MASK64___","___MASK66___","___MASK81___","___MASK91___","___MASK98___"],"string":"[\n \"___MASK13___\",\n \"___MASK27___\",\n \"___MASK53___\",\n \"___MASK56___\",\n \"___MASK64___\",\n \"___MASK66___\",\n \"___MASK81___\",\n \"___MASK91___\",\n \"___MASK98___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK91___"},"id":{"kind":"string","value":"MH_train_79"}}},{"rowIdx":80,"cells":{"query":{"kind":"string","value":"interacts_with DB08904?"},"supports":{"kind":"list like","value":["A review and expert opinion of the use of certolizumab for Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the last decade , one of the most significant developments in therapy has been a class of biological agents that neutralize TNFa . DB08904 ( CZP ) is the most recently FDA approved anti - P01375 agent for the induction and maintenance of moderate to severely active Crohn ' s disease . AREAS COVERED : The currently available evidence regarding the use of CZP in CD , the expected efficacy and possible adverse events associated with this population . EXPERT OPINION : CZP is a TNFa inhibitor that is a safe and effective agent for treatment of CD . It has several unique features which make it useful in patients with moderate to severe disease .","Cordycepin suppresses P01375 - α - induced NF - κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti - tumor and anti - inflammation , and is involved in the regulation of NF - κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF - κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF - κB activity in P29320 - 293T cells , and found that cordycepin resulted in a dose - dependent reduction in P01375 - α - induced NF - κB activation . Although cordycepin did not block P01375 - α - induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA - binding and transcriptional activities of NF - κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs - mediated NF - κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF - κB signaling through suppressing the activities of NF - κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation - associated disorders and cancer .","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK4___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","Pulmonary infectious complications of tumor necrosis factor blockade . The understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs first were introduced . Recent prospective studies have confirmed the risk of tuberculosis ( TB ) reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment , appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 or activate complement . Two - step ( boosted ) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of P01375 - dependent inflammation . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases .","DB08904 for the treatment of psoriatic arthritis . DB08904 ( CZP ) is a P01375 - α inhibitor approved for the treatment of psoriatic arthritis in 38 countries , including many European countries and the USA . It is a pegylated humanized anti - P01375 - α antigen - binding fragment , administered subcutaneously . As other P01375 - α antibodies , CZP binds to and neutralizes both soluble and membrane P01375 - α . In contrast to whole antibodies and etanercept , CZP does not activate antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity , as it does not have an Fc piece . CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate - to - severe plaque psoriasis . In a Phase III study of CZP in 409 psoriatic arthritis patients , CZP treatment resulted in improvements in peripheral arthritis , as well as dactylitis , enthesitis , nail disease and quality of life . The safety profile of CZP appears to be similar to that of other P01375 - α inhibitor .","How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn ' s disease . The chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , infliximab , is an effective therapy for Crohn ' s disease . However , the formation of human anti - chimeric antibodies to infliximab ( immunogenicity ) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions . The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment DB08904 are biologic therapies against P01375 that might be effective for Crohn ' s disease and less immunogenic than infliximab . Other potential alternatives to infliximab for Crohn ' s disease include the humanized anti - adhesion molecule antibodies natalizumab and DB05802 , the humanized anti - interleukin 12 antibody ABT - 874 , the humanized anti - interferon g antibody fontolizumab , the humanized anti - interleukin 6 receptor antibody DB06273 , and human recombinant granulocyte macrophage colony stimulating factor ( sargramostim ) . Some , or all , of these therapies will likely represent important treatments for Crohn ' s disease in the future .","Anti - P01375 therapy in Crohn ' s disease . Anti - tumour necrosis factor ( P01375 ) strategies , the most studied of biological therapies , include chimeric monoclonal ( infliximab ) , humanized monoclonal ( CDP571 and the PEGylated DB08904 ) and fully human monoclonal ( adalimumab ) antibodies , p75 fusion protein ( etanercept ) , p55 soluble receptor ( onercept ) and small molecules such as MAPkinase inhibitors . The principal use of infliximab is in treating active Crohn ' s disease patients not responding to or intolerant of conventional therapies . DB00065 is steroid sparing . The development of antibodies against infliximab is associated with an increased risk of infusion reactions , and a reduced duration of response to treatment , and concomitant immunosuppressive therapy reduces the immunogenic response . The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised , controlled , ACCENT I trial opened up the strategy for regular maintenance . In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates , and patients with fistulizing disease , where infliximab therapy is chosen , regular maintenance therapy with infliximab is likely to be required . On the other hand , patients with severely active , steroid - refractory disease in whom immunosuppressive therapy and infliximab are initiated together , may respond adequately and be continued on long - term immunosuppressive therapy alone . In ulcerative colitis the role of infliximab remains uncertain .","Simultaneous inhibition of epidermal growth factor receptor ( P00533 ) signaling and enhanced activation of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) receptor - mediated apoptosis induction by an scFv : sTRAIL fusion protein with specificity for human P00533 . P00533 ( P00533 ) signaling inhibition by monoclonal antibodies and P00533 - specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction . P01375 - related apoptosis - inducing ligand ( P50591 ) is a promising anti - cancer agent with tumor - selective apoptotic activity . Here we present a novel approach that combines P00533 - signaling inhibition with target cell - restricted apoptosis induction using a P50591 fusion protein with engineered specificity for P00533 . This fusion protein , scFv425 : sTRAIL , comprises the P00533 - blocking antibody fragment scFv425 genetically fused to soluble P50591 ( sTRAIL ) . Treatment with scFv425 : sTRAIL resulted in the specific accretion to the cell surface of P00533 - positive cells only . P00533 - specific binding rapidly induced a dephosphorylation of P00533 and down - stream mitogenic signaling , which was accompanied by cFLIP ( L ) down - regulation and Bad dephosphorylation . P00533 - specific binding converted soluble scFv425 : sTRAIL into a membrane - bound form of P50591 that cross - linked agonistic P50591 receptors in a paracrine manner , resulting in potent apoptosis induction in a series of P00533 - positive tumor cell lines . Co - treatment of P00533 - positive tumor cells with the P00533 - tyrosine kinase inhibitor ___MASK43___ resulted in a potent synergistic pro - apoptotic effect , caused by the specific down - regulation of O15519 . Furthermore , in mixed culture experiments binding ( L ) of scFv425 : sTRAIL to P00533 - positive target cells conveyed a potent apoptotic effect toward P00533 - negative bystander tumor cells . The favorable characteristics of scFv425 : sTRAIL , alone and in combination with ___MASK43___ , as well as its potent anti - tumor bystander activity indicate its potential value for treatment of P00533 - expressing cancers .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK32___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","DB08904 for the treatment of rheumatoid arthritis . INTRODUCTION : Improved understanding of the pathogenesis of rheumatoid arthritis ( RA ) , and subsequent development of targeted therapies , have greatly advanced the management of this chronic inflammatory disease . The aim of treatment is a state of clinical remission . DB08904 ( CZP ) is a novel pegylated P01375 alpha inhibitor ( TNFi ) therapy and is the focus of this review . AREAS COVERED : CZP is different from other TNFi as it contains a polyethylene glycol ( PEG ) moiety , and lacks the constant fragment ( Fc ) of immunoglobulin ; therefore it does not activate complement . In this review in addition to clinical efficacy of CZP , effects on radiographic and patient - reported outcomes , are discussed . Adverse event data from clinical trials and extension studies are also reviewed . EXPERT OPINION : The addition of novel TNFi therapies to treat RA is welcomed . As well as displaying clinical efficacy , there is evidence to suggest that CZP has unique characteristics , including reduced transfer across the placenta and reduced frequency of injection site reactions . Furthermore , randomised controlled trials ( RCTs ) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA .","Recommendations for the treatment of Crohn ' s disease with tumor necrosis factor antagonists : an expert consensus report . BACKGROUND : Symptom relief is the traditional treatment goal in Crohn ' s disease ( CD ) . New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor ( P01375 ) antagonists . DB00065 and adalimumab are approved as second - line treatments for severe , active CD . DB08904 is approved only in the U . S . and Switzerland as second - line treatment for moderate - to - severe , active CD . Data from trials of infliximab suggest that high - risk patients and patients with active inflammation ( CRP elevation and / or ileocolonic ulcers ) may benefit from earlier use of this drug . METHODS : A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of P01375 antagonists . At the time of this survey , infliximab was the only P01375 antagonist approved for the treatment of CD in Europe , Canada , and Australia . An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated . RESULTS : The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals , and form a rationale for using P01375 antagonists in CD patients . Control of inflammation and induction of mucosal healing were considered essential for bowel preservation . Consensus areas : 1 ) mucosal healing is predictive of improved long - term disease course and increases the likelihood of steroid - free remission ; 2 ) infliximab induces sustained mucosal healing , promotes bowel preservation , and reduces hospitalizations and surgeries ; 3 ) benefits of infliximab in relation to mucosal healing , bowel preservation , and clinical remission increase when therapy is initiated earlier . CONCLUSIONS : Treatment with P01375 antagonists helps preserve the bowel in CD patients .","Targeting nanomedicines in the treatment of Crohn ' s disease : focus on certolizumab pegol ( DB08904 ) . A variety of targets for therapeutic intervention are based upon advances in understanding of the immunopathogenesis of Crohn ' s disease . Crohn ' s disease is initiated by an innate immune response , which eventuates in a T - cell driven process , characterized by a T - helper cell 1 type cytokine profile . Several new treatments now focus on suppressing T - cell differentiation or T - cell inflammation . Since inflammatory bowel disease ( Q9UKU7 ) represents a state of dysregulated inflammation , drugs that augment the anti - inflammatory response have the potential to downregulate inflammation and thereby hopefully modify the disease . Tumour necrosis factor ( P01375 ) is a major target of research and clinical investigation . P01375 has proinflammatory effects in the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade . DB08904 ( DB08904 ) is a PEGylated , Fab ' fragment of a humanized anti - P01375 monoclonal antibody . PEGylation increases the half - life , reduces the requirement for frequent dosing , and possibly reduces antigenicity as well . Certolizumab has been shown in Phase III trials to achieve and maintain clinical response and remission in Crohn ' s disease patients . It improves the quality of life . DB08904 will be indicated for moderately to severely active Crohn ' s disease , but it is not yet licensed in Europe or the US . It is not possible to construct an algorithm for treatment , but when compared with infliximab the two principal advantages are likely to be lower immunogenicity ( as shown by anti - drug antibodies , absence of infusion reactions , and low rate of antinuclear antibodies ) , and a subcutaneous route of administration . These two factors may be sufficient to promote it up the pecking order of anti - P01375 agents .","DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .","DB08904 in the treatment of Crohn ' s disease . INTRODUCTION : The introduction of antibodies directed against tumour necrosis factor ( anti - P01375 ) has dramatically changed the concept of treating patients with Crohn ' s disease ( CD ) . Unfortunately , the long - term efficacy of anti - P01375 agents may be hampered by immunogenicity . The availability of more anti - P01375 agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti - P01375 . In this review , the authors will focus on the efficacy of certolizumab pegol ( CZP ) . AREAS COVERED : A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD . The authors first focused on the mechanism of action of CZP . Second , they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure . Next , they explored the influence of previous anti - P01375 exposure and baseline P02741 levels . Finally , they analysed the safety data on CZP , including the development of antibodies against CZP and the use of CZP during pregnancy . EXPERT OPINION : Based on the provided literature , CZP could be a good alternative in patients with moderate - to - severe CD failing another anti - P01375 agent . More data are required to conclude on its impact on the long - term outcome of CD .","Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .","DB08904 for the treatment of Crohn ' s disease . DB08904 is a polyethylene glycolated FAb ' fragment of a humanized anti - P01375 monoclonal antibody . This pegylated molecule binds with circulating P01375 and forms an inactive complex that is then eliminated from the body . The drug has been shown to be better than placebo in the treatment of Crohn ' s disease and maintaining a clinical response in adult patients with moderate - to - severe active disease who have had an inadequate response to conventional therapy , and the treatment of adults with moderately to severely active rheumatoid arthritis . Comparative trials with an active control group are lacking . The most common adverse reactions include abdominal pain , diarrhea , injection site reactions and infection . All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy , patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy , and the initiation of therapy should be avoided if the patient has an active infection . Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia . Therapy should be discontinued if the patient develops a serious infection during therapy .","The use of P01375 blocking agents in rheumatoid arthritis : an update . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are , at present , three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate : 2 monoclonal antibodies , infliximab and adalimumab , and a fusion protein with p75 receptors , etanercept . These three agents have proved to be effective and safe in large placebo - controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease , improving quality of life and in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs were described serious adverse events , particularly infections such as tuberculosis , especially with infliximab . The risk for malignancies under P01375 antagonists , especially lymphoma , remains controversial . Specific recommendations are given by international experts for selecting and monitoring RA patients with P01375 antagonists . Other drugs targeting P01375 such as PEGylated molecules ( DB08904 or certolizumab ) are in development . These new biological therapies blocking P01375 undoubtedly constitute a considerable advancement in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .","Prefilled certolizumab pegol ( Cimzia (®) ) syringes for self - use in the treatment of rheumatoid arthritis . A new anti - tumor necrosis factor alpha ( P01375 - α ) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis ( RA ) . DB08904 ( Cimzia (®) ) is a humanized Fab ' antibody fragment against P01375 - α with a polyethylene glycol tail that prevents complement - dependent and antibody - dependent cell - mediated cytotoxicity or apoptosis . Four randomized clinical trials have been published so far . Reported results are similar to those published in previous studies with other P01375 - α inhibitors , with ACR20 , ACR50 , and ACR70 responses of around 60 % , 40 % , and 20 % , respectively , when combined with methotrexate and slightly lower when used as monotherapy . Safety was shown to be similar to that seen with P01375 - α blockers and some cases of tuberculosis were seen in the trials , stressing the importance of a complete screening in these patients . Although we still need effectiveness and safety data in larger numbers of patients and longer follow - up , this new P01375 inhibitor is a welcome addition to our current armamentarium for the treatment of RA .","DB08904 in rheumatoid arthritis : current update . INTRODUCTION : The development of P01375 - α inhibitors ( P01375 - is ) represents a major advancement in the treatment of rheumatoid arthritis ( RA ) . Currently , there are five agents licensed for moderate - to - severely active RA . DB08904 ( CZP ) is a novel PEGylated , constant fragment - free P01375 - i therapy , which is the focus of this review . AREAS COVERED : Data from Phase III randomised controlled trials in terms of clinical efficacy , radiographic progression , patient - reported outcomes and safety profile are reviewed . These include long - term data from open - label extension studies . EXPERT OPINION : The advantages of CZP include rapid reduction of disease activity , low rates of injection - site reaction and may be safe for use in pregnancy . The long - term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti - rheumatic drugs ( DMARDs ) , in moderate - to - severely active RA , comparable to other P01375 - is . Notably , prolonged CZP exposure is not associated with increased risk of severe infection compared to general population , contrasting with preliminary analysis of short - term data . Over the next few years , evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD - naïve patients , biomarkers and the development and licensing of P01375 - i biosimilars .","P01375 and its inhibitors in cancer . P01375 ( P01375 ) - alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro - inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti - tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long - term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use .","P01375 as a therapeutic target in inflammatory diseases , ischemia - reperfusion injury and trauma . P01375 - alpha ( P01375 ) is a central regulator of inflammation , and P01375 antagonists may be effective in treating inflammatory disorders in which P01375 plays an important pathogenetic role . Recombinant or modified proteins are an emerging class of therapeutic agents . To date , several recombinant or modified proteins which acts as P01375 antagonists have been disclosed . In particular , antibodies that bind to and neutralise P01375 have been sought as a means to inhibit P01375 activity . Inhibition of P01375 has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis , psoriatic arthritis , and ankylosing spondylitis , inflammatory bowel disease . Additionally , the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research . The currently available therapies include a soluble p75 P01375 receptor : Fc construct , etanercept , a chimeric monoclonal antibody , infliximab , and a fully human monoclonal antibody , adalimumab . DB08904 is a novel P01375 inhibitor which is an antigen - binding domain of a humanized P01375 antibody coupled to polyethylene glycol ( PEG ) to increase half - life , and thus is Fc - domain - free . In this review , we discuss briefly the present understanding of P01375 - mediated biology and the current therapies in clinical use , and focus on some of the new therapeutic approaches with small - molecule inhibitors . Moreover , we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs , as P01375 activity inhibitories , especially in therapies of several inflammatory diseases within the nervous system .","Randomised clinical trial : improvement in health outcomes with certolizumab pegol in patients with active Crohn ' s disease with prior loss of response to infliximab . BACKGROUND : Crohn ' s disease ( CD ) is associated with impaired health - related quality of life ( HRQoL ) . DB08904 , administered either every 2 weeks ( q2w ) or q4w , maintains efficacy in patients previously failing on the anti - P01375 agent infliximab ( WELCOME study ) . AIM : To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study . METHODS : Patients with loss of response to infliximab received open - label certolizumab pegol induction and were randomised to receive double - blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24 , with a final evaluation at week 26 . Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment : CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively . RESULTS : Baseline HRQoL burden was representative of moderately to severely active CD . HRQoL , daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26 . Treatment benefits to HRQoL , daily activity and work productivity were similar between the certolizumab pegol q2w vs . q4w groups . CONCLUSIONS : DB08904 therapy results in meaningful improvements in work productivity , daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab ( ClinicalTrials . gov number : NCT00308581 ) .","DB08904 : a new biologic targeting rheumatoid arthritis . The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis . This is mostly due to targeted biologic agents that have changed the outcome of this disease . DB08904 ( Cimzia (®) , UCB Inc . , GA , USA ) , which targets P01375 - α with a different mechanism of action than widely used biologics , was initially investigated for Crohn ' s disease but has now been shown to be effective for rheumatoid arthritis . There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis ; two with combination methotrexate and one with monotherapy . This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease - modifying antirheumatic drugs and other biologic agents . Treatment recommendations are beyond the scope of this review ; however , with many options available , there will be annotations on current trends in the care of this chronic disease .","DB08904 : an evidence - based review of its place in the treatment of Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing / remitting course with transmural inflammation of potentially any section of the digestive tract . DB08904 ( CZP ) is a pegylated Fc - free Fab ' fragment of a humanized anti - P01375 - alfa monoclonal antibody that is in development for clinical use in CD . AIMS : To review the available data with CZP in CD , to investigate its possible place in therapy . EVIDENCE REVIEW : Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD , and to improve quality of life compared with placebo . Further studies with CZP are also ongoing . PLACE IN THERAPY : Although only suggested by currently available studies , successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti - P01375 treatment in CD . The impact on clinical management or on resources can not be estimated until the results from all phase III clinical trials are available and the price is determined .","Efficacy and safety of certolizumab pegol in rheumatoid arthritis : meeting rheumatologists ' requirements in routine clinical practice . DB08904 , a pegylated Fab ' anti - tumour necrosis factor ( P01375 ) - α agent , has shown efficacy in patients with rheumatoid arthritis ( RA ) unresponsive to previous treatment . In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease - modifying antirheumatic drug ( DMARD ) , the efficacy of certolizumab pegol , as monotherapy or with methotrexate , was similar to that reported in other anti - P01375 clinical studies , with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA . Rapid clinical response was also seen , with significant differences evident at week 1 , and efficacy maintained at study end and in open - label extensions . Adding certolizumab pegol to non - biological DMARDs is efficacious in other RA populations . In the CERTAIN study , certolizumab increased remission rates , prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA . In the REALISTIC study , rapid and consistent clinical responses were observed in a diverse group of anti - P01375 - eligible RA patients representing those seen in clinical practice . In the RAPID studies , rapid and sustained reduction in RA signs and symptoms , inhibition of structural joint damage progression , and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate . DB08904 was generally well - tolerated in clinical trials , although long - term observational data are not yet available . Current data suggest that certolizumab pegol suits a ' treat to target ' approach , providing rapid and sustained improvements in RA signs and symptoms , and beneficial effects on workplace and home productivity in patients with RA .","Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .","Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK67___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK67___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK67___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK67___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK67___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .","DB08904 attenuates the pro - inflammatory state in endothelial cells in a manner that is atheroprotective . OBJECTIVES : Rheumatoid arthritis ( RA ) is associated with accelerated atherosclerosis and premature cardiovascular death . Anti - P01375 therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients . However , the specific effects of P01375 inhibitors on endothelial cell function are largely unknown . Our aim was to explore the effects of certolizumab pegol ( CZP ) on P01375 - activated human aortic endothelial cells ( HAoECs ) . METHODS : HAoECs were cultured in vitro and exposed to i ) P01375 alone , ii ) P01375 plus CZP , or iii ) neither agent . Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression . Activation of NF - κB was investigated using immunocytochemistry , high content analysis and western blotting . Flow cytometry was performed to detect microparticle release from HAoECs . RESULTS : P01375 alone had strong effects on endothelial gene expression , while P01375 and CZP together produced a global gene expression pattern similar to untreated controls . In particular , genes for P16581 , P19320 and P05362 were significantly up - regulated by P01375 treatment . Notably , the P01375 / CZP cocktail prevented the up - regulation of these genes . P01375 - induced nuclear translocation of NF - κB was abolished by treatment with CZP . In addition the increased production of endothelial microparticles in P01375 - activated HAoECs was prevented by treatment with CZP . CONCLUSIONS : We have found at cellular level , that a clinically available P01375 inhibitor , CZP i ) reduces adhesion molecule expression ; ii ) prevents P01375 - induced activation of the NF - κB pathway and iii ) prevents the production of microparticles by activated endothelial cells . This could be central to the prevention of inflammatory environments underlying these conditions .","Current directions of biologic therapies in inflammatory bowel disease . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . A greater understanding of their pathophysiology has led to new therapies that target specific molecules of the inflammatory cascade . Three anti - tumor necrosis factor ( P01375 ) monoclonal antibodies have been developed . DB00065 and adalimumab can induce clinical response and sustained remission in CD . DB00065 is also effective in UC . DB08904 gives good short - term results but long - term efficacy has yet to be determined in other clinical trials . Therapies that target leucocyte trafficking ( anti - integrins ) have also been developed and are associated with good clinical response in CD . DB00108 ( anti - α4 integrin antibody ) is associated with important side effects and is not used anymore in gastroenterology in Europe but is still used in the USA . DB09033 ( MLN0002 ) , an anti - α4β7 integrin antibody , has a good efficacy and safety profile . Monoclonal antibodies targeting other cytokines are also under development . For example , ustekinumab ( CNTO 1275 ) inhibits interleukins 12 and 23 . It is associated with a good clinical response in CD .","New concepts in anti - tumor necrosis factor therapy for inflammatory bowel disease . Crohn ' s disease is a T helper type 1 response immune disease characterized by increased production of interleukin - 12 tumor necrosis factor - a ( P01375 ) , and interferon - g . Clinical trials have demonstrated that inhibition of P01375 is effective for the treatment of Crohn ' s disease . Adverse events reported in patients treated with anti - P01375 agents include immunogenicity , acute infusion reactions , delayed hypersensitivity - type reactions , autoimmune diseases including drug - induced lupus and demyelination , and infection . This article reviews new concepts in the treatment of Crohn ' s disease and ulcerative colitis with a variety of anti - P01375 biologic therapies : infliximab , adalimumab , DB08904 , CDP571 , etanercept , and onercept .","The efficacy and safety of certolizumab pegol ( CZP ) in the treatment of active rheumatoid arthritis ( RA ) : a meta - analysis from nine randomized controlled trials . OBJECTIVE : DB08904 ( CZP ) is a novel anti - P01375 agent that is used for patients with moderate to severe active rheumatoid arthritis ( RA ) . However , the efficacy of CZP in RA remains controversial . Thus , we performed this meta - analysis to assess the efficacy and safety of CZP in the treatment of RA patients . METHODS : Eligible studies were randomized controlled trials ( RCTs ) that evaluated the efficacy and safe of CZP in the patients with active RA . The primary outcome was American College of Rheumatology 20 % ( ACR20 ) , and secondary outcome were ACR50 , ACR70 , disease activity , patient - reported outcomes ( PROs ) , and adverse events . A fixed - effect model or random - effect model was used to pool the estimates , depending on the absence or presence of heterogeneity among the included studies . RESULTS : Nine RCTs with a total of 5228 patients were included in this meta - analysis , and all of the patients were administered CZP or placebo . The pooled results showed that CZP significantly improved the ACR20 , ACR50 , ACR70 response rates , and physical function . CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints - Erythrocyte sedimentation rate , arthritis pain , and fatigue . Patients who received CZP treatment did not have a higher incidence of treatment - related adverse events , no matter in any intensity . CONCLUSIONS : CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms , and improved physical function as compared with the placebo . More large - scale RCTs are needed to evaluate the long - term efficacy and safety of CZP in the treatment of active RA .","[ Treatment of patients with destructive arthritis with certolizumab pegol ] . DB08904 is a new anti - P01375 inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009 . Due to the modification of the antibody fragment by the adherence of polyethylene glycol ( PEG ) a sufficient distribution in inflammatory tissue was found in animal experiments . In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol .","Optimizing anti - tumor necrosis factor strategies in inflammatory bowel disease . The introduction of infliximab , a mouse / human chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , is an important advance in the treatment of Crohn ' s disease . DB00065 is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease . The development of human antichimeric antibodies ( HACAs ) has led to infusion reactions and loss of efficacy in patients treated with infliximab . Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three - dose regimen at 0 , 2 , and 6 weeks followed by systematic maintenance dosing every 8 weeks ; concomitant immunosuppressive therapy with azathioprine , 6 - mercaptopurine , or methotrexate ; and premedication with intravenous corticosteroids . Humanized or fully human anti - P01375 biotechnologic agents , including CDP571 , DB08904 , etanercept , adalimumab , and onercept , are theoretically less immunogenic than the chimeric antibody infliximab . DB00005 is not effective for Crohn ' s disease . CDP571 is not effective in unselected patients with active Crohn ' s disease , but it may be effective in patients with elevated P02741 . The efficacy of DB08904 , adalimumab , and onercept is under investigation . The different mechanisms of action of these anti - P01375 agents may account for their variable efficacy . Their benefits , however , must be considered in the context of their risks , including infusion reaction ; delayed hypersensitivity - like reaction ; new onset of autoimmunity , with rare cases of drug - induced lupus and new - onset demyelination ; and the potential for rare but serious infections .","Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK33___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .","Treatment of Crohn ' s disease with certolizumab pegol . Biologic therapies have revolutionized the treatment of Crohn ' s disease ( CD ) . Targeting P01375 with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD . Intravenous use of infliximab , a chimeric monoclonal antibody to P01375 is , however , limited by the occurrence of adverse events , infusion reactions , infectious complications , aggravation of heart failure , the occurrence of neurological demyelinating conditions and induction of rare malignancies . The incremental development of next - generation P01375 antibodies and binding proteins through antibody - engineering techniques has followed , with the aim of producing efficacious drugs that are less expensive to produce , have a convenient route of administration and have fewer side effects . DB08904 ( DB08904 , Cimzia ) is an engineered humanized anti - P01375 antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol . Clinical studies have demonstrated efficacy in the treatment of moderate - to - severe active CD . Reported adverse events in the clinical trial program have been largely of mild - to - moderate severity , and occurred at similar frequencies in the active - treatment and placebo groups . DB08904 will be a useful addition to the armamentarium of biologic agents that can be used for the long - term treatment of CD .","Inorganic lead enhances cytokine - induced elevation of matrix metalloproteinase P14780 expression in glial cells . Inorganic lead ( Pb ) is a ubiquitous environmental contaminant that produces a variety of deleterious effects in the central nervous system ( CNS ) . Matrix metalloproteinases ( MMPs ) , specifically P14780 , induced by inflammatory cytokines , are increasingly being implicated in CNS pathology . The present study demonstrates that low concentrations of either pro - inflammatory cytokines ( P01375 and IL - 1beta ) or Pb did not influence the P14780 expression in a glial cell line ( P13671 ) when added separately . However , combined administration of Pb and cytokines induced a marked synergized elevation of P14780 expression in spite of a reduction in the number of glial cells . These results demonstrate a possible new mechanism by which Pb may induce neuropathological processes .","The clinical efficacy and safety of certolizumab pegol in rheumatoid arthritis . IMPORTANCE OF THE FIELD : The treatment of rheumatoid arthritis has changed dramatically over the past 25 years , first with the introduction of methotrexate and then the introduction of biologic therapy . These agents have provided patients with multiple treatment options to try to achieve disease remission . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies , even those with the same mechanism of action , in different ways . Another medication , such as certolizumab pegol , is a welcome addition to our treatment armamentarium of rheumatoid arthritis . AREAS COVERED IN THIS REVIEW : The basis of this review is all the peer - reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years . WHAT THE READER WILL GAIN : This review should enable the reader to fully understand the benefit : risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis . TAKE HOME MESSAGE : DB08904 is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved P01375 inhibitors .","[ DB08904 ] . DB08904 is a new anti - P01375 drug formed by the Fab ' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol . DB08904 recognizes and binds to human P01375 - α , both in its soluble and membrane bound form , and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns ' disease . In this review we summarize the structural characteristics and clinical efficacy data , as well as safety data of this anti - P01375 agent in patients with RA .","DB08904 for the treatment of Crohn ' s disease . In this article we provide a contemporary overview of available clinical data on certolizumab pegol , a pegylated anti - tumor necrosis factor ( P01375 ) alpha agent that comprises a uniquely small protein , and its emerging role as a therapy for Crohn ' s disease ( CD ) . The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD . DB08904 is an effective and well - tolerated therapy both in patients who have already received biologics and in patients who are anti - P01375 naïve . Benefits of therapy include a stable dosing regimen , which allows for rapid induction of a clinical response followed by long - term maintenance of response and remission under one fixed dose . Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD , and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression . Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients .","The cytotoxic effects of certolizumab pegol and DB06674 mediated by transmembrane tumor necrosis factor α . BACKGROUND : Anti - tumor necrosis factor α ( anti - P01375 - α ) agents have been successfully applied for the treatment of rheumatoid arthritis , Crohn ' s disease , and other chronic inflammatory diseases . Not only the neutralization of soluble P01375 - α but also the effect on transmembrane P01375 - α is important mechanisms of action of anti - P01375 - α agents . This study investigated the cytotoxic effects of new anti - P01375 - α agents , certolizumab pegol and DB06674 , which are mediated by transmembrane P01375 - α . METHODS : Transmembrane P01375 - α - expressing Jurkat T cells that did not express P01375 receptors were used . The binding ability of each anti - P01375 - α agent to transmembrane P01375 - α , antibody - dependent cell - mediated cytotoxicity , complement - dependent cytotoxicity , and the apoptotic effect were examined . RESULTS : DB08904 and DB06674 bound to transmembrane P01375 - α . Golimumab induced antibody - dependent cell - mediated cytotoxicity and complement - dependent cytotoxicity , which was comparable to infliximab and adalimumab . However , certolizumab pegol did not induce antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity . DB08904 directly induced nonapoptotic cell death in transmembrane P01375 - α - expressing cells . Golimumab induced a weaker apoptotic effect than infliximab and adalimumab . CONCLUSIONS : The cytotoxic effects of anti - P01375 - α agents on P01375 - α - expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases . The direct cytotoxic effect of certolizumab pegol on P01375 - α - producing cells may contribute to its clinical efficacy in Crohn ' s disease . Golimumab may be less effective for granulomatous diseases .","Strategies for targeting tumour necrosis factor in Q9UKU7 . Tumour necrosis factor ( P01375 ) plays an important role in mediating the inflammation of inflammatory bowel disease , in particular , Crohn ' s disease . Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse / human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP571 , the human soluble P01375 p55 receptor onercept , the human monoclonal antibody D2E7 ( adalimumab ) , the anti - P01375 human antibody Fab ' fragment - polyethelene glycol ( PEG ) conjugate DB08904 , and the small molecules thalidomide and CNI - 1493 ( Q96HU1 - kinase inhibitor ) . DB00065 is effective for treating active Crohn ' s disease , maintaining remission , closing fistulas , maintaining fistula closure , and treating ankylosing spondylitis . DB00065 is also being investigated for the treatment of ulcerative colitis . Side - effects occurring in patients treated with infliximab include human anti - chimeric antibodies , infusion reactions , delayed hypersensitivity reactions , formation of autoantibodies , and , in rare circumstances , drug - induced lupus and serious infections , including tuberculosis . CDP571 is effective for treating active Crohn ' s disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side - effects occurring in patients treated with CDP571 include anti - idiotype antibodies , infusion reactions and the formation of autoantibodies . A controlled trial of etanercept in patients with Crohn ' s disease was negative . Pilot studies with onercept , thalidomide , and CNI - 1493 have suggested benefit for Crohn ' s disease . There are no published data on the efficacy of adalimumab ( D2E7 ) or DB08904 for either Crohn ' s disease or ulcerative colitis . Anti - tumour necrosis factor therapies are effective for the treatment of Crohn ' s disease and are being investigated for ulcerative colitis .","The PRECiSE 2 trial of certolizumab pegol , a new PEGylated anti - P01375 agent , in the treatment of Crohn ' s disease : An interview with David A Schwartz , 13 June 2007 . DB08904 ( CDP 870 ) is a new anti - tumor necrosis factor ( P01375 ) therapy currently in development for the treatment of Crohn ' s disease , rheumatoid arthritis , and psoriasis . DB08904 is the first PEGylated biologic anti - P01375 agent and has a high binding affinity for P01375 . Dr . Schwartz was an investigator of the PRECiSE ( PEGylated Antibody Fragment Evaluation in Crohn ' s Disease Safety and Efficacy ) 2 trial of certolizumab pegol in patients with Crohn ' s disease .","DB08904 in Crohn ' s disease . DB08904 is a humanized Fab ' fragment monoclonal antibody to tumor necrosis factor alpha ( P01375 ) . PEGylation increases its half - life , and it is administered subcutaneously to treat immune - mediated inflammatory diseases such as Crohn ' s disease and rheumatoid arthritis . DB08904 improves quality of life and reduces clinical disease activity . Inflammatory markers such as P02741 ( CRP ) also decrease after administration of certolizumab pegol . The dose for induction of remission is 400 mg subcutaneously at weeks 0 , 2 and 4 . The dose for maintenance of remission is 400 mg sc given every four weeks . The safety profile is comparable with other anti - P01375 agents , and the major adverse events are related to infections . This article reviews the published data regarding the efficacy and safety of certolizumab pegol .","Infectious complications of tumor necrosis factor blockade . PURPOSE OF REVIEW : Our understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs were first introduced . This review summarizes recent data regarding infection risk , examines potential structure - function relationships that may account for the differences , and discusses their implications with regard to tuberculosis prevention and management . RECENT FINDINGS : Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 . Screening and initiation of treatment for latent tuberculosis ( TB ) infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . However , alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of P01375 - dependent inflammation . Recent case reports suggest reinstitution of P01375 blockade may be safe and effective adjunctive treatment in such cases , but prospective studies are needed to confirm these observations . SUMMARY : P01375 blockers have transformed treatment of several chronic inflammatory conditions . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases .","Meta - analysis : the efficacy and safety of certolizumab pegol in Crohn ' s disease . BACKGROUND : DB08904 is the third anti - P01375 agent approved by the Food and Drug Administration of the United States . AIM : To provide a comprehensive up - to - date review of the efficacy and safety of certolizumab in Crohn ' s disease ( CD ) . METHODS : Electronic databases , including PubMed , EMBASE , the Cochrane library and the Science Citation Index , were searched to retrieve relevant trials . In addition , meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies . RESULTS : Three trials , enrolling a total of 1040 patients , are included in the meta - analysis to evaluate the short - term efficacy of certolizumab , which is effective for rapid induction and long - term maintenance of clinical response or remission and can improve quality of life in patients with Crohn ' s disease . Certolizumab is also effective for patients who have lost response to infliximab . However , its efficacy in infliximab - exposed patients is probably less than in infliximab - naive patients . Re - induction with certolizumab in patients who have flared on maintenance therapy can rescue a significant proportion of patients . There is no significant association between the efficacy of certolizumab and the baseline P02741 level . In comparison with placebo , certolizumab does not increase the risk of serious adverse events . CONCLUSIONS : Certolizumab is effective and safe in treating Crohn ' s disease . Further studies are still required to assess its full safety profile .","Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn ' s disease . INTRODUCTION : P01375 - α antagonists have transformed the treatment of patients with Crohn ' s disease ( CD ) . DB08904 ( CZP ) is the third P01375 - α antagonist to be approved for use in the United States but is not currently approved in Europe . AREAS COVERED : This review evaluates the pharmacokinetics , pharmacodynamics and efficacy of CZP in CD . Safety , immunogenicity and its use in pregnancy have also been assessed . A literature search was conducted using Pub Med ( 2004 - 2014 ) for the terms ' Crohn ' s disease ' and ' certolizumab pegol ' or ' certolizumab ' or ' cimzia ' . Additional studies were identified from other sources including citation . EXPERT OPINION : As a Fab ' fragment , CZP is effective in binding P01375 - α , but does not cause Fc - mediated effects . PEGylation has improved its pharmacokinetic profile and allowed for an increased half - life of 2 weeks . Benefit for inducing response ( an improvement in symptoms ) and maintenance of remission has been shown . However , the benefit is less clear for the more stringent end - points of inducing remission and mucosal healing . There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection - site reactions , reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab .","DB08904 and rheumatoid arthritis . Just another P01375 alpha antagonist , no therapeutic advantage . No comparison with other P01375 alpha antagonists ; possible bleeding risk .","The use of P01375 blocking agents in rheumatoid arthritis : an overview . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . The overexpression of P01375 in RA synovium , the data from in vitro synovial cell cultures with the use of anti - P01375 antibody and the results from P01375 blockade in animal models of arthritis argued for the importance of this cytokine in RA . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are currently three drugs available in the treatment of RA patients with active disease , which was refractory to conventional treatments including methotrexate , infliximab ( a chimeric mouse / human monoclonal antibody ) , etanercept ( a fusion protein combining 2 p75 P01375 receptors with a Fc fragment of human IgG ( 1 ) ) and adalimumab ( a fully human monoclonal antibody ) . These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs serious adverse events were described , particularly intracellular organism infections such as tuberculosis . Other drugs targeting P01375 are in development and include monoclonal antibody ( CDP571 ) , pegylated molecules ( DB08904 and PEG - r - Hu - sTNF - RI ) or soluble p55 P01375 receptor construct ( lenercept ) . These new biological therapies blocking P01375 undoubtedly constitute a considerable advance in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .","Pegylation of biological molecules and potential benefits : pharmacological properties of certolizumab pegol . PEGylation of biological proteins , defined as the covalent conjugation of proteins with polyethylene glycol ( PEG ) , leads to a number of biopharmaceutical improvements , including increased half - life , increased solubility and reduced aggregation , and reduced immunogenicity . Since their introduction in 1990 , PEGylated proteins have significantly improved the management of various chronic diseases , including rheumatoid arthritis ( RA ) and Crohn ' s disease . DB08904 is the only PEGylated anti - tumour necrosis factor ( P01375 ) - α agent . It is a PEGylated , humanised , antigen - binding fragment of an anti - P01375 monoclonal antibody . Unlike other anti - P01375 agents , it has no crystallisable fragment ( Fc ) domain . Because of its novel structure , certolizumab pegol may have a different mechanism of action to the other anti - P01375 agents , and also has different pharmacodynamic properties , which could possibly translate to a different safety profile . Pharmacodynamic studies have shown that certolizumab pegol binds to P01375 with a higher affinity than adalimumab and infliximab . DB08904 is also more potent at neutralising soluble P01375 - mediated signalling than adalimumab and infliximab , and has similar or lesser potency to etanercept . DB08904 does not cause detrimental in vitro effects such as degranulation , loss of cell integrity , apoptosis , complement - dependent cytotoxicity and antibody - dependent cell - mediated cytotoxicity . DB08904 may also penetrate more effectively into inflamed arthritic tissue than other anti - P01375 agents , and is not actively transported across the placenta during pregnancy . Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics . The pharmacokinetics of certolizumab pegol in patients with RA and Crohn ' s disease were consistent with pharmacokinetics in healthy volunteers .","DB08904 -- what role does this new P01375 inhibitor have in the treatment of RA ? The efficacy and safety of a new tumor necrosis factor inhibitor , certolizumab pegol , in active rheumatoid arthritis has now been assessed in three phase III , multicenter , randomized , double - blind , placebo - controlled clinical trials . This commentary focuses on the paper by Keystone et al . , in which patients were followed for the longest duration . This study , which compared two doses of subcutaneous certolizumab pegol with placebo in patients with active RA receiving methotrexate , showed no advantage of 400 mg over 200 mg certolizumab pegol over 52 weeks , after induction with 400 mg . The nature of the patients enrolled in this study , trial design and possible safety issues are discussed , as is whether this trial can teach us anything about tumor necrosis factor inhibitors in general . On the basis of the results from this study , certolizumab pegol does not represent a major addition to our armamentarium , but because of the slightly different mechanism of action and structure of this drug , and the apparently acceptable therapeutic effects over one year , it is , nevertheless , welcome .","Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK21___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .","DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .","DB08904 compared to natalizumab in patients with moderate to severe Crohn ' s disease : results of a decision analysis . INTRODUCTION : A significant proportion of patients with Crohn ' s disease ( CD ) lose response to antibodies directed against tumor necrosis factor α ( P01375 ) . Prior P01375 - antagonist failure is associated with lower rates of response to subsequent P01375 - antagonist therapy . In patients failing two anti - P01375 agents , a choice exists between using a third - anti - P01375 therapy or natalizumab ( NAT ) , an α - 4 integrin inhibitor . A cost - effectiveness analysis comparing these competing strategies has not been performed . METHODS : A decision analytic model was constructed to compare the performance of certolizumab pegol ( CZP ) versus NAT in patients with moderate to severe CD . Previously published estimates of efficacy of third - line anti - P01375 therapy and NAT were used to inform the model . Costs were expressed in 2010 US dollars . A 1 - year time frame was used for the analysis . RESULTS : In the base case estimate , use of NAT was only marginally more effective [ 0 . 71 vs . 0 . 70 quality adjusted life - years ( QALYs ) ] than CZP but was expensive with an incremental cost - effectiveness ratio ( Q03060 ) of $ 381 , 678 per QALY gained . For CZP 2 months response rate of at least 24 % , NAT had an Q03060 above the willingness - to - pay ( WTP ) threshold . The model was sensitive to the costs of both therapies ; for all CZP costs below $ 2 , 300 per dose , NAT had higher Q03060 than the WTP threshold . Substituting adalimumab for CZP resulted in similar Q03060 estimates and thresholds for NAT use . CONCLUSIONS : In patients with moderate to severe CD failing two P01375 - antagonists , using a third P01375 - antagonist therapy appears to be a cost - effective strategy without significantly compromising treatment efficacy .","Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK93___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .","DB08904 : a review of its use in the management of rheumatoid arthritis . DB08904 ( Cimzia (®) ) is a recombinant , polyethylene glycolylated , antigen - binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor ( P01375 ) - α . The drug is indicated for subcutaneous use every 2 or 4 weeks ( q2w or q4w ) for the treatment of adults with moderate to severe active rheumatoid arthritis ( RA ) . The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed , placebo - controlled trials . In four pivotal studies of ≤ 52 weeks duration , patients with moderate to severe disease receiving recommended dosages of certolizumab pegol ( 200 mg q2w or 400 mg q4w ) , either as monotherapy ( after failing prior disease - modifying anti - rheumatic drug [ DMARD ] therapy ) or in combination with methotrexate ( after responding inadequately to methotrexate alone ) , experienced rapid clinical improvement , with some combination trials also demonstrating inhibition of radiographic progression . The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈ 5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w . Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity , as well as more clinically representative patient populations . The tolerability profile of certolizumab pegol was acceptable , with infections / infestations the most common adverse events . Thus , certolizumab pegol is an effective option for the management of active RA in adults , although additional long - term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs , particularly other anti - P01375 agents .","Profile of certolizumab and its potential in the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory arthropathy associated with psoriasis ( PsO ) . PsA could be considered an enthesal disease because of the link between mechanical stress ( entheses ) and immunologically active tissue ( synovium ) . Evidence of efficacy of anti - tumor necrosis factor alpha ( P01375 - α ) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment . DB08904 ( CZP ) is a polyethylene glycolylated ( PEGylated ) Fab ' fragment of a humanized monoclonal antibody that binds and neutralizes human P01375 - α . The PEG moiety of the Fab fragment , markedly increases the half - life of CZP and confers to the drug a unique structure that differs from the other anti - P01375 - α agents tested for the treatment of Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , axial spondyloarthritis , nonradiographic spondyloarthritis , PsO , and PsA . In contrast to other anti - P01375 - α agents , CZP did not mediate increased levels of apoptosis , suggesting that these mechanisms are not essential for the anti - P01375 - α efficacy in Crohn ' s disease . As CZP , infliximab , and adalimumab , but not etanercept , almost completely inhibited lipopolysaccharide - induced interleukin - 1 beta release from monocytes , this cytokine - production inhibition may be relevant for drug efficacy . Due to these characteristics , it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO , with a safety profile similar to rheumatoid arthritis . This drug can be considered as a valid treatment in patients affected by PsA . The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA .","[ Biologic therapies in chronic inflammatory bowel diseases ] . Crohn ' s disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . Thanks to a better knowledge of their physiopathology , new therapies aimed at specific targets of the inflammatory cascade were developed . Three monoclonal anti - P01375 antibodies were produced . DB00065 and adalimumab , currently widely used , can induce sustained remission in Crohn ' s disease . DB00065 is also efficacious in UC . DB08904 provides good short term results ; its long term efficacy , however , remains to be assessed by further clinical trials . Therapies targeting leucocyte trafficking ( anti - integrine ) have also been provided and are associated with good clinical responses in Crohn ' s disease . DB00108 ( anti - alpha4 ) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 ( anti - alpha417 ) has a good profile in terms of efficacy and safety . Monoclonal anti bodies targeting other cytokines are under development , mainly ustekinumab which inhibits IL12 and IL23 . Ustekinumab generates favourable clinical responses in Crohn ' s disease . The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders .","[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK24___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .","___MASK54___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK54___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway ."],"string":"[\n \"A review and expert opinion of the use of certolizumab for Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the last decade , one of the most significant developments in therapy has been a class of biological agents that neutralize TNFa . DB08904 ( CZP ) is the most recently FDA approved anti - P01375 agent for the induction and maintenance of moderate to severely active Crohn ' s disease . AREAS COVERED : The currently available evidence regarding the use of CZP in CD , the expected efficacy and possible adverse events associated with this population . EXPERT OPINION : CZP is a TNFa inhibitor that is a safe and effective agent for treatment of CD . It has several unique features which make it useful in patients with moderate to severe disease .\",\n \"Cordycepin suppresses P01375 - α - induced NF - κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti - tumor and anti - inflammation , and is involved in the regulation of NF - κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF - κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF - κB activity in P29320 - 293T cells , and found that cordycepin resulted in a dose - dependent reduction in P01375 - α - induced NF - κB activation . Although cordycepin did not block P01375 - α - induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA - binding and transcriptional activities of NF - κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs - mediated NF - κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF - κB signaling through suppressing the activities of NF - κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation - associated disorders and cancer .\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK4___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"Pulmonary infectious complications of tumor necrosis factor blockade . The understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs first were introduced . Recent prospective studies have confirmed the risk of tuberculosis ( TB ) reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment , appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 or activate complement . Two - step ( boosted ) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of P01375 - dependent inflammation . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases .\",\n \"DB08904 for the treatment of psoriatic arthritis . DB08904 ( CZP ) is a P01375 - α inhibitor approved for the treatment of psoriatic arthritis in 38 countries , including many European countries and the USA . It is a pegylated humanized anti - P01375 - α antigen - binding fragment , administered subcutaneously . As other P01375 - α antibodies , CZP binds to and neutralizes both soluble and membrane P01375 - α . In contrast to whole antibodies and etanercept , CZP does not activate antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity , as it does not have an Fc piece . CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate - to - severe plaque psoriasis . In a Phase III study of CZP in 409 psoriatic arthritis patients , CZP treatment resulted in improvements in peripheral arthritis , as well as dactylitis , enthesitis , nail disease and quality of life . The safety profile of CZP appears to be similar to that of other P01375 - α inhibitor .\",\n \"How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn ' s disease . The chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , infliximab , is an effective therapy for Crohn ' s disease . However , the formation of human anti - chimeric antibodies to infliximab ( immunogenicity ) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions . The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment DB08904 are biologic therapies against P01375 that might be effective for Crohn ' s disease and less immunogenic than infliximab . Other potential alternatives to infliximab for Crohn ' s disease include the humanized anti - adhesion molecule antibodies natalizumab and DB05802 , the humanized anti - interleukin 12 antibody ABT - 874 , the humanized anti - interferon g antibody fontolizumab , the humanized anti - interleukin 6 receptor antibody DB06273 , and human recombinant granulocyte macrophage colony stimulating factor ( sargramostim ) . Some , or all , of these therapies will likely represent important treatments for Crohn ' s disease in the future .\",\n \"Anti - P01375 therapy in Crohn ' s disease . Anti - tumour necrosis factor ( P01375 ) strategies , the most studied of biological therapies , include chimeric monoclonal ( infliximab ) , humanized monoclonal ( CDP571 and the PEGylated DB08904 ) and fully human monoclonal ( adalimumab ) antibodies , p75 fusion protein ( etanercept ) , p55 soluble receptor ( onercept ) and small molecules such as MAPkinase inhibitors . The principal use of infliximab is in treating active Crohn ' s disease patients not responding to or intolerant of conventional therapies . DB00065 is steroid sparing . The development of antibodies against infliximab is associated with an increased risk of infusion reactions , and a reduced duration of response to treatment , and concomitant immunosuppressive therapy reduces the immunogenic response . The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised , controlled , ACCENT I trial opened up the strategy for regular maintenance . In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates , and patients with fistulizing disease , where infliximab therapy is chosen , regular maintenance therapy with infliximab is likely to be required . On the other hand , patients with severely active , steroid - refractory disease in whom immunosuppressive therapy and infliximab are initiated together , may respond adequately and be continued on long - term immunosuppressive therapy alone . In ulcerative colitis the role of infliximab remains uncertain .\",\n \"Simultaneous inhibition of epidermal growth factor receptor ( P00533 ) signaling and enhanced activation of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) receptor - mediated apoptosis induction by an scFv : sTRAIL fusion protein with specificity for human P00533 . P00533 ( P00533 ) signaling inhibition by monoclonal antibodies and P00533 - specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction . P01375 - related apoptosis - inducing ligand ( P50591 ) is a promising anti - cancer agent with tumor - selective apoptotic activity . Here we present a novel approach that combines P00533 - signaling inhibition with target cell - restricted apoptosis induction using a P50591 fusion protein with engineered specificity for P00533 . This fusion protein , scFv425 : sTRAIL , comprises the P00533 - blocking antibody fragment scFv425 genetically fused to soluble P50591 ( sTRAIL ) . Treatment with scFv425 : sTRAIL resulted in the specific accretion to the cell surface of P00533 - positive cells only . P00533 - specific binding rapidly induced a dephosphorylation of P00533 and down - stream mitogenic signaling , which was accompanied by cFLIP ( L ) down - regulation and Bad dephosphorylation . P00533 - specific binding converted soluble scFv425 : sTRAIL into a membrane - bound form of P50591 that cross - linked agonistic P50591 receptors in a paracrine manner , resulting in potent apoptosis induction in a series of P00533 - positive tumor cell lines . Co - treatment of P00533 - positive tumor cells with the P00533 - tyrosine kinase inhibitor ___MASK43___ resulted in a potent synergistic pro - apoptotic effect , caused by the specific down - regulation of O15519 . Furthermore , in mixed culture experiments binding ( L ) of scFv425 : sTRAIL to P00533 - positive target cells conveyed a potent apoptotic effect toward P00533 - negative bystander tumor cells . The favorable characteristics of scFv425 : sTRAIL , alone and in combination with ___MASK43___ , as well as its potent anti - tumor bystander activity indicate its potential value for treatment of P00533 - expressing cancers .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK32___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"DB08904 for the treatment of rheumatoid arthritis . INTRODUCTION : Improved understanding of the pathogenesis of rheumatoid arthritis ( RA ) , and subsequent development of targeted therapies , have greatly advanced the management of this chronic inflammatory disease . The aim of treatment is a state of clinical remission . DB08904 ( CZP ) is a novel pegylated P01375 alpha inhibitor ( TNFi ) therapy and is the focus of this review . AREAS COVERED : CZP is different from other TNFi as it contains a polyethylene glycol ( PEG ) moiety , and lacks the constant fragment ( Fc ) of immunoglobulin ; therefore it does not activate complement . In this review in addition to clinical efficacy of CZP , effects on radiographic and patient - reported outcomes , are discussed . Adverse event data from clinical trials and extension studies are also reviewed . EXPERT OPINION : The addition of novel TNFi therapies to treat RA is welcomed . As well as displaying clinical efficacy , there is evidence to suggest that CZP has unique characteristics , including reduced transfer across the placenta and reduced frequency of injection site reactions . Furthermore , randomised controlled trials ( RCTs ) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA .\",\n \"Recommendations for the treatment of Crohn ' s disease with tumor necrosis factor antagonists : an expert consensus report . BACKGROUND : Symptom relief is the traditional treatment goal in Crohn ' s disease ( CD ) . New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor ( P01375 ) antagonists . DB00065 and adalimumab are approved as second - line treatments for severe , active CD . DB08904 is approved only in the U . S . and Switzerland as second - line treatment for moderate - to - severe , active CD . Data from trials of infliximab suggest that high - risk patients and patients with active inflammation ( CRP elevation and / or ileocolonic ulcers ) may benefit from earlier use of this drug . METHODS : A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of P01375 antagonists . At the time of this survey , infliximab was the only P01375 antagonist approved for the treatment of CD in Europe , Canada , and Australia . An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated . RESULTS : The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals , and form a rationale for using P01375 antagonists in CD patients . Control of inflammation and induction of mucosal healing were considered essential for bowel preservation . Consensus areas : 1 ) mucosal healing is predictive of improved long - term disease course and increases the likelihood of steroid - free remission ; 2 ) infliximab induces sustained mucosal healing , promotes bowel preservation , and reduces hospitalizations and surgeries ; 3 ) benefits of infliximab in relation to mucosal healing , bowel preservation , and clinical remission increase when therapy is initiated earlier . CONCLUSIONS : Treatment with P01375 antagonists helps preserve the bowel in CD patients .\",\n \"Targeting nanomedicines in the treatment of Crohn ' s disease : focus on certolizumab pegol ( DB08904 ) . A variety of targets for therapeutic intervention are based upon advances in understanding of the immunopathogenesis of Crohn ' s disease . Crohn ' s disease is initiated by an innate immune response , which eventuates in a T - cell driven process , characterized by a T - helper cell 1 type cytokine profile . Several new treatments now focus on suppressing T - cell differentiation or T - cell inflammation . Since inflammatory bowel disease ( Q9UKU7 ) represents a state of dysregulated inflammation , drugs that augment the anti - inflammatory response have the potential to downregulate inflammation and thereby hopefully modify the disease . Tumour necrosis factor ( P01375 ) is a major target of research and clinical investigation . P01375 has proinflammatory effects in the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade . DB08904 ( DB08904 ) is a PEGylated , Fab ' fragment of a humanized anti - P01375 monoclonal antibody . PEGylation increases the half - life , reduces the requirement for frequent dosing , and possibly reduces antigenicity as well . Certolizumab has been shown in Phase III trials to achieve and maintain clinical response and remission in Crohn ' s disease patients . It improves the quality of life . DB08904 will be indicated for moderately to severely active Crohn ' s disease , but it is not yet licensed in Europe or the US . It is not possible to construct an algorithm for treatment , but when compared with infliximab the two principal advantages are likely to be lower immunogenicity ( as shown by anti - drug antibodies , absence of infusion reactions , and low rate of antinuclear antibodies ) , and a subcutaneous route of administration . These two factors may be sufficient to promote it up the pecking order of anti - P01375 agents .\",\n \"DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .\",\n \"DB08904 in the treatment of Crohn ' s disease . INTRODUCTION : The introduction of antibodies directed against tumour necrosis factor ( anti - P01375 ) has dramatically changed the concept of treating patients with Crohn ' s disease ( CD ) . Unfortunately , the long - term efficacy of anti - P01375 agents may be hampered by immunogenicity . The availability of more anti - P01375 agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti - P01375 . In this review , the authors will focus on the efficacy of certolizumab pegol ( CZP ) . AREAS COVERED : A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD . The authors first focused on the mechanism of action of CZP . Second , they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure . Next , they explored the influence of previous anti - P01375 exposure and baseline P02741 levels . Finally , they analysed the safety data on CZP , including the development of antibodies against CZP and the use of CZP during pregnancy . EXPERT OPINION : Based on the provided literature , CZP could be a good alternative in patients with moderate - to - severe CD failing another anti - P01375 agent . More data are required to conclude on its impact on the long - term outcome of CD .\",\n \"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .\",\n \"DB08904 for the treatment of Crohn ' s disease . DB08904 is a polyethylene glycolated FAb ' fragment of a humanized anti - P01375 monoclonal antibody . This pegylated molecule binds with circulating P01375 and forms an inactive complex that is then eliminated from the body . The drug has been shown to be better than placebo in the treatment of Crohn ' s disease and maintaining a clinical response in adult patients with moderate - to - severe active disease who have had an inadequate response to conventional therapy , and the treatment of adults with moderately to severely active rheumatoid arthritis . Comparative trials with an active control group are lacking . The most common adverse reactions include abdominal pain , diarrhea , injection site reactions and infection . All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy , patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy , and the initiation of therapy should be avoided if the patient has an active infection . Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia . Therapy should be discontinued if the patient develops a serious infection during therapy .\",\n \"The use of P01375 blocking agents in rheumatoid arthritis : an update . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are , at present , three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate : 2 monoclonal antibodies , infliximab and adalimumab , and a fusion protein with p75 receptors , etanercept . These three agents have proved to be effective and safe in large placebo - controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease , improving quality of life and in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs were described serious adverse events , particularly infections such as tuberculosis , especially with infliximab . The risk for malignancies under P01375 antagonists , especially lymphoma , remains controversial . Specific recommendations are given by international experts for selecting and monitoring RA patients with P01375 antagonists . Other drugs targeting P01375 such as PEGylated molecules ( DB08904 or certolizumab ) are in development . These new biological therapies blocking P01375 undoubtedly constitute a considerable advancement in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .\",\n \"Prefilled certolizumab pegol ( Cimzia (®) ) syringes for self - use in the treatment of rheumatoid arthritis . A new anti - tumor necrosis factor alpha ( P01375 - α ) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis ( RA ) . DB08904 ( Cimzia (®) ) is a humanized Fab ' antibody fragment against P01375 - α with a polyethylene glycol tail that prevents complement - dependent and antibody - dependent cell - mediated cytotoxicity or apoptosis . Four randomized clinical trials have been published so far . Reported results are similar to those published in previous studies with other P01375 - α inhibitors , with ACR20 , ACR50 , and ACR70 responses of around 60 % , 40 % , and 20 % , respectively , when combined with methotrexate and slightly lower when used as monotherapy . Safety was shown to be similar to that seen with P01375 - α blockers and some cases of tuberculosis were seen in the trials , stressing the importance of a complete screening in these patients . Although we still need effectiveness and safety data in larger numbers of patients and longer follow - up , this new P01375 inhibitor is a welcome addition to our current armamentarium for the treatment of RA .\",\n \"DB08904 in rheumatoid arthritis : current update . INTRODUCTION : The development of P01375 - α inhibitors ( P01375 - is ) represents a major advancement in the treatment of rheumatoid arthritis ( RA ) . Currently , there are five agents licensed for moderate - to - severely active RA . DB08904 ( CZP ) is a novel PEGylated , constant fragment - free P01375 - i therapy , which is the focus of this review . AREAS COVERED : Data from Phase III randomised controlled trials in terms of clinical efficacy , radiographic progression , patient - reported outcomes and safety profile are reviewed . These include long - term data from open - label extension studies . EXPERT OPINION : The advantages of CZP include rapid reduction of disease activity , low rates of injection - site reaction and may be safe for use in pregnancy . The long - term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti - rheumatic drugs ( DMARDs ) , in moderate - to - severely active RA , comparable to other P01375 - is . Notably , prolonged CZP exposure is not associated with increased risk of severe infection compared to general population , contrasting with preliminary analysis of short - term data . Over the next few years , evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD - naïve patients , biomarkers and the development and licensing of P01375 - i biosimilars .\",\n \"P01375 and its inhibitors in cancer . P01375 ( P01375 ) - alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro - inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti - tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long - term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use .\",\n \"P01375 as a therapeutic target in inflammatory diseases , ischemia - reperfusion injury and trauma . P01375 - alpha ( P01375 ) is a central regulator of inflammation , and P01375 antagonists may be effective in treating inflammatory disorders in which P01375 plays an important pathogenetic role . Recombinant or modified proteins are an emerging class of therapeutic agents . To date , several recombinant or modified proteins which acts as P01375 antagonists have been disclosed . In particular , antibodies that bind to and neutralise P01375 have been sought as a means to inhibit P01375 activity . Inhibition of P01375 has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis , psoriatic arthritis , and ankylosing spondylitis , inflammatory bowel disease . Additionally , the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research . The currently available therapies include a soluble p75 P01375 receptor : Fc construct , etanercept , a chimeric monoclonal antibody , infliximab , and a fully human monoclonal antibody , adalimumab . DB08904 is a novel P01375 inhibitor which is an antigen - binding domain of a humanized P01375 antibody coupled to polyethylene glycol ( PEG ) to increase half - life , and thus is Fc - domain - free . In this review , we discuss briefly the present understanding of P01375 - mediated biology and the current therapies in clinical use , and focus on some of the new therapeutic approaches with small - molecule inhibitors . Moreover , we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs , as P01375 activity inhibitories , especially in therapies of several inflammatory diseases within the nervous system .\",\n \"Randomised clinical trial : improvement in health outcomes with certolizumab pegol in patients with active Crohn ' s disease with prior loss of response to infliximab . BACKGROUND : Crohn ' s disease ( CD ) is associated with impaired health - related quality of life ( HRQoL ) . DB08904 , administered either every 2 weeks ( q2w ) or q4w , maintains efficacy in patients previously failing on the anti - P01375 agent infliximab ( WELCOME study ) . AIM : To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study . METHODS : Patients with loss of response to infliximab received open - label certolizumab pegol induction and were randomised to receive double - blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24 , with a final evaluation at week 26 . Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment : CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively . RESULTS : Baseline HRQoL burden was representative of moderately to severely active CD . HRQoL , daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26 . Treatment benefits to HRQoL , daily activity and work productivity were similar between the certolizumab pegol q2w vs . q4w groups . CONCLUSIONS : DB08904 therapy results in meaningful improvements in work productivity , daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab ( ClinicalTrials . gov number : NCT00308581 ) .\",\n \"DB08904 : a new biologic targeting rheumatoid arthritis . The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis . This is mostly due to targeted biologic agents that have changed the outcome of this disease . DB08904 ( Cimzia (®) , UCB Inc . , GA , USA ) , which targets P01375 - α with a different mechanism of action than widely used biologics , was initially investigated for Crohn ' s disease but has now been shown to be effective for rheumatoid arthritis . There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis ; two with combination methotrexate and one with monotherapy . This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease - modifying antirheumatic drugs and other biologic agents . Treatment recommendations are beyond the scope of this review ; however , with many options available , there will be annotations on current trends in the care of this chronic disease .\",\n \"DB08904 : an evidence - based review of its place in the treatment of Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing / remitting course with transmural inflammation of potentially any section of the digestive tract . DB08904 ( CZP ) is a pegylated Fc - free Fab ' fragment of a humanized anti - P01375 - alfa monoclonal antibody that is in development for clinical use in CD . AIMS : To review the available data with CZP in CD , to investigate its possible place in therapy . EVIDENCE REVIEW : Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD , and to improve quality of life compared with placebo . Further studies with CZP are also ongoing . PLACE IN THERAPY : Although only suggested by currently available studies , successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti - P01375 treatment in CD . The impact on clinical management or on resources can not be estimated until the results from all phase III clinical trials are available and the price is determined .\",\n \"Efficacy and safety of certolizumab pegol in rheumatoid arthritis : meeting rheumatologists ' requirements in routine clinical practice . DB08904 , a pegylated Fab ' anti - tumour necrosis factor ( P01375 ) - α agent , has shown efficacy in patients with rheumatoid arthritis ( RA ) unresponsive to previous treatment . In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease - modifying antirheumatic drug ( DMARD ) , the efficacy of certolizumab pegol , as monotherapy or with methotrexate , was similar to that reported in other anti - P01375 clinical studies , with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA . Rapid clinical response was also seen , with significant differences evident at week 1 , and efficacy maintained at study end and in open - label extensions . Adding certolizumab pegol to non - biological DMARDs is efficacious in other RA populations . In the CERTAIN study , certolizumab increased remission rates , prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA . In the REALISTIC study , rapid and consistent clinical responses were observed in a diverse group of anti - P01375 - eligible RA patients representing those seen in clinical practice . In the RAPID studies , rapid and sustained reduction in RA signs and symptoms , inhibition of structural joint damage progression , and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate . DB08904 was generally well - tolerated in clinical trials , although long - term observational data are not yet available . Current data suggest that certolizumab pegol suits a ' treat to target ' approach , providing rapid and sustained improvements in RA signs and symptoms , and beneficial effects on workplace and home productivity in patients with RA .\",\n \"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .\",\n \"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK67___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK67___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK67___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK67___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK67___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .\",\n \"DB08904 attenuates the pro - inflammatory state in endothelial cells in a manner that is atheroprotective . OBJECTIVES : Rheumatoid arthritis ( RA ) is associated with accelerated atherosclerosis and premature cardiovascular death . Anti - P01375 therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients . However , the specific effects of P01375 inhibitors on endothelial cell function are largely unknown . Our aim was to explore the effects of certolizumab pegol ( CZP ) on P01375 - activated human aortic endothelial cells ( HAoECs ) . METHODS : HAoECs were cultured in vitro and exposed to i ) P01375 alone , ii ) P01375 plus CZP , or iii ) neither agent . Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression . Activation of NF - κB was investigated using immunocytochemistry , high content analysis and western blotting . Flow cytometry was performed to detect microparticle release from HAoECs . RESULTS : P01375 alone had strong effects on endothelial gene expression , while P01375 and CZP together produced a global gene expression pattern similar to untreated controls . In particular , genes for P16581 , P19320 and P05362 were significantly up - regulated by P01375 treatment . Notably , the P01375 / CZP cocktail prevented the up - regulation of these genes . P01375 - induced nuclear translocation of NF - κB was abolished by treatment with CZP . In addition the increased production of endothelial microparticles in P01375 - activated HAoECs was prevented by treatment with CZP . CONCLUSIONS : We have found at cellular level , that a clinically available P01375 inhibitor , CZP i ) reduces adhesion molecule expression ; ii ) prevents P01375 - induced activation of the NF - κB pathway and iii ) prevents the production of microparticles by activated endothelial cells . This could be central to the prevention of inflammatory environments underlying these conditions .\",\n \"Current directions of biologic therapies in inflammatory bowel disease . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . A greater understanding of their pathophysiology has led to new therapies that target specific molecules of the inflammatory cascade . Three anti - tumor necrosis factor ( P01375 ) monoclonal antibodies have been developed . DB00065 and adalimumab can induce clinical response and sustained remission in CD . DB00065 is also effective in UC . DB08904 gives good short - term results but long - term efficacy has yet to be determined in other clinical trials . Therapies that target leucocyte trafficking ( anti - integrins ) have also been developed and are associated with good clinical response in CD . DB00108 ( anti - α4 integrin antibody ) is associated with important side effects and is not used anymore in gastroenterology in Europe but is still used in the USA . DB09033 ( MLN0002 ) , an anti - α4β7 integrin antibody , has a good efficacy and safety profile . Monoclonal antibodies targeting other cytokines are also under development . For example , ustekinumab ( CNTO 1275 ) inhibits interleukins 12 and 23 . It is associated with a good clinical response in CD .\",\n \"New concepts in anti - tumor necrosis factor therapy for inflammatory bowel disease . Crohn ' s disease is a T helper type 1 response immune disease characterized by increased production of interleukin - 12 tumor necrosis factor - a ( P01375 ) , and interferon - g . Clinical trials have demonstrated that inhibition of P01375 is effective for the treatment of Crohn ' s disease . Adverse events reported in patients treated with anti - P01375 agents include immunogenicity , acute infusion reactions , delayed hypersensitivity - type reactions , autoimmune diseases including drug - induced lupus and demyelination , and infection . This article reviews new concepts in the treatment of Crohn ' s disease and ulcerative colitis with a variety of anti - P01375 biologic therapies : infliximab , adalimumab , DB08904 , CDP571 , etanercept , and onercept .\",\n \"The efficacy and safety of certolizumab pegol ( CZP ) in the treatment of active rheumatoid arthritis ( RA ) : a meta - analysis from nine randomized controlled trials . OBJECTIVE : DB08904 ( CZP ) is a novel anti - P01375 agent that is used for patients with moderate to severe active rheumatoid arthritis ( RA ) . However , the efficacy of CZP in RA remains controversial . Thus , we performed this meta - analysis to assess the efficacy and safety of CZP in the treatment of RA patients . METHODS : Eligible studies were randomized controlled trials ( RCTs ) that evaluated the efficacy and safe of CZP in the patients with active RA . The primary outcome was American College of Rheumatology 20 % ( ACR20 ) , and secondary outcome were ACR50 , ACR70 , disease activity , patient - reported outcomes ( PROs ) , and adverse events . A fixed - effect model or random - effect model was used to pool the estimates , depending on the absence or presence of heterogeneity among the included studies . RESULTS : Nine RCTs with a total of 5228 patients were included in this meta - analysis , and all of the patients were administered CZP or placebo . The pooled results showed that CZP significantly improved the ACR20 , ACR50 , ACR70 response rates , and physical function . CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints - Erythrocyte sedimentation rate , arthritis pain , and fatigue . Patients who received CZP treatment did not have a higher incidence of treatment - related adverse events , no matter in any intensity . CONCLUSIONS : CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms , and improved physical function as compared with the placebo . More large - scale RCTs are needed to evaluate the long - term efficacy and safety of CZP in the treatment of active RA .\",\n \"[ Treatment of patients with destructive arthritis with certolizumab pegol ] . DB08904 is a new anti - P01375 inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009 . Due to the modification of the antibody fragment by the adherence of polyethylene glycol ( PEG ) a sufficient distribution in inflammatory tissue was found in animal experiments . In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol .\",\n \"Optimizing anti - tumor necrosis factor strategies in inflammatory bowel disease . The introduction of infliximab , a mouse / human chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , is an important advance in the treatment of Crohn ' s disease . DB00065 is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease . The development of human antichimeric antibodies ( HACAs ) has led to infusion reactions and loss of efficacy in patients treated with infliximab . Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three - dose regimen at 0 , 2 , and 6 weeks followed by systematic maintenance dosing every 8 weeks ; concomitant immunosuppressive therapy with azathioprine , 6 - mercaptopurine , or methotrexate ; and premedication with intravenous corticosteroids . Humanized or fully human anti - P01375 biotechnologic agents , including CDP571 , DB08904 , etanercept , adalimumab , and onercept , are theoretically less immunogenic than the chimeric antibody infliximab . DB00005 is not effective for Crohn ' s disease . CDP571 is not effective in unselected patients with active Crohn ' s disease , but it may be effective in patients with elevated P02741 . The efficacy of DB08904 , adalimumab , and onercept is under investigation . The different mechanisms of action of these anti - P01375 agents may account for their variable efficacy . Their benefits , however , must be considered in the context of their risks , including infusion reaction ; delayed hypersensitivity - like reaction ; new onset of autoimmunity , with rare cases of drug - induced lupus and new - onset demyelination ; and the potential for rare but serious infections .\",\n \"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK33___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .\",\n \"Treatment of Crohn ' s disease with certolizumab pegol . Biologic therapies have revolutionized the treatment of Crohn ' s disease ( CD ) . Targeting P01375 with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD . Intravenous use of infliximab , a chimeric monoclonal antibody to P01375 is , however , limited by the occurrence of adverse events , infusion reactions , infectious complications , aggravation of heart failure , the occurrence of neurological demyelinating conditions and induction of rare malignancies . The incremental development of next - generation P01375 antibodies and binding proteins through antibody - engineering techniques has followed , with the aim of producing efficacious drugs that are less expensive to produce , have a convenient route of administration and have fewer side effects . DB08904 ( DB08904 , Cimzia ) is an engineered humanized anti - P01375 antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol . Clinical studies have demonstrated efficacy in the treatment of moderate - to - severe active CD . Reported adverse events in the clinical trial program have been largely of mild - to - moderate severity , and occurred at similar frequencies in the active - treatment and placebo groups . DB08904 will be a useful addition to the armamentarium of biologic agents that can be used for the long - term treatment of CD .\",\n \"Inorganic lead enhances cytokine - induced elevation of matrix metalloproteinase P14780 expression in glial cells . Inorganic lead ( Pb ) is a ubiquitous environmental contaminant that produces a variety of deleterious effects in the central nervous system ( CNS ) . Matrix metalloproteinases ( MMPs ) , specifically P14780 , induced by inflammatory cytokines , are increasingly being implicated in CNS pathology . The present study demonstrates that low concentrations of either pro - inflammatory cytokines ( P01375 and IL - 1beta ) or Pb did not influence the P14780 expression in a glial cell line ( P13671 ) when added separately . However , combined administration of Pb and cytokines induced a marked synergized elevation of P14780 expression in spite of a reduction in the number of glial cells . These results demonstrate a possible new mechanism by which Pb may induce neuropathological processes .\",\n \"The clinical efficacy and safety of certolizumab pegol in rheumatoid arthritis . IMPORTANCE OF THE FIELD : The treatment of rheumatoid arthritis has changed dramatically over the past 25 years , first with the introduction of methotrexate and then the introduction of biologic therapy . These agents have provided patients with multiple treatment options to try to achieve disease remission . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies , even those with the same mechanism of action , in different ways . Another medication , such as certolizumab pegol , is a welcome addition to our treatment armamentarium of rheumatoid arthritis . AREAS COVERED IN THIS REVIEW : The basis of this review is all the peer - reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years . WHAT THE READER WILL GAIN : This review should enable the reader to fully understand the benefit : risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis . TAKE HOME MESSAGE : DB08904 is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved P01375 inhibitors .\",\n \"[ DB08904 ] . DB08904 is a new anti - P01375 drug formed by the Fab ' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol . DB08904 recognizes and binds to human P01375 - α , both in its soluble and membrane bound form , and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns ' disease . In this review we summarize the structural characteristics and clinical efficacy data , as well as safety data of this anti - P01375 agent in patients with RA .\",\n \"DB08904 for the treatment of Crohn ' s disease . In this article we provide a contemporary overview of available clinical data on certolizumab pegol , a pegylated anti - tumor necrosis factor ( P01375 ) alpha agent that comprises a uniquely small protein , and its emerging role as a therapy for Crohn ' s disease ( CD ) . The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD . DB08904 is an effective and well - tolerated therapy both in patients who have already received biologics and in patients who are anti - P01375 naïve . Benefits of therapy include a stable dosing regimen , which allows for rapid induction of a clinical response followed by long - term maintenance of response and remission under one fixed dose . Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD , and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression . Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients .\",\n \"The cytotoxic effects of certolizumab pegol and DB06674 mediated by transmembrane tumor necrosis factor α . BACKGROUND : Anti - tumor necrosis factor α ( anti - P01375 - α ) agents have been successfully applied for the treatment of rheumatoid arthritis , Crohn ' s disease , and other chronic inflammatory diseases . Not only the neutralization of soluble P01375 - α but also the effect on transmembrane P01375 - α is important mechanisms of action of anti - P01375 - α agents . This study investigated the cytotoxic effects of new anti - P01375 - α agents , certolizumab pegol and DB06674 , which are mediated by transmembrane P01375 - α . METHODS : Transmembrane P01375 - α - expressing Jurkat T cells that did not express P01375 receptors were used . The binding ability of each anti - P01375 - α agent to transmembrane P01375 - α , antibody - dependent cell - mediated cytotoxicity , complement - dependent cytotoxicity , and the apoptotic effect were examined . RESULTS : DB08904 and DB06674 bound to transmembrane P01375 - α . Golimumab induced antibody - dependent cell - mediated cytotoxicity and complement - dependent cytotoxicity , which was comparable to infliximab and adalimumab . However , certolizumab pegol did not induce antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity . DB08904 directly induced nonapoptotic cell death in transmembrane P01375 - α - expressing cells . Golimumab induced a weaker apoptotic effect than infliximab and adalimumab . CONCLUSIONS : The cytotoxic effects of anti - P01375 - α agents on P01375 - α - expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases . The direct cytotoxic effect of certolizumab pegol on P01375 - α - producing cells may contribute to its clinical efficacy in Crohn ' s disease . Golimumab may be less effective for granulomatous diseases .\",\n \"Strategies for targeting tumour necrosis factor in Q9UKU7 . Tumour necrosis factor ( P01375 ) plays an important role in mediating the inflammation of inflammatory bowel disease , in particular , Crohn ' s disease . Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse / human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP571 , the human soluble P01375 p55 receptor onercept , the human monoclonal antibody D2E7 ( adalimumab ) , the anti - P01375 human antibody Fab ' fragment - polyethelene glycol ( PEG ) conjugate DB08904 , and the small molecules thalidomide and CNI - 1493 ( Q96HU1 - kinase inhibitor ) . DB00065 is effective for treating active Crohn ' s disease , maintaining remission , closing fistulas , maintaining fistula closure , and treating ankylosing spondylitis . DB00065 is also being investigated for the treatment of ulcerative colitis . Side - effects occurring in patients treated with infliximab include human anti - chimeric antibodies , infusion reactions , delayed hypersensitivity reactions , formation of autoantibodies , and , in rare circumstances , drug - induced lupus and serious infections , including tuberculosis . CDP571 is effective for treating active Crohn ' s disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side - effects occurring in patients treated with CDP571 include anti - idiotype antibodies , infusion reactions and the formation of autoantibodies . A controlled trial of etanercept in patients with Crohn ' s disease was negative . Pilot studies with onercept , thalidomide , and CNI - 1493 have suggested benefit for Crohn ' s disease . There are no published data on the efficacy of adalimumab ( D2E7 ) or DB08904 for either Crohn ' s disease or ulcerative colitis . Anti - tumour necrosis factor therapies are effective for the treatment of Crohn ' s disease and are being investigated for ulcerative colitis .\",\n \"The PRECiSE 2 trial of certolizumab pegol , a new PEGylated anti - P01375 agent , in the treatment of Crohn ' s disease : An interview with David A Schwartz , 13 June 2007 . DB08904 ( CDP 870 ) is a new anti - tumor necrosis factor ( P01375 ) therapy currently in development for the treatment of Crohn ' s disease , rheumatoid arthritis , and psoriasis . DB08904 is the first PEGylated biologic anti - P01375 agent and has a high binding affinity for P01375 . Dr . Schwartz was an investigator of the PRECiSE ( PEGylated Antibody Fragment Evaluation in Crohn ' s Disease Safety and Efficacy ) 2 trial of certolizumab pegol in patients with Crohn ' s disease .\",\n \"DB08904 in Crohn ' s disease . DB08904 is a humanized Fab ' fragment monoclonal antibody to tumor necrosis factor alpha ( P01375 ) . PEGylation increases its half - life , and it is administered subcutaneously to treat immune - mediated inflammatory diseases such as Crohn ' s disease and rheumatoid arthritis . DB08904 improves quality of life and reduces clinical disease activity . Inflammatory markers such as P02741 ( CRP ) also decrease after administration of certolizumab pegol . The dose for induction of remission is 400 mg subcutaneously at weeks 0 , 2 and 4 . The dose for maintenance of remission is 400 mg sc given every four weeks . The safety profile is comparable with other anti - P01375 agents , and the major adverse events are related to infections . This article reviews the published data regarding the efficacy and safety of certolizumab pegol .\",\n \"Infectious complications of tumor necrosis factor blockade . PURPOSE OF REVIEW : Our understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs were first introduced . This review summarizes recent data regarding infection risk , examines potential structure - function relationships that may account for the differences , and discusses their implications with regard to tuberculosis prevention and management . RECENT FINDINGS : Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 . Screening and initiation of treatment for latent tuberculosis ( TB ) infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . However , alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of P01375 - dependent inflammation . Recent case reports suggest reinstitution of P01375 blockade may be safe and effective adjunctive treatment in such cases , but prospective studies are needed to confirm these observations . SUMMARY : P01375 blockers have transformed treatment of several chronic inflammatory conditions . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases .\",\n \"Meta - analysis : the efficacy and safety of certolizumab pegol in Crohn ' s disease . BACKGROUND : DB08904 is the third anti - P01375 agent approved by the Food and Drug Administration of the United States . AIM : To provide a comprehensive up - to - date review of the efficacy and safety of certolizumab in Crohn ' s disease ( CD ) . METHODS : Electronic databases , including PubMed , EMBASE , the Cochrane library and the Science Citation Index , were searched to retrieve relevant trials . In addition , meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies . RESULTS : Three trials , enrolling a total of 1040 patients , are included in the meta - analysis to evaluate the short - term efficacy of certolizumab , which is effective for rapid induction and long - term maintenance of clinical response or remission and can improve quality of life in patients with Crohn ' s disease . Certolizumab is also effective for patients who have lost response to infliximab . However , its efficacy in infliximab - exposed patients is probably less than in infliximab - naive patients . Re - induction with certolizumab in patients who have flared on maintenance therapy can rescue a significant proportion of patients . There is no significant association between the efficacy of certolizumab and the baseline P02741 level . In comparison with placebo , certolizumab does not increase the risk of serious adverse events . CONCLUSIONS : Certolizumab is effective and safe in treating Crohn ' s disease . Further studies are still required to assess its full safety profile .\",\n \"Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn ' s disease . INTRODUCTION : P01375 - α antagonists have transformed the treatment of patients with Crohn ' s disease ( CD ) . DB08904 ( CZP ) is the third P01375 - α antagonist to be approved for use in the United States but is not currently approved in Europe . AREAS COVERED : This review evaluates the pharmacokinetics , pharmacodynamics and efficacy of CZP in CD . Safety , immunogenicity and its use in pregnancy have also been assessed . A literature search was conducted using Pub Med ( 2004 - 2014 ) for the terms ' Crohn ' s disease ' and ' certolizumab pegol ' or ' certolizumab ' or ' cimzia ' . Additional studies were identified from other sources including citation . EXPERT OPINION : As a Fab ' fragment , CZP is effective in binding P01375 - α , but does not cause Fc - mediated effects . PEGylation has improved its pharmacokinetic profile and allowed for an increased half - life of 2 weeks . Benefit for inducing response ( an improvement in symptoms ) and maintenance of remission has been shown . However , the benefit is less clear for the more stringent end - points of inducing remission and mucosal healing . There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection - site reactions , reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab .\",\n \"DB08904 and rheumatoid arthritis . Just another P01375 alpha antagonist , no therapeutic advantage . No comparison with other P01375 alpha antagonists ; possible bleeding risk .\",\n \"The use of P01375 blocking agents in rheumatoid arthritis : an overview . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . The overexpression of P01375 in RA synovium , the data from in vitro synovial cell cultures with the use of anti - P01375 antibody and the results from P01375 blockade in animal models of arthritis argued for the importance of this cytokine in RA . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are currently three drugs available in the treatment of RA patients with active disease , which was refractory to conventional treatments including methotrexate , infliximab ( a chimeric mouse / human monoclonal antibody ) , etanercept ( a fusion protein combining 2 p75 P01375 receptors with a Fc fragment of human IgG ( 1 ) ) and adalimumab ( a fully human monoclonal antibody ) . These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs serious adverse events were described , particularly intracellular organism infections such as tuberculosis . Other drugs targeting P01375 are in development and include monoclonal antibody ( CDP571 ) , pegylated molecules ( DB08904 and PEG - r - Hu - sTNF - RI ) or soluble p55 P01375 receptor construct ( lenercept ) . These new biological therapies blocking P01375 undoubtedly constitute a considerable advance in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .\",\n \"Pegylation of biological molecules and potential benefits : pharmacological properties of certolizumab pegol . PEGylation of biological proteins , defined as the covalent conjugation of proteins with polyethylene glycol ( PEG ) , leads to a number of biopharmaceutical improvements , including increased half - life , increased solubility and reduced aggregation , and reduced immunogenicity . Since their introduction in 1990 , PEGylated proteins have significantly improved the management of various chronic diseases , including rheumatoid arthritis ( RA ) and Crohn ' s disease . DB08904 is the only PEGylated anti - tumour necrosis factor ( P01375 ) - α agent . It is a PEGylated , humanised , antigen - binding fragment of an anti - P01375 monoclonal antibody . Unlike other anti - P01375 agents , it has no crystallisable fragment ( Fc ) domain . Because of its novel structure , certolizumab pegol may have a different mechanism of action to the other anti - P01375 agents , and also has different pharmacodynamic properties , which could possibly translate to a different safety profile . Pharmacodynamic studies have shown that certolizumab pegol binds to P01375 with a higher affinity than adalimumab and infliximab . DB08904 is also more potent at neutralising soluble P01375 - mediated signalling than adalimumab and infliximab , and has similar or lesser potency to etanercept . DB08904 does not cause detrimental in vitro effects such as degranulation , loss of cell integrity , apoptosis , complement - dependent cytotoxicity and antibody - dependent cell - mediated cytotoxicity . DB08904 may also penetrate more effectively into inflamed arthritic tissue than other anti - P01375 agents , and is not actively transported across the placenta during pregnancy . Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics . The pharmacokinetics of certolizumab pegol in patients with RA and Crohn ' s disease were consistent with pharmacokinetics in healthy volunteers .\",\n \"DB08904 -- what role does this new P01375 inhibitor have in the treatment of RA ? The efficacy and safety of a new tumor necrosis factor inhibitor , certolizumab pegol , in active rheumatoid arthritis has now been assessed in three phase III , multicenter , randomized , double - blind , placebo - controlled clinical trials . This commentary focuses on the paper by Keystone et al . , in which patients were followed for the longest duration . This study , which compared two doses of subcutaneous certolizumab pegol with placebo in patients with active RA receiving methotrexate , showed no advantage of 400 mg over 200 mg certolizumab pegol over 52 weeks , after induction with 400 mg . The nature of the patients enrolled in this study , trial design and possible safety issues are discussed , as is whether this trial can teach us anything about tumor necrosis factor inhibitors in general . On the basis of the results from this study , certolizumab pegol does not represent a major addition to our armamentarium , but because of the slightly different mechanism of action and structure of this drug , and the apparently acceptable therapeutic effects over one year , it is , nevertheless , welcome .\",\n \"Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK21___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .\",\n \"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .\",\n \"DB08904 compared to natalizumab in patients with moderate to severe Crohn ' s disease : results of a decision analysis . INTRODUCTION : A significant proportion of patients with Crohn ' s disease ( CD ) lose response to antibodies directed against tumor necrosis factor α ( P01375 ) . Prior P01375 - antagonist failure is associated with lower rates of response to subsequent P01375 - antagonist therapy . In patients failing two anti - P01375 agents , a choice exists between using a third - anti - P01375 therapy or natalizumab ( NAT ) , an α - 4 integrin inhibitor . A cost - effectiveness analysis comparing these competing strategies has not been performed . METHODS : A decision analytic model was constructed to compare the performance of certolizumab pegol ( CZP ) versus NAT in patients with moderate to severe CD . Previously published estimates of efficacy of third - line anti - P01375 therapy and NAT were used to inform the model . Costs were expressed in 2010 US dollars . A 1 - year time frame was used for the analysis . RESULTS : In the base case estimate , use of NAT was only marginally more effective [ 0 . 71 vs . 0 . 70 quality adjusted life - years ( QALYs ) ] than CZP but was expensive with an incremental cost - effectiveness ratio ( Q03060 ) of $ 381 , 678 per QALY gained . For CZP 2 months response rate of at least 24 % , NAT had an Q03060 above the willingness - to - pay ( WTP ) threshold . The model was sensitive to the costs of both therapies ; for all CZP costs below $ 2 , 300 per dose , NAT had higher Q03060 than the WTP threshold . Substituting adalimumab for CZP resulted in similar Q03060 estimates and thresholds for NAT use . CONCLUSIONS : In patients with moderate to severe CD failing two P01375 - antagonists , using a third P01375 - antagonist therapy appears to be a cost - effective strategy without significantly compromising treatment efficacy .\",\n \"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK93___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .\",\n \"DB08904 : a review of its use in the management of rheumatoid arthritis . DB08904 ( Cimzia (®) ) is a recombinant , polyethylene glycolylated , antigen - binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor ( P01375 ) - α . The drug is indicated for subcutaneous use every 2 or 4 weeks ( q2w or q4w ) for the treatment of adults with moderate to severe active rheumatoid arthritis ( RA ) . The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed , placebo - controlled trials . In four pivotal studies of ≤ 52 weeks duration , patients with moderate to severe disease receiving recommended dosages of certolizumab pegol ( 200 mg q2w or 400 mg q4w ) , either as monotherapy ( after failing prior disease - modifying anti - rheumatic drug [ DMARD ] therapy ) or in combination with methotrexate ( after responding inadequately to methotrexate alone ) , experienced rapid clinical improvement , with some combination trials also demonstrating inhibition of radiographic progression . The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈ 5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w . Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity , as well as more clinically representative patient populations . The tolerability profile of certolizumab pegol was acceptable , with infections / infestations the most common adverse events . Thus , certolizumab pegol is an effective option for the management of active RA in adults , although additional long - term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs , particularly other anti - P01375 agents .\",\n \"Profile of certolizumab and its potential in the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory arthropathy associated with psoriasis ( PsO ) . PsA could be considered an enthesal disease because of the link between mechanical stress ( entheses ) and immunologically active tissue ( synovium ) . Evidence of efficacy of anti - tumor necrosis factor alpha ( P01375 - α ) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment . DB08904 ( CZP ) is a polyethylene glycolylated ( PEGylated ) Fab ' fragment of a humanized monoclonal antibody that binds and neutralizes human P01375 - α . The PEG moiety of the Fab fragment , markedly increases the half - life of CZP and confers to the drug a unique structure that differs from the other anti - P01375 - α agents tested for the treatment of Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , axial spondyloarthritis , nonradiographic spondyloarthritis , PsO , and PsA . In contrast to other anti - P01375 - α agents , CZP did not mediate increased levels of apoptosis , suggesting that these mechanisms are not essential for the anti - P01375 - α efficacy in Crohn ' s disease . As CZP , infliximab , and adalimumab , but not etanercept , almost completely inhibited lipopolysaccharide - induced interleukin - 1 beta release from monocytes , this cytokine - production inhibition may be relevant for drug efficacy . Due to these characteristics , it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO , with a safety profile similar to rheumatoid arthritis . This drug can be considered as a valid treatment in patients affected by PsA . The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA .\",\n \"[ Biologic therapies in chronic inflammatory bowel diseases ] . Crohn ' s disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . Thanks to a better knowledge of their physiopathology , new therapies aimed at specific targets of the inflammatory cascade were developed . Three monoclonal anti - P01375 antibodies were produced . DB00065 and adalimumab , currently widely used , can induce sustained remission in Crohn ' s disease . DB00065 is also efficacious in UC . DB08904 provides good short term results ; its long term efficacy , however , remains to be assessed by further clinical trials . Therapies targeting leucocyte trafficking ( anti - integrine ) have also been provided and are associated with good clinical responses in Crohn ' s disease . DB00108 ( anti - alpha4 ) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 ( anti - alpha417 ) has a good profile in terms of efficacy and safety . Monoclonal anti bodies targeting other cytokines are under development , mainly ustekinumab which inhibits IL12 and IL23 . Ustekinumab generates favourable clinical responses in Crohn ' s disease . The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK24___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"___MASK54___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK54___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK21___","___MASK24___","___MASK32___","___MASK33___","___MASK43___","___MASK4___","___MASK54___","___MASK67___","___MASK93___"],"string":"[\n \"___MASK21___\",\n \"___MASK24___\",\n \"___MASK32___\",\n \"___MASK33___\",\n \"___MASK43___\",\n \"___MASK4___\",\n \"___MASK54___\",\n \"___MASK67___\",\n \"___MASK93___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK21___"},"id":{"kind":"string","value":"MH_train_80"}}},{"rowIdx":81,"cells":{"query":{"kind":"string","value":"interacts_with DB00136?"},"supports":{"kind":"list like","value":["( Pro ) renin promotes fibrosis gene expression in P29320 cells through a Nox4 - dependent mechanism . The ( pro ) renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this study , we report that human embryonic kidney cells ( P29320 ) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin - converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence ( lucigenin ) and electron spin resonance spectroscopy ( hydroxylamine radical transition ) . Also , both renin and prorenin increased Nox4 expression while Nox2 , p47 ( phox ) , and p67 ( phox ) remained unchanged . In an investigation of the effects of renin and prorenin on fibrosis genes , it appeared that both proteins stimulated transforming growth factor - β ( TGF - β ) , fibronectin , and plasminogen activator inhibitor type 1 ( P05121 ) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells . When the cells were transfected with a siRNA targeting the PRR , Nox4 expression was efficiently prevented as well as the increase in superoxide production , TGF - β , fibronectin , and P05121 . Finally , we demonstrated that transfection of the cells with a Nox4 - specific small interfering ( si ) RNA also prevented fibrosis gene expression following treatment with renin or prorenin . The results demonstrate that renin and prorenin , through their specific membrane receptor and independently of angiotensin II , promote fibrosis gene expression via a Nox4 - dependent mechanism .","20 - Hydroxycholecalciferol , product of vitamin D3 hydroxylation by P450scc , decreases NF - kappaB activity by increasing IkappaB alpha levels in human keratinocytes . The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc ( P05108 ) to form 20 - hydroxycholecalciferol , which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes . Since nuclear factor - kappaB ( NF - kappaB ) plays a pivotal role in the regulation of cell proliferation , differentiation and apoptosis , we examined the capability of 20 - hydroxycholecalciferol to modulate the activity of NF - kappaB , using DB00136 ( calcitriol ) as a positive control . 20 - hydroxycholecalciferol inhibits the activation of NFkappaB DNA binding activity as well as NF - kappaB - driven reporter gene activity in keratinocytes . Also , 20 - hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF - kappaB inhibitor protein , IkappaB alpha , in a time dependent manner , while no changes in total NF - kappaB - p65 mRNA or protein levels were observed . Another measure of NF - kappaB activity , p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20 - hydroxycholecalciferol treated keratinocytes . Increased IkappaB alpha was concomitantly observed in cytosolic extracts of 20 - hydroxycholecalciferol treated keratinocytes , as determined by immunoblotting and immunofluorescent staining . In keratinocytes lacking vitamin D receptor ( P11473 ) , 20 - hydroxycholecalciferol did not affect IkappaB alpha mRNA levels , indicating that it requires P11473 for its action on NF - kappaB activity . Comparison of the effects of calcitrol , hormonally active form of vitamin D3 , with 20 - hydrocholecalciferol show that both agents have a similar potency in inhibiting NF - kappaB . Since NF - kappaB is a major transcription factor for the induction of inflammatory mediators , our findings indicate that 20 - hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases .","Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK55___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .","Genetics of type 2 diabetes mellitus and other specific types of diabetes ; its role in treatment modalities . Type 2 diabetes mellitus ( T2DM ) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence . The pathophysiological processes that lead to development of T2DM are still unclear , however impairment in insulin secretion and / or action is clearly indicated . Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility . Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder . Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young ( MODY ) . Previous studies indicated that variants in genes encoding the pancreatic β - cell K + DB00171 channel subunits Kir6 . 2 ( Q14654 ) and Q09428 ( Q09428 ) are associated with neonatal diabetes . Six different types of maturity onset diabetes of young ( MODY ) have been identified based on characteristic gene defect . The common Pro12Ala polymorphism in peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) gene was confirmed in several studies to be associated with type 2 diabetes as well . More recently , studies reported variants within a novel gene , Q9NQB0 , as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world . MODY patients respond better to sulphonylureas and metformin , while neonatal diabetes patients with genetic mutations can be changed from insulin to oral drugs . We hereby provide a comprehensive review on the role of genetics in type 2 diabetes mellitus .","___MASK52___ block of cloned human T - type voltage - gated calcium channels . ___MASK52___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .","Extended kindred with recessive late - onset Alzheimer disease maps to locus 8p22 - P38936 . 2 : a genome - wide linkage analysis . Late - onset Alzheimer disease ( LOAD ) is a complex genetic disorder . Although genes involved in early - onset forms were discovered more than a decade ago , LOAD research has only been able to point out small effect loci , with the exception of P02649 . We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region ( 24 sampled individuals , 12 of whom are affected ) , completing a genome - wide screen with an Affymetrix10 K single nucleotide polymorphism microarray . Genotyping results were evaluated under model - dependent ( dominant and recessive ) and model - free analysis . We obtained a maximum nonparametric linkage score of 3 . 24 ( P = 0 . 00006 ) on chromosome 8p22 - P38936 . 2 . The same genomic position also yielded the highest multipoint heterogeneity LOD ( HLOD ) under a recessive model ( HLOD = 3 . 04 ) . When we compared the results of the model - dependent analysis , a higher score was obtained in the recessive model ( 3 . 04 ) than in the dominant model ( 1 . 0 ) . This is a new locus identified in LOAD , in chromosome 8p22 - P38936 . 2 and encompassing several candidate genes , among them P10909 and P48454 that were excluded by sequencing . The finding of a recessive model of inheritance , consistent with the assumption of inbreeding as a morbidity factor in this population , supports the notion of a role of recessive genes in LOAD .","Caveolae and caveolin - 1 are implicated in 1alpha , 25 ( OH ) 2 - vitamin D3 - dependent modulation of Src , MAPK cascades and P11473 localization in skeletal muscle cells . We previously reported that DB00136 induces non - transcriptional rapid responses through activation of MAPKs in C2C12 skeletal muscle cells . However , there is little information on the molecular mechanism underlying the initiation of DB00136 signaling through this pathway . Plasma membrane components have been involved in some non - genomic effects . In this work , we investigated the role of caveolae and caveolin - 1 ( cav - 1 ) in DB00136 - stimulation of c - Src and MAPKs . When proliferating cells were pretreated with methyl beta cyclodextrin ( MbetaCD ) , a caveolae disrupting agent , under conditions in which cell morphology is not affected and no signs of apoptosis are observed , DB00136 - dependent activation of P27361 / 2 , p38 MAPK and c - Src was suppressed . Similar results were obtained by siRNA technology whereby silencing of cav - 1 expression abolished activation of c - Src and MAPKs induced by the hormone . By confocal immunocytochemistry it was observed that cav - 1 colocalizes with c - Src in the periplasma membrane zone at basal conditions . Hormone treatment disrupted the colocalization of these proteins and redistributed them into cytoplasm and nucleus . Co - immunoprecipitation assays corroborated these observations . Changes in P11473 localization after DB00136 exposure were also investigated . Confocal microscopy images showed that the hormone induces P11473 translocation to the plasma membrane , and this effect is abolished by MbetaCD . Altogether , these data suggest that caveolae is involved upstream in c - Src - MAPKs activation by DB00136 and that P11473 and cav - 1 participate in the rapid signaling elicited by the hormone .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK58___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","A tumor - infiltrating lymphocyte from a melanoma metastasis with decreased expression of melanoma differentiation antigens recognizes MAGE - 12 . Twenty separate tumor infiltrating lymphocyte ( Q15399 ) bulk cultures and a tumor cell line were originated simultaneously from a fine needle aspiration biopsy of a metastasis in a patient with melanoma ( F001 ) previously immunized with the HLA - A * 0201 - associated gp100 : 209 - 217 ( 210 M ) peptide . None of the Q15399 recognized gp100 . However , 12 recognized autologous ( F001 - P61006 ) and allogeneic melanoma cells expressing the HLA haplotype A * 0201 , B * 0702 , Cw * 0702 . Further characterization of F001 - P61006 demonstrated loss of gp100 / PMel17 , severely decreased expression of other melanoma differentiation Ags and retained expression of tumor - specific Ags . Transfection of HLA class I alleles into B * 0702 / Cw * 0702 - negative melanoma cell lines identified HLA - Cw * 0702 as the restriction element for F001 - Q15399 . A cDNA library from F001 - P61006 was used to transfect IFN - alpha - stimulated 293 human embryonal kidney ( 293 - P29320 ) cells expressing HLA - Cw * 0702 . A 100 - gene pool was identified that induced recognition of 293 - P29320 cells by F001 - Q15399 . Subsequent cloning of the pool identified a cDNA sequence homologous , except for one amino acid ( aa 187 D --> A ) , to MAGE - 12 . Among 25 peptide sequences from MAGE - 12 with the HLA - Cw * 0702 binding motif , MAGE - 12 : 170 - 178 ( VRIGHLYIL ) induced P01579 release by F001 - Q15399 when pulsed on F001 - EBV - B cells at concentrations as low as 10 pg / ml . Peptide sequences from MAGE - 1 , 2 , 3 , 4a , and 6 aligned to MAGE - 12 : 170 - 178 were not recognized by F001 - Q15399 . In summary a Q15399 recognizing a MAGE protein was developed from an HLA - A * 0201 expressing tumor with strongly reduced expression of melanoma differentiation Ags . Persisting tumor - specific Ag expression maintained tumor immune competence suggesting that tumor - specific Ags / melanoma differentiation Ags may complement each other in the context of melanoma Ag - specific vaccination .","___MASK69___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK69___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Chemical synthesis and in vitro biological evaluation of a phosphorylated bisubstrate inhibitor of type 3 17beta - hydroxysteroid dehydrogenase . Type 3 17beta - hydroxysteroid dehydrogenase ( 17beta - HSD ) catalyzes the last step in the biosynthesis of the potent androgen testosterone ( T ) by selectively reducing the C17 ketone of 4 - androstene - 3 , 17 - dione ( delta4 - dione ) , with NADPH as cofactor . This enzyme is thus an interesting therapeutic target for androgen - sensitive diseases . Using an efficient convergent chemical approach we synthesized a phosphorylated version of the best delta4 - dione / adenosine hybrid inhibitor of type 3 17beta - HSD previously reported . An appropriately protected P06681 ' phosphorylated adenosine was first prepared and linked by esterification to the steroid delta4 - dione bearing an alkyl spacer . After three deprotection steps , the phosphorylated bisubstrate inhibitor was obtained . The inhibitory potency of this compound was evaluated on homogenated P29320 - 293 cells overexpressing type 3 17beta - HSD and compared to the best non - phosphorylated bisubstrate inhibitor . Unexpectedly , the phosphorylated derivative was slightly less potent than the non - phosphorylated bisubstrate inhibitor of type 3 17beta - HSD . Two hypotheses are discussed to explain this result : 1 ) the phosphorylated adenosine moiety does not interact optimally with the cofactor - binding site and 2 ) the bisubstrate inhibitors , phosphorylated or not , interact only with the substrate - binding site of type 3 17beta - HSD .","The anti - proliferative effects of DB00136 on breast and prostate cancer cells are associated with induction of P38398 gene expression . The anti - proliferative action of the seco - steroid hormone 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] extends to some , but not all breast and prostate cancer cell lines . By elucidating the molecular mechanisms mediating the sensitivity of these cells , we can identify critical target genes regulated directly or indirectly by DB00136 and pathways potentially disrupted during transformation . In this study , we demonstrated the induction of expression of P38398 mRNA and protein as well as transcriptional activation from the P38398 - promoter by DB00136 in the sensitive breast cancer cell line MCF - 7 . This was not observed in the DB00136 - resistant breast cancer cell line MDA - MB - 436 . The induction of P38398 mRNA was blocked by cyclohexamide . This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor ( P11473 ) . Inhibition of P11473 protein levels by stable transformation of the anti - sense P11473 in MCF - 7 reduced the sensitivity of MCF - 7 to DB00136 by 50 - fold . In addition , the induction of P38398 protein and transcriptional activation of a P38398 promoter - luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of P11473 levels . Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti - proliferative effects of 1alpha , 25 ( OH ) 2D3 was strongly associated with an ability to modulate P38398 protein . Furthermore , the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to DB00136 and their ability to modulate P38398 expression . Taken together , our data support a model whereby the anti - proliferative effects of DB00136 are mediated , in part , by the induction of P38398 gene expression via transcriptional activation by factors induced by the P11473 and that this pathway is disrupted during the development of prostate and breast cancers .","Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levels . It is well - known that baseline levels of P02741 ( CRP ) are an independent cardiovascular risk factor . We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system . We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes ( Q9HC29 , P51617 , Q9NWZ3 , P18428 , O95711 , O15553 , O60603 , O00206 and P19838 ) in relation to CRP levels . Seven hundred and seventeen subjects from the Women ' s Health Study population were studied : 359 and 358 samples with extremely low ( < 0 . 2 mg / liter ) and high ( > 5 mg / liter ) CRP levels , respectively . SNPs were identified from publicly available resequencing data , using a minor allele frequency threshold of > 5 % and a linkage disequilibrium ( LD ) - based strategy ( r ( 2 ) > 0 . 8 ) to select 63 LD - independent markers . One non - synonymous SNP in O00206 and two non - synonymous SNPs in Q9HC29 , previously associated with atherosclerosis and Crohn ' s disease , respectively , were also studied . Univariate , haplotype and gene - gene interaction analyses all indicated no significant association with CRP levels . Although this work excludes a significant association of common SNPs in these nine genes with CRP levels , it is possible that rarer alleles in these genes , or variation in other innate immunity genes , could be associated with variation in CRP .","Effect of the IkBα mutant gene delivery to DB05914 on rat chronic pancreatitis . This study aimed to investigate the effect of inhibitors of the NF - kΒ alpha mutant gene ( IkBaM ) delivery to mensenchymal stem cells ( MSCs ) on rat chronic pancreatitis ( CP ) . A total of 120 Sprague - Dawley rats were randomly divided into 6 groups of 20 : Group A was injected with sterile saline solution , Group B was injected with allogenic MSCs , Group C1 was injected with allogenic IkBαM - MSCs cultured in vitro 4 h before CP modeling , Group P06681 was injected with allogenic IkBαM - MSCs cultured in vitro during CP modeling , Group P01024 was cultured with allogenic IkBαM - MSCs cultured in vitro 4 h after CP modeling , and Group D was injected with rAAV2 - MSCs . Cytokine levels of P05362 , P29279 , IL - 1 , P05231 , P10145 , P01375 - α , P01033 , P16035 , P22301 , FN , P03956 , P08253 , P08254 , and P14780 were examined . The results indicated that allogenic IκBαM - MSCs could reduce pro - inflammatory cytokine levels and increase anti - inflammatory cytokine levels in CP . The allogenic IkBαM - MSCs reduced the activation and promoted the apoptosis of pancreatic stellate cells in the rat model of CP . IkBαM - MSCs influenced the proliferation and apoptosis of pancreatic stellate cells by regulating the activation of the Q07869 , MAPK , P42345 , TGF - β , NOD - like receptor , Notch , WNT , TGF - β1 - SMAD - 2 / 3 , and P04637 signal transduction pathways .","Synthesis and biological activities of 14 - epi - MART - 10 and 14 - epi - MART - 11 : implications for cancer and osteoporosis treatment . The 14 - epimer of MART - 10 , namely 14 - epi - MART - 10 ( 14 - epi - 2alpha -( 3 - hydroxypropyl )- 1alpha , 25 - dihydroxy - 19 - norvitamin D3 ) and its 2 - epimeric analog ( 14 - epi - MART - 11 ) were efficiently synthesized using the Julia coupling reaction to connect between the P01031 and P13671 positions ( steroid numbering ) . An A - ring precursor was prepared from (-)- quinic acid as shown in the previous MART - 10 synthesis . The novel 14 - epi - CD - ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14 - epi - 25 - hydroxy Grundmann ' s ketone in good yield . The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14 - epi - MART - 10 and 14 - epi - MART - 11 in 40 % yield . To separate 14 - epi - MART - 10 and 14 - epi - MART - 11 , each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2alpha and 2beta were separated by high performance liquid chromatography . After the separation , the P06681 - stereochemistry of each ( 2alpha or 2beta ) was determined by 1H NMR ( nuclear magnetic resonance ) studies including NOE ( nuclear Overhauser effect ) experiments . The pivaloyl group was removed under basic conditions to obtain the target molecules of 14 - epi - MART - 10 and 14 - epi - MART - 11 , respectively . The P11473 ( vitamin D receptor ) - binding affinity , HL - 60 ( human promyelocytic leukemia ) cell differentiation activity , antiproliferative activity in PZ - HPV - 7 ( immortalized normal prostate ) cells and transactivation activity of the osteocalcin promoter in Q9UKB1 ( human osteoblast cell line ) cells ( serum - free conditions ) were investigated . In addition , the effects on bone mineral density ( BMD ) and the blood and urine calcium concentrations of ovariectomized ( OVX ) rats were examined . 14 - epi - MART - 10 has much greater antiproliferative and cell differentiation activities compared to 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage . The vitamin D receptor knockout ( P11473 - KO ) mouse presents with a skeletal phenotype typical for complete lack of genomic DB00136 effects . Our previous data from human colorectal tissue suggest that the steroid hormone and its receptor may have protective function against tumour progression . In order to investigate the relevance of the vitamin D system for pre - malignant site - directed changes in the colon , we characterized the amount and site - specific distribution of the P11473 along the large intestine in wild - type ( WT ) , heterozygote ( HT ) and KO mice . We also evaluated expression of proliferating cell nuclear antigen ( P12004 ) , of cyclin D1 and the levels of 8 - hydroxy - 2 '- deoxyguanosine ( 8 - OHdG ) , a marker of oxidative stress . In colon ascendens , proliferative cells were dispersed all along the crypt and expression levels of all three markers were high in WT mice . A decrease of P11473 expression did not affect expression significantly . In colon descendens , however , fewer proliferative cells were solely located in the lower third of the crypt , and an inverse relationship between P11473 reduction , P12004 positivity and cyclin D1 expression was found in HT and KO mice . In parallel to enhanced proliferation a highly significant increase of 8 - OHdG positivity occurred . Therefore , the sigmoid colon of P11473 - KO mice , fed on an appropriate lactose / calcium - enriched diet to alleviate impaired calcium homeostasis - related phenotypic changes , is an excellent model for investigating induction and prevention of pre - malignant changes in one of the hotspots for human colorectal cancer incidence .","Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .","Q15109 / RAGE - mediated autophagy promotes pancreatic tumorigenesis and bioenergetics through the P05231 - pSTAT3 pathway . Pancreatic ductal adenocarcinoma ( PDA ) , the fourth leading cause of cancer death in the United States , is a complex disease that arises in the setting of genetic alterations ( P01116 , P38398 , Q13485 , CDKN2A / p16 ( INK4a ) and P04637 ) , epigenetic perturbations ( MIR155 , acetylation and methylation ) and epicellular events ( diabetes and inflammation ) . We have demonstrated that the advanced glycation end product - specific receptor ( Q15109 , also called RAGE ) contributes to pancreatic tumorigenesis . Targeted ablation of Q15109 diminishes the amount of autophagic flux and attenuates the development of early pancreatic intraepithelial neoplasia ( PanIN ) lesions in a murine model of P01116 - drivien carcinogenesis . Autophagy ( programmed cell survival ) , a metabolic process of lysosome - mediated self - digestion , promotes pancreatic cancer growth . In pancreatic tumor cell lines , Q15109 - mediated autophagy promotes interleukin - 6 ( P05231 ) - induced phosphorylation of signal transducer and activator of transcription 3 ( pSTAT3 ) and mitochondrial localization of pSTAT3 . Enhanced mitochondrial pSTAT3 increases the pool of available DB00171 and increases cellular proliferation . Moreover , we observed a positive feedback loop between activation of autophagy and the P05231 - pSTAT3 pathway , perhaps different from the role of cytosolic nonphosphorylated P40763 , which has been reported to inhibit autophagy . These Q15109 - dependent changes were found during the earliest stages of pancreatic cancer development . These observations of inflammation and altered metabolism in PDA provide a pathological link to early precursor lesion development . Thus , Q15109 is an important inflammatory mediator that modulates crosstalk between prosurvival pathways , P05231 - pSTAT3 and autophagy , in PDA tumor cells , and contributes to early PanIN formation .","Nongenotropic , anti - apoptotic signaling of 1alpha , 25 ( OH ) 2 - vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes . Mediation by Src , phosphatidylinositol 3 - , and JNK kinases . Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors , we have explored the possibility that the vitamin D nuclear receptor ( P11473 ) might exhibit similar nongenotropic actions . We report that the conformationally flexible full P11473 agonist , 1alpha , 25 ( OH ) 2 - vitamin D3 ( DB00136 ) , and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 ( JN ) analog , also acting through the P11473 but with poor transcriptional activity , protected murine osteoblastic or osteocytic cells from apoptosis . This effect was reproduced in HeLa cells transiently transfected with either wild type P11473 or a mutant consisting of only the P11473 ligand binding domain . The P11473 ligand binding domain bound [ 3H ] DB00136 as effectively as wild type P11473 but did not induce vitamin D response element - mediated transcription . The anti - apoptotic effects of DB00136 and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors : Src kinase inhibitor 4 - amino - 5 -( 4 - methylphenyl )- 7 -( t - butyl ) pyrazolo [ 3 , 4 - d ] pyrimidine ( P50391 ) , phosphatidylinositol 3 kinase inhibitor Wortmannin , and the JNK kinase inhibitor SP600125 . However , inhibition of p38 with SB203580 or P29323 with either U0126 or a transfected dominant negative MEK did not interfere with these anti - apoptotic actions . Further , DB00136 induced rapid ( 5 min ) association of P11473 with Src kinase in OB - 6 cells . Finally , actinomycin D or cycloheximide prevented the anti - apoptotic effect of DB00136 , indicating that transcriptional events are also required . These findings suggest that nongenotropic modulation of kinase activity is also a general property of the P11473 and that ligands that activate nongenotropic signals , but lack transcriptional activity , display different biological profiles from the steroid hormone DB00136 .","Interactions between DB00136 and residues in the ligand - binding pocket of the vitamin D receptor : a correlated fragment molecular orbital study . To provide physicochemical insight into the role of each residue in the ligand - binding pocket ( P18428 ) of the vitamin D receptor ( P11473 ) , we evaluated the energies of the interactions between the P18428 residues and DB00136 by using an ab initio fragment molecular orbital ( FMO ) method at the Møller - Plesset second - order perturbation ( MP2 ) level . This FMO - MP2 method can be used to correctly evaluate both electrostatic and van der Waals dispersion interactions , and it affords these interaction energies separately . We deduced the nature of each interaction and determined the importance of all the P18428 residues involved in ligand recognition by the P11473 . We previously reported the results of alanine - scanning mutational analysis ( ASMA ) of all 34 non - alanine residues lining the P18428 of the human P11473 . The theoretical results in combination with the ASMA results enabled us to assign the role of each P18428 residue . We concluded that electrostatic interactions are the major determinant of the ligand - binding activity and ligand recognition specificity and that van der Waals interactions are important for protein folding and , in turn , for cofactor binding .","Nuclear factor of activated T cells ( NFAT ) as a molecular target for 1alpha , 25 - dihydroxyvitamin D3 - mediated effects . The molecular basis of the immunomodulatory properties of 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) remains elusive . We demonstrate here that DB00136 - mediated suppressive effects on the inducible expression of cytokine genes in human T cells may , in part , be due to diminished activity of the transcription factor NFAT . The vitamin D3 receptor ( P11473 ) and its heterodimeric partner retinoid X receptor alpha ( RXR alpha ) specifically bound to the distal NFAT site in the human P60568 promoter , and this binding was abolished by mutating unique regions in the NFAT oligonucleotide . In vitro inhibition of NFAT complex formation was noted when P11473 - RXR alpha heterodimers were added to DNA binding reactions containing nuclear extracts from activated B or T cells , whereas in vitro NFkappaB complex formation was not significantly influenced . Furthermore , DB00136 treatment of activated T cells resulted in decreased formation of NFAT complexes detected upon incubation of nuclear extracts from these cells with 32P - labeled probe . Transient expression of both P11473 and RXR alpha , but not of a single component , was capable of inhibiting expression of a NFAT - driven reporter gene in stimulated jurkat cells in a ligand - dependent manner . These results suggest that NFAT plays a crucial role in DB00136 - mediated immunosuppressive activity .","DB00091 up - regulates Krüppel - like factor - 4 ( O43474 ) in vascular smooth muscle cells and drives phenotypic modulation in vivo . DB00091 A ( Q13216 , calcineurin inhibitor ) has been shown to block both vascular smooth muscle cell ( VSMC ) proliferation in cell culture and vessel neointimal formation following injury in vivo . The purpose of this study was to determine molecular and pathological effects of Q13216 on VSMCs . Using real - time reverse transcription - polymerase chain reaction , Western blot analysis , and immunofluorescence microscopy , we show that Q13216 up - regulated the expression of Krüppel - like factor - 4 ( O43474 ) in VSMCs . O43474 plays a key role in regulating VSMC phenotypic modulation . O43474 antagonizes proliferation , facilitates migration , and down - regulates VSMC differentiation marker gene expression . We show that the VSMC differentiation marker genes smooth muscle alpha - actin ( P62736 ) , transgelin ( Q01995 ) , smoothelin ( P53814 ) , and myocardin ( Q8IZQ8 ) are all down - regulated by Q13216 in VSMC monoculture , whereas cyclin - dependent kinase inhibitor - 1A ( P38936 ) and matrix metalloproteinase - 3 ( P08254 ) are up - regulated . Q13216 did not affect the abundance of the VSMC microRNA ( MIR ) markers MIR143 and MIR145 . Administration of Q13216 to rat carotid artery in vivo resulted in acute and transient suppression of P62736 , Q01995 , P53814 , Q8IZQ8 , and smooth muscle myosin heavy chain ( P35749 ) mRNA levels . The tumor suppressor genes O43474 , p53 , and P38936 , however , were up - regulated , as well as P08254 , P14780 , and collagen - VIII . Q13216 - treated arteries showed remarkable remodeling , including breakdown of the internal elastic lamina and reorientation of VSMCs , as well as increased O43474 immunostaining in VSMCs and endothelial cells . Altogether , these data show that cyclosporin up - regulates O43474 expression and promotes phenotypic modulation of VSMCs .","The human peroxisome proliferator - activated receptor delta gene is a primary target of 1alpha , 25 - dihydroxyvitamin D3 and its nuclear receptor . Peroxisome proliferator - activated receptor ( Q07869 ) delta is the most widely expressed member of the Q07869 family of nuclear receptor fatty acid sensors . Real - time PCR analysis of breast and prostate cancer cell lines demonstrated that PPARdelta expression was increased 1 . 5 to 3 . 2 - fold after three hours stimulation with the natural vitamin D receptor ( P11473 ) agonist , 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . In silico analysis of the 20 kb of the human PPARdelta promoter revealed a Q93038 - type DB00136 response element approximately 350 bp upstream of the transcription start site , which was able to bind P11473 - retinoid X receptor ( RXR ) heterodimers and mediate a DB00136 - dependent upregulation of reporter gene activity . Chromatin immuno - precipitation assays demonstrated that a number of proteins representative for DB00136 - mediated gene activation , such as P11473 , RXR and RNA polymerase II , displayed a DB00136 - dependent association with a region of the proximal PPARdelta promoter that contained the putative Q93038 - type VDRE . This was also true for other proteins that are involved in or are the subject of chromatin modification , such as the histone acetyltransferase CBP and histone 4 , which displayed ligand - dependent association and acetylation , respectively . Finally , real - time PCR analysis demonstrated that DB00136 and the synthetic PPARdelta ligand L783483 show a cell and time - dependent interference in each other ' s effects on P11473 mRNA expression , so that their combined application shows complex effects on the induction of P11473 target genes , such as Q07973 . Taken together , we conclude that PPARdelta is a primary DB00136 - responding gene and that P11473 and PPARdelta signaling pathways are interconnected at the level of cross - regulation of their respective transcription factor mRNA levels .","Genetic susceptibility to aseptic loosening following total hip arthroplasty : a systematic review . Introduction Aseptic loosening is the most common cause of total hip arthroplasty ( DB00382 ) failure and revision surgery . Genetic polymorphisms could be determinant factors for implant loosening . Source of data We performed a comprehensive search of Medline , CINAHL , Googlescholar , Embase and Cochrane databases , using various combinations of the keyword terms ' aseptic loosening ' , ' gene ' , ' hip arthoplasty ' , ' genetics ' , ' loosening ' . Twelve studies detailing the genetic investigation of patients with aseptic loosening of a DB00382 were identified . Areas of agreement SNPs of GNAS1 , P01375 - 238 A allele , P01375 - α promoter ( - 308G → A ) transition , P05231 - 174 G allele , interleukin ( IL ) - 6 ( - 597 ) and ( - 572 ) , P03956 - promoting gene , C / C genotype for the P03956 , P50281 , P08253 , transforming growth factor - beta1 signal sequence ( 29T → C ) transitions , A / A genotype for the O00300 - 163 , and P11226 were overexpressed in patients with aseptic loosening and periprosthetic osteolysis . Areas of controversy Data from single centre studies do not allow one to compare the results of different studies . Conclusion Several gene pathways and genes contribute to the genetic susceptibility to aseptic loosening following DB00382 . Further studies will enhance the understanding of prosthesis failure , and may inform and direct pharmaceutical interventions . Growing points Further multi - centre prospective studies are necessary to confirm the general validity of the findings reported . Single - centre findings should be replicated in other centres and populations to open new avenues for pre - surgical genetic testing and to investigate immune response modulation in DB00382 . Areas timely for developing research Research in this field could lead to better understanding of mechanisms behind aseptic osteolysis , and improve the results of DB00382 .","A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor - mediated signal transduction . P14324 ( FPPS ) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways . Here we describe a novel role for this enzyme in fibroblast growth factor ( FGF ) - mediated signalling . We demonstrate the binding of FPPS to FGF receptors ( FGFRs ) using the yeast two - hybrid assay , pull - down assays and co - immunoprecipitation . The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with P09038 . Overexpression of FPPS inhibits P09038 - induced cell proliferation , accompanied by a failure of the P09038 - mediated induction of cyclins D1 and E . Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras , and temporally extends P09038 - stimulated activation of the Ras / P29323 ( extracellular - signal - regulated kinase ) cascade . These data suggest that , in addition to its role in isoprenoid biosynthesis , FPPS may function as a modulator of the cellular response to FGF treatment .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK26___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK99___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK99___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .","Hypoxia enhances P61073 expression in human microvascular endothelial cells and human melanoma cells . The influence of environmental factors ( cytokines , matrix components , serum factors and O ( 2 ) level ) on expression of receptors for angiogenic versus angiostatic CXC chemokines in human microvascular endothelial cells has not been extensively investigated . Our semi - quantitative RT - PCR analysis demonstrated that P01375 and P01579 repressed P61073 mRNA levels in immortalized human microvascular endothelial HMEC - 1 cells after 4 h , whereas only P01375 displayed inhibitory activity in primary human microvascular endothelial cells ( HMVEC ) . P61073 mRNA expression was not affected by P15692 , GM - P04141 , IL - 1beta or various basal membrane matrix components , but was significantly up - regulated after serum starvation and / or hypoxic treatment of the microvascular endothelial cells . The alternative P48061 receptor , P25106 / RDC1 , was also up - regulated by hypoxia in HMEC - 1 cells , although less consistently than P61073 . Furthermore , hypoxia and serum starvation were required for cell surface display of P61073 and P48061 induction of P29323 activation in HMEC - 1 cells . In contrast , P25025 and P49682 mRNA levels remained , respectively , low and undetectable under all the conditions tested , and surface expression of P25025 , P49682 and P25106 on the HMEC - 1 cells could not be demonstrated by FACS . In the human SK - P61006 - 5 melanoma cell line , P61073 mRNA expression was also increased under hypoxic conditions , whereas P25025 mRNA levels remained low and levels of P49682 and P25106 were undetectable . However , immunohistochemical staining of human metastatic melanoma sections demonstrated that P25025 , P49682 , P61073 and P25106 are expressed on tumor cells and , to a lesser extent , on endothelial cells . These results demonstrate that the tumor microenvironment regulates chemokine receptor expression through both cytokine and oxygen levels .","Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK55___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .","Q13507 - like protein and vitamin D receptor mediate DB00136 - induced Q5T124 influx in muscle cells . 1alpha , 25 - Dihydroxy - Vitamin - D3 ( 1alpha , 25 ( OH ) 2 - DB00169 ) stimulates in skeletal muscle cells Ca2 + release from inner stores and influx through both voltage - dependent and store - operated Ca2 + ( Q5T124 , CCE ) channels . We investigated the involvement of TRPC proteins and Vitamin D receptor ( P11473 ) in CCE induced by DB00136 in chick muscle cells . Two fragments were amplified by RT - PCR , exhibiting approximately 80 % sequence homology with mammalian Q13507 / 6 / 7 . Northern and Western blots employing a Q13507 - probe and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein of 140 kDa . Spectrofluorimetric measurements in Fura - 2 loaded cells showed reduced CCE and Mn2 + entry in response to either thapsigargin or DB00136 upon transfection with anti - Q13507 / 6 / 7 antisense oligodeoxynucleotides ( ODNs ) . Transfection with anti - P11473 antisense ODNs diminished DB00136 - dependent Ca2 + and Mn2 + influx . Co - immunoprecipitation of Q13507 - like protein and P11473 under non - denaturating conditions was observed . We propose that endogenous Q13507 - like proteins and the P11473 participate in the modulation of CCE by DB00136 in muscle cells , which could be mediated by an interaction between these proteins .","The genes of the coactivator Q15596 and the corepressor Q9Y618 are primary DB00136 targets . The complex of the receptor for the hormone 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1alpha , 25 ( OH )( 2 ) D ( 3 ) ) , Vitamin D ( 3 ) receptor ( P11473 ) , the retinoid X receptor ( RXR ) and a 1alpha , 25 ( OH )( 2 ) D ( 3 ) response element ( VDRE ) is considered to be the molecular switch for nuclear 1alpha , 25 ( OH )( 2 ) D ( 3 ) signaling . In the presence of ligand the P11473 - RXR complex interacts with coactivator ( DB01992 ) proteins that in turn contact components of the basal transcriptional machinery resulting in an enhanced transcription of 1alpha , 25 ( OH )( 2 ) D ( 3 ) target genes . In the absence of ligand the P11473 remains bound to the DNA and interacts with corepressor ( CoR ) proteins that are involved in gene silencing activity . We treated MCF - 7 breast cancer cells with 1alpha , 25 ( OH )( 2 ) D ( 3 ) for increasing amounts of time , extracted mRNA and screened by real - time PCR the members of the P52701 DB01992 and NCoR CoR families . We find that of the P52701 coactivators , only Q15596 was responsive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) . Similarly Q9Y618 but not NCoR1 gene transcription was sensitive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) treatment . In silico analysis revealed that both Q15596 and Q9Y618 promoters have substantial numbers of VDREs compared to the promoters of the other family members . These VDREs are formed by direct repeats of the core binding motif RGKTCA with a three nucleotide spacing ( Q93038 ) . We suggest that some or all of these Q93038 - type VDREs are responsible for the observed responsiveness of Q15596 and Q9Y618 to 1alpha , 25 ( OH )( 2 ) D ( 3 ) .","Expression and effect of fibroblast growth factor 9 in bovine theca cells . P31371 ( P31371 ) protein affects granulosa cell ( GC ) function but is mostly localized to theca cell ( TC ) and stromal cell of rat ovaries . The objectives of this study were to determine the 1 ) effects of P31371 on TC steroidogenesis , gene expression , and cell proliferation ; 2 ) mechanism of action of P31371 on TCs ; and 3 ) hormonal control of P31371 mRNA expression in TCs . Bovine ovaries were collected from a local slaughterhouse and TCs were collected from large ( 8 - 22 mm ) follicles and treated with various hormones in serum - free medium for 24 or 48 h . P31371 caused a dose - dependent inhibition ( P < 0 · 05 ) of LH - and LH + IGF1 - induced androstenedione and progesterone production . Also , P31371 inhibited ( P < 0 · 05 ) LH + IGF1 - induced expression of P22888 , P05108 , and P05093 mRNA ( via real - time RT - PCR ) in TCs . P31371 had no effect ( P > 0 · 10 ) on STAR mRNA abundance . Furthermore , P31371 inhibited dibutyryl DB02527 - induced progesterone and androstenedione production in LH + IGF1 - treated TCs . By contrast , P31371 increased ( P < 0 · 05 ) the number of bovine TCs . Abundance of P31371 mRNA in GCs and TCs was several - fold greater ( P < 0 · 05 ) in small ( 1 - 5 mm ) vs large follicles . P01375 α and P41221 increased ( P < 0 · 05 ) abundance of P31371 mRNA in TCs . In summary , expression of P31371 mRNA in TCs is developmentally and hormonally regulated . P31371 may act as an autocrine regulator of ovarian function in cattle by slowing TC differentiation via inhibiting LH + IGF1 action via decreasing gonadotropin receptors and the DB02527 signaling cascade while stimulating proliferation of TCs .","Role of transient receptor potential P01024 in P01375 - enhanced calcium influx in human airway myocytes . Previous studies have suggested that the proinflammatory cytokine , P01375 , contributes to airway hyperresponsivness by altering airway smooth muscle ( P17405 ) Ca ( 2 +) responses to agonist stimulation . The present study examined the effects of P01375 on Ca ( 2 +) influx pathways in cultured human P17405 cells ( HASMCs ) . Proteins encoded by the transient receptor potential ( TRP ) gene family function as channels through which receptor - operated and store - operated Ca ( 2 +) entry ( SOCE ) occur . In the present study , the presence of P48995 , Q13507 , Q9UBN4 , Q9UL62 , and Q9Y210 mRNA and protein expression was confirmed in cultured HASMCs using RT - PCR and Western blot analysis . P01375 treatment significantly increased Q13507 mRNA and protein levels in HASMCs as well as SOCE . P01375 treatment also increased both the peak and plateau intracellular Ca ( 2 +) concentration responses in HASMCs elicited by acetylcholine and bradykinin . The effects of P01375 treatment on SOCE and agonist - induced intracellular Ca ( 2 +) concentration responses were attenuated using small interfering RNA transfection , which knocked down Q13507 expression . Thus , in inflammatory airway diseases , P01375 treatment may result in increased myocyte activation due to altered Ca ( 2 +) influx pathways . These results suggest that Q13507 may be an important therapeutic target in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease .","Orai proteins interact with TRPC channels and confer responsiveness to store depletion . The TRPC ( C - type transient receptor potential ) class of ion channels has been hypothesized to participate in store - operated Ca ( 2 +) entry ( SOCE ) . Recently , however , Q13586 and Orai1 proteins have been proposed to form SOCE channels . Whether TRPCs participate in SOCE that is dependent on or regulated by Orai has not been explored . Here we show that Orai1 physically interacts with the N and C termini of Q13507 and Q9Y210 , and that in cells overexpressing either Q13507 or Q9Y210 in a store - depletion insensitive manner , these TRPCs become sensitive to store depletion upon expression of an exogenous Orai . Thus , Orai - 1 , - 2 , and - 3 enhanced thapsigargin - induced calcium entry by 50 - 150 % in cells stably overexpressing either Q13507 or Q9Y210 . Orai1 expression had no significant effect on endogenous , thapsigargin - induced calcium entry in wild - type cells ( P29320 - 293 , COS1 ) , in P29320 cells expressing a thapsigargin - sensitive variant of Q13507 ( TRPC3a ) , or in P29320 cells overexpressing another membrane protein , P37288 . Single - channel cation currents present in membrane patches of Q13507 - overexpressing cells were suppressed by expression of Orai1 . We propose that Orai proteins by interacting with TRPCs act as regulatory subunits that confer Q13586 - mediated store depletion sensitivity to these channels .","P18075 blocks the cyclosporine - A - induced epithelial - to - mesenchymal transition in renal tubular epithelial cells . AIMS : The nephrotoxic side effects of cyclosporine A ( DB00091 ) are partly due to induction of the epithelial - to - mesenchymal transition ( EMT ) , possibly through upregulation of connective tissue growth factor ( P29279 ) . Bone morphogenetic protein ( P18075 ) has been reported to protect against and reverse renal injury via its renotropic and antifibrotic effects . We therefore designed a method to investigate the mechanism by which P18075 inhibits Q13216 - induced EMT in cultured human renal proximal tubular epithelial ( HK - 2 ) cells and whether P18075 can antagonize DB00091 - induced profibrogenic effects . METHODS : Cultured HK - 2 cells were treated with DB00091 or a combination of DB00091 and P18075 for 72 h . Morphological changes were assessed by phase - contrast microscopy . The expression of alpha - smooth muscle actin ( alpha - SMA ) , P12830 , collagen type I and P29279 was analyzed by immunofluorescence , RT - PCR , and Western blot . Additionally , the effect of P29279 silencing on DB00091 - mediated gene expression was assessed . RESULTS : DB00091 - induced EMT was associated with decreased expression of P12830 , increased expression of alpha - SMA , collagen type I and P29279 , and loss of epithelial morphology . P18075 inhibited these effects in a dose - dependent manner . Using siRNA , P29279 knock - down also attenuated EMT - associated phenotypic changes induced by DB00091 . CONCLUSION : These data suggest that P18075 can block DB00091 - induced EMT by downregulating the expression of P29279 , a downstream mediator of EMT .","An in vitro osteoclast - forming assay to measure myeloma cell - derived osteoclast - activating factors . Much of the morbidity and mortality associated with the plasma cell ( PC ) malignancy , multiple myeloma ( MM ) , is owing to the severe osteolytic bone disease seen in patients with this disease . Although the molecular mechanisms responsible for osteolysis remain to be fully elucidated , it is clear from numerous studies that it is owing , in part , to an increase in osteoclastic bone resorption . Several known osteoclast ( OC ) - activating factors ( OAFs ) are produced by myeloma PCs ( MPCs ) , or by stromal cells in response to MPCs and include interleukin - 1beta ( IL - 1beta ) ; tumor necrosis factor - alpha ( P01375 ) ; P05231 ; parathyroid hormone - related protein ; macrophage inflammatory protein - 1alpha ; and , most recently , the P01375 - ligand family member receptor activator of nuclear factor - kappaB ligand ( O14788 ) . The identification and significance of any one of these myeloma - derived OAFs is dependent on robust and reliable assays that measure the de novo formation and activation of OCs . A number of in vitro assay systems have been described that examine the requirements for normal OC formation and are easily adaptable for examining which MM - derived Q86UD1 and to what extent it is responsible for the bone loss observed in individuals with myeloma . This chapter describes one such in vitro model system .","P12004 D - 1 , interleukin - 6 , HER - 2 / neu , transforming growth factor receptor - II and prediction of relapse in women with early stage , hormone receptor - positive breast cancer treated with tamoxifen . We hypothesized that amplification or overexpression of HER - 2 ( c - erbB - 2 ) , the Ki - 67 antigen ( Mib1 ) , cyclin D - 1 ( CD1 ) , interleukin - 6 ( P05231 ) , or the transforming growth factor beta II receptor , ( TGFbetaRII ) , would predict relapse in women with early stage , estrogen ( ER ) and / or progesterone receptor ( PR ) positive breast cancer treated with tamoxifen . Conditional logistic regression models and a new novel analytic method - support vector machines ( SVM ) were used to assess the effect of multiple variables on treatment outcome . All patients had stage I - IIIa breast cancer ( AJCC version 5 ) . We paired 63 patients who were disease - free on or after tamoxifen with 63 patients who had relapsed ( total 126 ) ; both disease - free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence . These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM . In a multivariate analysis , larger tumor size , increasing extent of lymph node involvement , and poorer tumor grade were significant predictors of relapse . When HER - 2 or CD1 were added to the model both were borderline significant predictors of relapse . The SVM model , after including all of the clinical and marker variables in the 126 patients as a training set , correctly predicted relapse in 78 % of the 18 patient validation samples . In this trial , HER - 2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen . An SVM model that included all clinical and biologic variables correctly predicted relapse in > 75 % of patients .","Increased serum osteoprotegerin in patients with primary adrenal insufficiency receiving conventional hydrocortisone substitution . Patients treated for primary adrenal insufficiency ( P05121 ) are at risk of steroid over - replacement , which may affect their skeleton . The study was aimed to investigate the effect of steroid substitution on serum osteoprotegerin and receptor activator of nuclear factor kappa - beta ligand ( O14788 ) levels in relation to bone mineral density ( BMD ) in P05121 . Eighty patients ( mean age 47 . 2 ± 14 . 5 years , mean hydrocortisone dose 0 . 49 ± 0 . 14 mg / kg / day ) and 63 healthy subjects were included . Serum osteoprotegerin , O14788 , 25 - hydroxyvitamin D₃ , calcium , phosphate , alkaline phosphatase , intact parathormone , and dehydroepiandrosterone - sulfate levels were evaluated in patients and controls . BMD was assessed in affected subjects using dual - energy X - ray absorptiometry . Mean osteoprotegerin concentration in P05121 patients appeared significantly higher vs . controls ( p = 0 . 002 ) , while O14788 levels were similar ( p = 0 . 430 ) . Serum osteoprotegerin increased with age ( p < 0 . 001 ) , but showed no correlation with daily hydrocortisone dose . O00300 was negatively correlated with serum dehydroepiandrosterone - sulfate ( p = 0 . 008 ) and with BMD at the lumbar spine ( p < 0 . 001 ) and femoral neck ( p = 0 . 003 ) . O14788 correlated negatively with P05121 duration ( p = 0 . 029 ) and positively with daily hydrocortisone dose ( p = 0 . 018 ) . Lumbar spine osteoporosis and osteopenia were found in 12 and 31 patients , respectively , whereas in femoral neck : in 5 and 33 individuals . Patients with osteoporosis displayed higher osteoprotegerin levels , but after the age - adjustment the correlation was lost . In conclusion , increased osteoprotegerin in P05121 might reflect a compensatory response to enhanced bone resorption due to exogenous steroid excess and / or result from a deficit in adrenal androgens . O14788 levels remain within normal range on standard steroid replacement .","Polymorphisms in genes implicated in dopamine , serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis . BACKGROUND : Homovanillic acid ( HVA ) , 5 - hydroxyindoleacetic acid ( 5 - HIAA ) and 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) are the major monoamine metabolites in the central nervous system ( CNS ) . Their cerebrospinal fluid ( P04141 ) concentrations , reflecting the monoamine turnover rates in CNS , are partially under genetic influence and have been associated with schizophrenia . We have hypothesized that P04141 monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms ( SNPs ) in genes implicated in monoaminergic pathways and psychosis . METHODS : We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [ tryptophan hydroxylase 1 ( P17752 ) , Q8IWU9 , tyrosine hydroxylase ( TH ) , P20711 ( DDC ) , dopamine beta - hydroxylase ( P09172 ) , catechol - O - methyltransferase ( P21964 ) , monoamine oxidase A ( P21397 ) and P27338 ] and monoamine metabolite concentrations in P04141 in 74 patients with psychotic disorder . RESULTS : There were 42 nominally significant associations between SNPs and P04141 monoamine metabolite concentrations , which exceeded the expected number ( 20 ) of nominal associations given the total number of tests performed . The strongest association ( p = 0 . 0004 ) was found between P27338 rs5905512 , a SNP previously reported to be associated with schizophrenia in men , and MHPG concentrations in men with psychotic disorder . Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls . CONCLUSIONS : The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis .","Osteoclast progenitors from cats with and without tooth resorption respond differently to 1 , 25 - dihydroxyvitamin D and interleukin - 6 . Both vitamin D and inflammatory cytokines can stimulate osteoclast formation and activity . We studied the effect of DB00136 ( 1 , 25 ( OH )( 2 ) D ) , and interleukin - 6 ( P05231 ) , on the formation and activity of feline osteoclasts , using peripheral blood mononuclear cells ( PBMCs ) from cats with and without tooth resorption ( TR (+) and TR (-) ) as a source of osteoclast precursors . The formation of osteoclast - like cells ( defined as multinucleated , tartrate - resistant acid phosphatase - positive cells ) was assessed at 7 and 14 days . In the presence of P09603 and O14788 , with and without P05231 , more osteoclasts were formed from TR (-) PBMCs than from TR (+) PBMCs on plastic . More osteoclasts were formed from TR (+) PBMCs on bone slices in the presence of P09603 / O14788 with 1 , 25 ( OH )( 2 ) D . This opposite effect may be due to a higher expression of the vitamin D receptor ( P11473 ) in TR (+) osteoclasts and precursors on bone . Formation of resorption pits was analyzed and confirmed with scanning electron microscopy . In conclusion , we propose that TR (+) PBMCs when cultured on bone are sensitive to 1 , 25 ( OH )( 2 ) D , whereas the differentiation of TR (-) PMBCs on bone seem more sensitive to P05231 , suggesting that osteoclast precursors from cats with and without tooth resorption respond differently to osteoclast stimulating factors .","1 , 25 - Dihydroxycholecalciferol enhances butyrate - induced P38936 ( Waf1 / Cip1 ) expression . Butyrate , a short - chain fatty acid produced in the colon , as well as its prodrug tributyrin , reduce proliferation and increase differentiation of colon cancer cells . P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) are negative regulators of cell cycle and are thought to have a key function in the differentiation of various cell lines . We studied the effects of butyrate on differentiation , P11473 expression , as well as on P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) expression in human colon cancer cells ( Caco - 2 ) . Butyrate induced cell differentiation , which was further enhanced after addition of DB00136 . Synergistic effect of butyrate and dihydroxycholecalciferol in Caco - 2 cells was due to butyrate - induced overexpression of P11473 . While butyrate as well as dihydroxycholecalciferol increased P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) expression , in contrast combined exposure of butyrate and dihydroxycholecalciferol resulted in a synergistic amplification of P38936 ( Waf1 / Cip1 ) , but not of p27 ( Kip1 ) expression . These data imply that butyrate selectively increases P38936 ( Waf1 / Cip1 ) expression via upregulation of P11473 in Caco - 2 cells .","Inhibition by 1alpha , 25 - dihydroxyvitamin D3 of activin A - induced differentiation of murine erythroleukemic P12259 - 5 cells . DB00136 ( 1alpha , 25 -( OH ) 2D3 ) and other vitamin D3 ( VD3 ) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia ( P61006 ) cell proliferation and differentiation in a dose - dependent manner . 1alpha , 25 -( OH ) 2D3 inhibited differentiation more potently than proliferation by one order of magnitude . The VD3 analog study demonstrated either effect of VD3 on P61006 cells via vitamin D receptor ( P11473 ) , as evidenced from the close relationship with the reported affinities for P11473 . The effects of 1alpha , 25 -( OH ) 2D3 were preceded by the suppression of ornithine decarboxylase ( ODC ) activity , a rate - limiting enzyme in polyamine metabolism . Difluoromethylornithine ( DB06243 ) , an inhibitor of ODC , inhibited P61006 cell proliferation , which was reversed by the simultaneous addition of putrescine , a product of ODC , but did not affect differentiation . 1alpha , 25 -( OH ) 2D3 inhibited cell differentiation during the phenotype - expression stage as reflected by the inhibition of beta - globin gene expression , while it inhibited proliferation in the commitment stage . Furthermore , it seems unlikely that the different effects of VD3 on proliferation and differentiation may be a result of upregulation of P11473 or nongenomic action . In summary , it was suggested that 1alpha , 25 -( OH ) 2D3 inhibited Activin A - induced P61006 cell proliferation and differentiation by distinct mechanisms and inhibited the proliferation by inhibiting ODC activity . We demonstrated the presence of 1alpha , 25 -( OH ) 2D3 action on leukemic cells at physiological concentration , which was distinct from the pharmacological effect of VD3 reported thus far .","Nuclear translocation of Q02750 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor . Q02750 phosphorylates P27361 / 2 and regulates T cell generation , differentiation , and function . Q02750 has recently been shown to translocate to the nucleus . Its nuclear function is largely unknown . By studying human P01730 T cells , we demonstrate that a low level of Q02750 is present in the nucleus of P01730 T cells under basal conditions . T cell activation further increases the nuclear translocation of Q02750 . Q02750 interacts with the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptor ( Q9Y618 ) . Q02750 reduces the nuclear level of Q9Y618 in an activation - dependent manner . Q02750 is recruited to the promoter of c - Fos upon TCR stimulation . Conversely , Q9Y618 is bound to the c - Fos promoter under basal conditions and is removed upon TCR stimulation . We examined the role of Q9Y618 in regulation of T cell function . Small interfering RNA - mediated knockdown of Q9Y618 results in a biphasic effect on cytokine production . The production of the cytokines P60568 , P05112 , P22301 , and IFN - γ increases in the early phase ( 8 h ) and then decreases in the late phase ( 48 h ) . The late - phase decrease is associated with inhibition of T cell proliferation . The late - phase inhibition of T cell activation is , in part , mediated by P22301 that is produced in the early phase and , in part , by β - catenin signaling . Thus , we have identified a novel nuclear function of Q02750 . Q02750 triggers a complex pattern of early T cell activation , followed by a late inhibition through its interaction with Q9Y618 . This biphasic dual effect most likely reflects a homeostatic regulation of T cell function by Q02750 .","P12259 Q506 mutation and the low prevalence of cardiovascular disease in Canadian Inuit . BACKGROUND : The Keewatin Inuit have a very low age - adjusted mortality rate from vascular diseases compared to the general population of Canada . Interethnic differences in both genetic and lifestyle factors have been offered as explanations for this observation . We previously found that compared to white subjects , the Inuit had a significantly increased prevalence of 4 candidate alleles for atherosclerosis - related phenotypes , namely AGT T235 , P12104 Q92917 , PONI R192 , and P02649 E4 , and a significantly decreased prevalence of 2 candidate alleles for atherosclerosis - related phenotypes , namely P12821 D and P42898 677T . METHODS : We tested the hypothesis that 165 Canadian Inuit would have a significantly different frequency of the thrombosis - associated P12259 Q506 allele compared with reference controls . RESULTS : We found a complete absence of P12259 Q506 in 165 Inuit , which was significantly different from the frequency of 3 . 92 % observed in regional control White subjects . CONCLUSIONS : The aggregate of results from our studies in Inuit to date suggests that the beneficial influence of the low prevalence of any or all of the P12821 D , P42898 677T and P12259 Q506 outweighs the deleterious influence of the high prevalence of any or all of the other disease - associated alleles . However , it remains possible that other genetic and / or environmental factors determine the low susceptibility to vascular disease in the Inuit .","Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK30___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK30___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .","Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate - induced colitis . The active form of vitamin D [ DB00136 , 1 , 25 ( OH ) 2D3 ] and the vitamin D receptor ( P11473 ) regulate susceptibility to experimental colitis . The effect of the bacterial microflora on the susceptibility of C57BL / 6 mice to dextran sodium sulfate - induced colitis was determined . Mice that can not produce 1 , 25 ( OH ) 2D3 [ Cyp27b1 ( Cyp ) knockout ( KO ) ] , P11473 KO as well as their wild - type littermates were used . Cyp KO and P11473 KO mice had more bacteria from the Bacteroidetes and Proteobacteria phyla and fewer bacteria from the Firmicutes and Deferribacteres phyla in the feces compared with wild - type . In particular , there were more beneficial bacteria , including the Lactobacillaceae and Lachnospiraceae families , in feces from Cyp KO and P11473 KO mice than in feces from wild - type . Helicobacteraceae family member numbers were elevated in Cyp KO compared with wild - type mice . Depletion of the gut bacterial flora using antibiotics protected mice from colitis . 1 , 25 ( OH ) 2D3 treatment ( 1 . 25 μg / 100 g diet ) of Cyp KO mice decreased colitis severity and reduced the numbers of Helicobacteraceae in the feces compared with the numbers in the feces of untreated Cyp KO mice . The mechanisms by which the dysbiosis occurs in P11473 KO and Cyp KO mice included lower expression of P12830 on gut epithelial and immune cells and fewer tolerogenic dendritic cells that resulted in more gut inflammation in P11473 and Cyp KO mice compared with wild - type mice . Increased host inflammation has been shown to provide pathogens with substrates to out - compete more beneficial bacterial species . Our data demonstrate that vitamin D regulates the gut microbiome and that 1 , 25 ( OH ) 2D3 or P11473 deficiency results in dysbiosis , leading to greater susceptibility to injury in the gut .","Microarray analysis revealed different gene expression patterns in HepG2 cells treated with low and high concentrations of the extracts of Anacardium occidentale shoots . In this study , the effects of low and high concentrations of the Anacardium occidentale shoot extracts on gene expression in liver HepG2 cells were investigated . From MTT assays , the concentration of the shoot extracts that maintained 50 % cell viability ( IC ( 50 ) ) was 1 . 7 mg / ml . Cell viability was kept above 90 % at both 0 . 4 mg / ml and 0 . 6 mg / ml of the extracts . The three concentrations were subsequently used for the gene expression analysis using Affymetrix Human Genome 1 . 0 S . T arrays . The microarray data were validated using real - time qRT - PCR . A total of 246 , 696 and 4503 genes were significantly regulated ( P < 0 . 01 ) by at least 1 . 5 - fold in response to 0 . 4 , 0 . 6 and 1 . 7 mg / ml of the extracts , respectively . Mutually regulated genes in response to the three concentrations included CDKN3 , LOC100289612 , P00374 , Q99986 , Q99741 , Q96GD4 and P78334 . Genes like Q07973 , P38398 , O14965 , P06493 , P24941 , P11802 and P06213 were significantly regulated at 0 . 6 mg / ml and 1 . 7 mg but not at 0 . 4 mg / ml . However , the expression of genes including O75473 , P17936 , P06400 , P14735 , P01130 , P55157 , P04114 , MTIX , P04179 and P08294 were exclusively regulated at the IC ( 50 ) concentration . In conclusion , low concentrations of the extracts were able to significantly regulate a sizable number of genes . The type of genes that were expressed was highly dependent on the concentration of the extracts used .","DB01373 as a mediator between erythropoietin and protein tyrosine phosphatase 1B . Erythropoietin ( Epo ) is crucial for promoting the survival , proliferation , and differentiation of mammalian erythroid progenitors . The central role played by tyrosine phosphorylation of erythropoietin receptor ( EpoR ) in Epo - cell activation has focused attention on protein tyrosine phosphatases ( PTPs ) as candidates implicated in the pathogenesis of the resistance to therapy with human recombinant Epo . Prototypic member of the PTP family is P18031 , which has been implicated in the regulation of EpoR signaling pathways . In previous reports we have shown that P18031 is reciprocally modulated by Epo in undifferentiated UT - 7 cell line . However , no information is available with respect to the modulation of this phosphatase in non - Epo depending cells or at late stages of erythroid differentiation . In order to investigate these issues we induced UT - 7 cells to differentiate and studied their P18031 expression pattern . Simultaneous observations were performed in TF - 1 cells which can be cultured either with GM - P04141 , P08700 or Epo . We found that Epo induced P18031 cleaveage in TF - 1 and differentiated UT - 7 cells . This pattern of P18031 modulation may be due to an increased Q13507 / Q9Y210 expression ratio which could explain the larger and sustained calcium response to Epo and calpain activation in Epo treated TF - 1 and differentiated UT - 7 cells .","Association of novel SNPs in the candidate genes affecting caprine milk fatty acids related to human health . In the present investigation , 618 milk samples of Sirohi breed of goat were collected , and analyzed for conjugated linoleic acid ( DB01211 , C18 : 2 ) and other fatty acids . The DB01211 in studied goat milk samples was 4 . 87 mg / g of milk fat and C18 : 2 cis - 9 , trans - 11 contributes 2 . 9 mg / g of milk fat and trans10 cis12 contributes 0 . 82 mg / g of milk fat . The saturated fatty acids in the milk accounted for 69 . 55 % and unsaturated fatty acid accounted for 28 . 50 % . The unsaturated fatty acid was constituted by monounsaturated fatty acid ( 24 . 57 % ) and polyunsaturated fatty acids ( 3 . 96 % . ) . The major contribution ( 45 . 56 % ) in total fatty acid was of C12 : 0 , C14 : 0 and C16 : 0 . C18 : 0 and short chain ones ( C4 : 0 , P13671 : 0 , Q99618 : 0 , and Q99622 : 0 ) have a neutral or cholesterol - decreasing effect . The DNA sequence analysis of the genes ( O75907 , SCAP , P37231 , OLR , P05413 and PRL ) in a random panel of 8 Sirohi goats revealed 38 SNPs across the targeted regions . Out of the studied SNPs ( 38 ) across these genes , 22 SNPs had significant effect on one or a group of fatty acids including DB01211 . The genotypes at these loci showed significant differences in the least square means of a particular fatty acid or a group of fatty acids including DB01211 and its isomers .","The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .","c - Fos protein as a target of anti - osteoclastogenic action of vitamin D , and synthesis of new analogs . Although active vitamin D drugs have been used for the treatment of osteoporosis , how the vitamin D receptor ( P11473 ) regulates bone cell function remains largely unknown . Using osteoprotegerin - deficient mice , which exhibit severe osteoporosis due to excessive receptor activator of NF - kappaB ligand / receptor activator of NF - kappaB ( O14788 / Q9Y6Q6 ) stimulation , we show herein that oral treatment of these mice with 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] inhibited bone resorption and prevented bone loss , suggesting that P11473 counters O14788 / Q9Y6Q6 signaling . In P09603 - dependent osteoclast precursor cells isolated from mouse bone marrow , DB00136 potently and dose - dependently inhibited their differentiation into multinucleate osteoclasts induced by O14788 . Among signaling molecules downstream of Q9Y6Q6 , DB00136 inhibited the induction of c - Fos protein after O14788 stimulation , and retroviral expression of c - Fos protein abrogated the suppressive effect of DB00136 on osteoclast development . By screening vitamin D analogs based on their c - Fos - suppressing activity , we identified a new analog , named DD281 , that inhibited bone resorption and prevented bone loss in ovariectomized mice , more potently than DB00136 , with similar levels of calcium absorption . Thus , c - Fos protein is an important target of the skeletal action of P11473 - based drugs , and DD281 is a bone - selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK29___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","DB00136 induces capacitative calcium entry involving a Q13507 protein in skeletal muscle and osteoblastic cells . This work describes the involvement of TRPC proteins in capacitative calcium entry ( CCE ) induced by 1alpha , 25 - dihydroxy - vitamin - D3 [ DB00136 ] in chick skeletal muscle and in rat osteoblast - like cells ( ROS 17 / 2 . 8 ) and the role of the vitamin D receptor ( P11473 ) in this non - genomic rapid response mediated by the hormone . We propose that an endogenous Q13507 protein mediates DB00136 modulation of CCE in these cells , which seems to implicate P11473 - Q13507 association and the participation of an INAD - like scaffold protein .","Stimulation of the peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy . Monocytes and macrophages play a key role in the progression of atheromatous changes . The peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) can limit macroangiopathy through the control of cytokine transcription . The objectives of this study were to examine the influence of Q07869 gamma and its agonist ( rosiglitazone ) on the TNFalpha , P05231 , P10145 and P22301 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion . TNFalpha , P05231 , P10145 , P22301 and Q07869 gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy ( real - time PCR [ Applied Biosystems ] ) . As indicators of endothelial lesion , concentration of thrombomodulin ( immunoassay [ Diagnostica Stago ] ) and amount of circulating blood endothelial cells ( immunofluorescence method with MoAb Q8N0X4 - HEC19 ) were determined . Following rosiglitazone therapy , a statistically significant downward tendency of TNFalpha ( p = 0 . 026 ) and P10145 ( p = 0 . 008 ) gene expression was noted . Before and following rosiglitazone treatment , Q07869 gamma , P05231 and P22301 gene expression was undetectable in studied monocytes in vivo . In conclusion , TNFalpha and P10145 play an important role in monocyte atherogenic activity . Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines ( Q07869 gamma - independent pathway ) .","Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats . P14324 ( FPPS ) , an essential enzyme in the mevalonate pathway , was reported to be upregulated in young spontaneously hypertensive rats ( SHR ) when compared with Wistar - Kyoto ( WKY ) rats , and this was accompanied by development of left ventricular hypertrophy . Five - week - old rats were daily gavaged with vehicle or an FPPS inhibitor ( alendronate , 1 or 10 mg / kg ) and blood pressures was monitored by the tail - cuff method every other week . Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio ( LVW / BW ) , hydroxyproline content , collagen deposition in the interstitia , and gene expression of atrial natriuretic peptide , B - type natriuretic peptide , and procollagen type I / III in the SHR left ventricle , all of which were significantly higher in SHRs than in WKY rats . Furthermore , long - term treatment with an FPPS inhibitor significantly reduced RhoA activation , P29323 phosphorylation , and TGF - beta1 expression in the SHR left ventricle , all of which were upregulated more in SHRs than in WKY rats . In conclusion , chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis , and the suppression of P27361 / 2 phosphorylation and TGF - beta1 expression with inhibition of RhoA activation may be an important mechanism .","Characterization of the antitumor activity of a polyantigenic immunomodulator ( P05121 ) : I -- Utilization of cimetidine and cyclosporine A . DB00501 ( CMT ) , cyclosporine A ( DB00091 ) , interleukin 2 ( IL 2 ) , were used to characterize the anticancerous effect of a polyantigenic immunodulator ( P05121 ) . P05121 consists of a mixture of inactivated bacteria and influenza virus in a peanut oil - arlacel A - aluminum monoesterate emulsion . Antitumoral activity was tested on Ehrlich ' s ascites tumor ( EAT ) implanted into Swiss - Webster ( allogeneic ) or C57BL / 6J ( syngeneic ) mice . P05121 antitumor activity was enhanced by CMT acting synergistically by reducing substantially the tumor growth and increasing the percentage of surviving mice , while DB00091 suppressed this activity . P05121 or its individual components were able to induce significant lymphocyte blastogenesis in mouse ( C57BL / 6J ) - spleen lymphocytes and P60568 enhanced considerably this lymphoproliferative response . The results suggest that P05121 acts at the level of cellular immunity .","Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .","[ Moclobemide ( ___MASK40___ ) , the first P21397 - inhibitor : really something new ? ] .","Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor - derived endothelial cells and tumor angiogenesis in vivo . Calcitriol ( DB00136 ) , the major active form of vitamin D , is antiproliferative in tumor cells and tumor - derived endothelial cells ( TDEC ) . These actions of calcitriol are mediated at least in part by vitamin D receptor ( P11473 ) , which is expressed in many tissues including endothelial cells . To investigate the role of P11473 in calcitriol effects on tumor vasculature , we established TRAMP - 2 tumors subcutaneously into either P11473 wild - type ( WT ) or knockout ( KO ) mice . Within 30 days post - inoculation , tumors in KO mice were larger than those in WT ( P < 0 . 001 ) . TDEC from WT expressed P11473 and were able to transactivate a reporter gene whereas TDEC from KO mice were not . Treatment with calcitriol resulted in growth inhibition in TDEC expressing P11473 . However , TDEC from KO mice were relatively resistant , suggesting that calcitriol - mediated growth inhibition on TDEC is P11473 - dependent . Further analysis of the TRAMP - P06681 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared with WT ( P < 0 . 001 ) . Contrast - enhanced magnetic resonance imaging showed an increase in vascular volume of TRAMP tumors grown in P11473 KO mice compared with WT mice ( P < 0 . 001 ) and FITC - dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice . Using ELISA and Western blot analysis , there was an increase of hypoxia - inducible factor - 1alpha , vascular endothelial growth factor , angiopoietin 1 , and platelet - derived growth factor - BB levels observed in tumors from KO mice . These results indicate that calcitriol - mediated antiproliferative effects on TDEC are P11473 - dependent and loss of P11473 can lead to abnormal tumor angiogenesis ."],"string":"[\n \"( Pro ) renin promotes fibrosis gene expression in P29320 cells through a Nox4 - dependent mechanism . The ( pro ) renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this study , we report that human embryonic kidney cells ( P29320 ) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin - converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence ( lucigenin ) and electron spin resonance spectroscopy ( hydroxylamine radical transition ) . Also , both renin and prorenin increased Nox4 expression while Nox2 , p47 ( phox ) , and p67 ( phox ) remained unchanged . In an investigation of the effects of renin and prorenin on fibrosis genes , it appeared that both proteins stimulated transforming growth factor - β ( TGF - β ) , fibronectin , and plasminogen activator inhibitor type 1 ( P05121 ) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells . When the cells were transfected with a siRNA targeting the PRR , Nox4 expression was efficiently prevented as well as the increase in superoxide production , TGF - β , fibronectin , and P05121 . Finally , we demonstrated that transfection of the cells with a Nox4 - specific small interfering ( si ) RNA also prevented fibrosis gene expression following treatment with renin or prorenin . The results demonstrate that renin and prorenin , through their specific membrane receptor and independently of angiotensin II , promote fibrosis gene expression via a Nox4 - dependent mechanism .\",\n \"20 - Hydroxycholecalciferol , product of vitamin D3 hydroxylation by P450scc , decreases NF - kappaB activity by increasing IkappaB alpha levels in human keratinocytes . The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc ( P05108 ) to form 20 - hydroxycholecalciferol , which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes . Since nuclear factor - kappaB ( NF - kappaB ) plays a pivotal role in the regulation of cell proliferation , differentiation and apoptosis , we examined the capability of 20 - hydroxycholecalciferol to modulate the activity of NF - kappaB , using DB00136 ( calcitriol ) as a positive control . 20 - hydroxycholecalciferol inhibits the activation of NFkappaB DNA binding activity as well as NF - kappaB - driven reporter gene activity in keratinocytes . Also , 20 - hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF - kappaB inhibitor protein , IkappaB alpha , in a time dependent manner , while no changes in total NF - kappaB - p65 mRNA or protein levels were observed . Another measure of NF - kappaB activity , p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20 - hydroxycholecalciferol treated keratinocytes . Increased IkappaB alpha was concomitantly observed in cytosolic extracts of 20 - hydroxycholecalciferol treated keratinocytes , as determined by immunoblotting and immunofluorescent staining . In keratinocytes lacking vitamin D receptor ( P11473 ) , 20 - hydroxycholecalciferol did not affect IkappaB alpha mRNA levels , indicating that it requires P11473 for its action on NF - kappaB activity . Comparison of the effects of calcitrol , hormonally active form of vitamin D3 , with 20 - hydrocholecalciferol show that both agents have a similar potency in inhibiting NF - kappaB . Since NF - kappaB is a major transcription factor for the induction of inflammatory mediators , our findings indicate that 20 - hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases .\",\n \"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK55___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .\",\n \"Genetics of type 2 diabetes mellitus and other specific types of diabetes ; its role in treatment modalities . Type 2 diabetes mellitus ( T2DM ) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence . The pathophysiological processes that lead to development of T2DM are still unclear , however impairment in insulin secretion and / or action is clearly indicated . Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility . Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder . Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young ( MODY ) . Previous studies indicated that variants in genes encoding the pancreatic β - cell K + DB00171 channel subunits Kir6 . 2 ( Q14654 ) and Q09428 ( Q09428 ) are associated with neonatal diabetes . Six different types of maturity onset diabetes of young ( MODY ) have been identified based on characteristic gene defect . The common Pro12Ala polymorphism in peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) gene was confirmed in several studies to be associated with type 2 diabetes as well . More recently , studies reported variants within a novel gene , Q9NQB0 , as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world . MODY patients respond better to sulphonylureas and metformin , while neonatal diabetes patients with genetic mutations can be changed from insulin to oral drugs . We hereby provide a comprehensive review on the role of genetics in type 2 diabetes mellitus .\",\n \"___MASK52___ block of cloned human T - type voltage - gated calcium channels . ___MASK52___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .\",\n \"Extended kindred with recessive late - onset Alzheimer disease maps to locus 8p22 - P38936 . 2 : a genome - wide linkage analysis . Late - onset Alzheimer disease ( LOAD ) is a complex genetic disorder . Although genes involved in early - onset forms were discovered more than a decade ago , LOAD research has only been able to point out small effect loci , with the exception of P02649 . We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region ( 24 sampled individuals , 12 of whom are affected ) , completing a genome - wide screen with an Affymetrix10 K single nucleotide polymorphism microarray . Genotyping results were evaluated under model - dependent ( dominant and recessive ) and model - free analysis . We obtained a maximum nonparametric linkage score of 3 . 24 ( P = 0 . 00006 ) on chromosome 8p22 - P38936 . 2 . The same genomic position also yielded the highest multipoint heterogeneity LOD ( HLOD ) under a recessive model ( HLOD = 3 . 04 ) . When we compared the results of the model - dependent analysis , a higher score was obtained in the recessive model ( 3 . 04 ) than in the dominant model ( 1 . 0 ) . This is a new locus identified in LOAD , in chromosome 8p22 - P38936 . 2 and encompassing several candidate genes , among them P10909 and P48454 that were excluded by sequencing . The finding of a recessive model of inheritance , consistent with the assumption of inbreeding as a morbidity factor in this population , supports the notion of a role of recessive genes in LOAD .\",\n \"Caveolae and caveolin - 1 are implicated in 1alpha , 25 ( OH ) 2 - vitamin D3 - dependent modulation of Src , MAPK cascades and P11473 localization in skeletal muscle cells . We previously reported that DB00136 induces non - transcriptional rapid responses through activation of MAPKs in C2C12 skeletal muscle cells . However , there is little information on the molecular mechanism underlying the initiation of DB00136 signaling through this pathway . Plasma membrane components have been involved in some non - genomic effects . In this work , we investigated the role of caveolae and caveolin - 1 ( cav - 1 ) in DB00136 - stimulation of c - Src and MAPKs . When proliferating cells were pretreated with methyl beta cyclodextrin ( MbetaCD ) , a caveolae disrupting agent , under conditions in which cell morphology is not affected and no signs of apoptosis are observed , DB00136 - dependent activation of P27361 / 2 , p38 MAPK and c - Src was suppressed . Similar results were obtained by siRNA technology whereby silencing of cav - 1 expression abolished activation of c - Src and MAPKs induced by the hormone . By confocal immunocytochemistry it was observed that cav - 1 colocalizes with c - Src in the periplasma membrane zone at basal conditions . Hormone treatment disrupted the colocalization of these proteins and redistributed them into cytoplasm and nucleus . Co - immunoprecipitation assays corroborated these observations . Changes in P11473 localization after DB00136 exposure were also investigated . Confocal microscopy images showed that the hormone induces P11473 translocation to the plasma membrane , and this effect is abolished by MbetaCD . Altogether , these data suggest that caveolae is involved upstream in c - Src - MAPKs activation by DB00136 and that P11473 and cav - 1 participate in the rapid signaling elicited by the hormone .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK58___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"A tumor - infiltrating lymphocyte from a melanoma metastasis with decreased expression of melanoma differentiation antigens recognizes MAGE - 12 . Twenty separate tumor infiltrating lymphocyte ( Q15399 ) bulk cultures and a tumor cell line were originated simultaneously from a fine needle aspiration biopsy of a metastasis in a patient with melanoma ( F001 ) previously immunized with the HLA - A * 0201 - associated gp100 : 209 - 217 ( 210 M ) peptide . None of the Q15399 recognized gp100 . However , 12 recognized autologous ( F001 - P61006 ) and allogeneic melanoma cells expressing the HLA haplotype A * 0201 , B * 0702 , Cw * 0702 . Further characterization of F001 - P61006 demonstrated loss of gp100 / PMel17 , severely decreased expression of other melanoma differentiation Ags and retained expression of tumor - specific Ags . Transfection of HLA class I alleles into B * 0702 / Cw * 0702 - negative melanoma cell lines identified HLA - Cw * 0702 as the restriction element for F001 - Q15399 . A cDNA library from F001 - P61006 was used to transfect IFN - alpha - stimulated 293 human embryonal kidney ( 293 - P29320 ) cells expressing HLA - Cw * 0702 . A 100 - gene pool was identified that induced recognition of 293 - P29320 cells by F001 - Q15399 . Subsequent cloning of the pool identified a cDNA sequence homologous , except for one amino acid ( aa 187 D --> A ) , to MAGE - 12 . Among 25 peptide sequences from MAGE - 12 with the HLA - Cw * 0702 binding motif , MAGE - 12 : 170 - 178 ( VRIGHLYIL ) induced P01579 release by F001 - Q15399 when pulsed on F001 - EBV - B cells at concentrations as low as 10 pg / ml . Peptide sequences from MAGE - 1 , 2 , 3 , 4a , and 6 aligned to MAGE - 12 : 170 - 178 were not recognized by F001 - Q15399 . In summary a Q15399 recognizing a MAGE protein was developed from an HLA - A * 0201 expressing tumor with strongly reduced expression of melanoma differentiation Ags . Persisting tumor - specific Ag expression maintained tumor immune competence suggesting that tumor - specific Ags / melanoma differentiation Ags may complement each other in the context of melanoma Ag - specific vaccination .\",\n \"___MASK69___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK69___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Chemical synthesis and in vitro biological evaluation of a phosphorylated bisubstrate inhibitor of type 3 17beta - hydroxysteroid dehydrogenase . Type 3 17beta - hydroxysteroid dehydrogenase ( 17beta - HSD ) catalyzes the last step in the biosynthesis of the potent androgen testosterone ( T ) by selectively reducing the C17 ketone of 4 - androstene - 3 , 17 - dione ( delta4 - dione ) , with NADPH as cofactor . This enzyme is thus an interesting therapeutic target for androgen - sensitive diseases . Using an efficient convergent chemical approach we synthesized a phosphorylated version of the best delta4 - dione / adenosine hybrid inhibitor of type 3 17beta - HSD previously reported . An appropriately protected P06681 ' phosphorylated adenosine was first prepared and linked by esterification to the steroid delta4 - dione bearing an alkyl spacer . After three deprotection steps , the phosphorylated bisubstrate inhibitor was obtained . The inhibitory potency of this compound was evaluated on homogenated P29320 - 293 cells overexpressing type 3 17beta - HSD and compared to the best non - phosphorylated bisubstrate inhibitor . Unexpectedly , the phosphorylated derivative was slightly less potent than the non - phosphorylated bisubstrate inhibitor of type 3 17beta - HSD . Two hypotheses are discussed to explain this result : 1 ) the phosphorylated adenosine moiety does not interact optimally with the cofactor - binding site and 2 ) the bisubstrate inhibitors , phosphorylated or not , interact only with the substrate - binding site of type 3 17beta - HSD .\",\n \"The anti - proliferative effects of DB00136 on breast and prostate cancer cells are associated with induction of P38398 gene expression . The anti - proliferative action of the seco - steroid hormone 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] extends to some , but not all breast and prostate cancer cell lines . By elucidating the molecular mechanisms mediating the sensitivity of these cells , we can identify critical target genes regulated directly or indirectly by DB00136 and pathways potentially disrupted during transformation . In this study , we demonstrated the induction of expression of P38398 mRNA and protein as well as transcriptional activation from the P38398 - promoter by DB00136 in the sensitive breast cancer cell line MCF - 7 . This was not observed in the DB00136 - resistant breast cancer cell line MDA - MB - 436 . The induction of P38398 mRNA was blocked by cyclohexamide . This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor ( P11473 ) . Inhibition of P11473 protein levels by stable transformation of the anti - sense P11473 in MCF - 7 reduced the sensitivity of MCF - 7 to DB00136 by 50 - fold . In addition , the induction of P38398 protein and transcriptional activation of a P38398 promoter - luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of P11473 levels . Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti - proliferative effects of 1alpha , 25 ( OH ) 2D3 was strongly associated with an ability to modulate P38398 protein . Furthermore , the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to DB00136 and their ability to modulate P38398 expression . Taken together , our data support a model whereby the anti - proliferative effects of DB00136 are mediated , in part , by the induction of P38398 gene expression via transcriptional activation by factors induced by the P11473 and that this pathway is disrupted during the development of prostate and breast cancers .\",\n \"Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levels . It is well - known that baseline levels of P02741 ( CRP ) are an independent cardiovascular risk factor . We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system . We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes ( Q9HC29 , P51617 , Q9NWZ3 , P18428 , O95711 , O15553 , O60603 , O00206 and P19838 ) in relation to CRP levels . Seven hundred and seventeen subjects from the Women ' s Health Study population were studied : 359 and 358 samples with extremely low ( < 0 . 2 mg / liter ) and high ( > 5 mg / liter ) CRP levels , respectively . SNPs were identified from publicly available resequencing data , using a minor allele frequency threshold of > 5 % and a linkage disequilibrium ( LD ) - based strategy ( r ( 2 ) > 0 . 8 ) to select 63 LD - independent markers . One non - synonymous SNP in O00206 and two non - synonymous SNPs in Q9HC29 , previously associated with atherosclerosis and Crohn ' s disease , respectively , were also studied . Univariate , haplotype and gene - gene interaction analyses all indicated no significant association with CRP levels . Although this work excludes a significant association of common SNPs in these nine genes with CRP levels , it is possible that rarer alleles in these genes , or variation in other innate immunity genes , could be associated with variation in CRP .\",\n \"Effect of the IkBα mutant gene delivery to DB05914 on rat chronic pancreatitis . This study aimed to investigate the effect of inhibitors of the NF - kΒ alpha mutant gene ( IkBaM ) delivery to mensenchymal stem cells ( MSCs ) on rat chronic pancreatitis ( CP ) . A total of 120 Sprague - Dawley rats were randomly divided into 6 groups of 20 : Group A was injected with sterile saline solution , Group B was injected with allogenic MSCs , Group C1 was injected with allogenic IkBαM - MSCs cultured in vitro 4 h before CP modeling , Group P06681 was injected with allogenic IkBαM - MSCs cultured in vitro during CP modeling , Group P01024 was cultured with allogenic IkBαM - MSCs cultured in vitro 4 h after CP modeling , and Group D was injected with rAAV2 - MSCs . Cytokine levels of P05362 , P29279 , IL - 1 , P05231 , P10145 , P01375 - α , P01033 , P16035 , P22301 , FN , P03956 , P08253 , P08254 , and P14780 were examined . The results indicated that allogenic IκBαM - MSCs could reduce pro - inflammatory cytokine levels and increase anti - inflammatory cytokine levels in CP . The allogenic IkBαM - MSCs reduced the activation and promoted the apoptosis of pancreatic stellate cells in the rat model of CP . IkBαM - MSCs influenced the proliferation and apoptosis of pancreatic stellate cells by regulating the activation of the Q07869 , MAPK , P42345 , TGF - β , NOD - like receptor , Notch , WNT , TGF - β1 - SMAD - 2 / 3 , and P04637 signal transduction pathways .\",\n \"Synthesis and biological activities of 14 - epi - MART - 10 and 14 - epi - MART - 11 : implications for cancer and osteoporosis treatment . The 14 - epimer of MART - 10 , namely 14 - epi - MART - 10 ( 14 - epi - 2alpha -( 3 - hydroxypropyl )- 1alpha , 25 - dihydroxy - 19 - norvitamin D3 ) and its 2 - epimeric analog ( 14 - epi - MART - 11 ) were efficiently synthesized using the Julia coupling reaction to connect between the P01031 and P13671 positions ( steroid numbering ) . An A - ring precursor was prepared from (-)- quinic acid as shown in the previous MART - 10 synthesis . The novel 14 - epi - CD - ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14 - epi - 25 - hydroxy Grundmann ' s ketone in good yield . The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14 - epi - MART - 10 and 14 - epi - MART - 11 in 40 % yield . To separate 14 - epi - MART - 10 and 14 - epi - MART - 11 , each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2alpha and 2beta were separated by high performance liquid chromatography . After the separation , the P06681 - stereochemistry of each ( 2alpha or 2beta ) was determined by 1H NMR ( nuclear magnetic resonance ) studies including NOE ( nuclear Overhauser effect ) experiments . The pivaloyl group was removed under basic conditions to obtain the target molecules of 14 - epi - MART - 10 and 14 - epi - MART - 11 , respectively . The P11473 ( vitamin D receptor ) - binding affinity , HL - 60 ( human promyelocytic leukemia ) cell differentiation activity , antiproliferative activity in PZ - HPV - 7 ( immortalized normal prostate ) cells and transactivation activity of the osteocalcin promoter in Q9UKB1 ( human osteoblast cell line ) cells ( serum - free conditions ) were investigated . In addition , the effects on bone mineral density ( BMD ) and the blood and urine calcium concentrations of ovariectomized ( OVX ) rats were examined . 14 - epi - MART - 10 has much greater antiproliferative and cell differentiation activities compared to 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage . The vitamin D receptor knockout ( P11473 - KO ) mouse presents with a skeletal phenotype typical for complete lack of genomic DB00136 effects . Our previous data from human colorectal tissue suggest that the steroid hormone and its receptor may have protective function against tumour progression . In order to investigate the relevance of the vitamin D system for pre - malignant site - directed changes in the colon , we characterized the amount and site - specific distribution of the P11473 along the large intestine in wild - type ( WT ) , heterozygote ( HT ) and KO mice . We also evaluated expression of proliferating cell nuclear antigen ( P12004 ) , of cyclin D1 and the levels of 8 - hydroxy - 2 '- deoxyguanosine ( 8 - OHdG ) , a marker of oxidative stress . In colon ascendens , proliferative cells were dispersed all along the crypt and expression levels of all three markers were high in WT mice . A decrease of P11473 expression did not affect expression significantly . In colon descendens , however , fewer proliferative cells were solely located in the lower third of the crypt , and an inverse relationship between P11473 reduction , P12004 positivity and cyclin D1 expression was found in HT and KO mice . In parallel to enhanced proliferation a highly significant increase of 8 - OHdG positivity occurred . Therefore , the sigmoid colon of P11473 - KO mice , fed on an appropriate lactose / calcium - enriched diet to alleviate impaired calcium homeostasis - related phenotypic changes , is an excellent model for investigating induction and prevention of pre - malignant changes in one of the hotspots for human colorectal cancer incidence .\",\n \"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .\",\n \"Q15109 / RAGE - mediated autophagy promotes pancreatic tumorigenesis and bioenergetics through the P05231 - pSTAT3 pathway . Pancreatic ductal adenocarcinoma ( PDA ) , the fourth leading cause of cancer death in the United States , is a complex disease that arises in the setting of genetic alterations ( P01116 , P38398 , Q13485 , CDKN2A / p16 ( INK4a ) and P04637 ) , epigenetic perturbations ( MIR155 , acetylation and methylation ) and epicellular events ( diabetes and inflammation ) . We have demonstrated that the advanced glycation end product - specific receptor ( Q15109 , also called RAGE ) contributes to pancreatic tumorigenesis . Targeted ablation of Q15109 diminishes the amount of autophagic flux and attenuates the development of early pancreatic intraepithelial neoplasia ( PanIN ) lesions in a murine model of P01116 - drivien carcinogenesis . Autophagy ( programmed cell survival ) , a metabolic process of lysosome - mediated self - digestion , promotes pancreatic cancer growth . In pancreatic tumor cell lines , Q15109 - mediated autophagy promotes interleukin - 6 ( P05231 ) - induced phosphorylation of signal transducer and activator of transcription 3 ( pSTAT3 ) and mitochondrial localization of pSTAT3 . Enhanced mitochondrial pSTAT3 increases the pool of available DB00171 and increases cellular proliferation . Moreover , we observed a positive feedback loop between activation of autophagy and the P05231 - pSTAT3 pathway , perhaps different from the role of cytosolic nonphosphorylated P40763 , which has been reported to inhibit autophagy . These Q15109 - dependent changes were found during the earliest stages of pancreatic cancer development . These observations of inflammation and altered metabolism in PDA provide a pathological link to early precursor lesion development . Thus , Q15109 is an important inflammatory mediator that modulates crosstalk between prosurvival pathways , P05231 - pSTAT3 and autophagy , in PDA tumor cells , and contributes to early PanIN formation .\",\n \"Nongenotropic , anti - apoptotic signaling of 1alpha , 25 ( OH ) 2 - vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes . Mediation by Src , phosphatidylinositol 3 - , and JNK kinases . Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors , we have explored the possibility that the vitamin D nuclear receptor ( P11473 ) might exhibit similar nongenotropic actions . We report that the conformationally flexible full P11473 agonist , 1alpha , 25 ( OH ) 2 - vitamin D3 ( DB00136 ) , and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 ( JN ) analog , also acting through the P11473 but with poor transcriptional activity , protected murine osteoblastic or osteocytic cells from apoptosis . This effect was reproduced in HeLa cells transiently transfected with either wild type P11473 or a mutant consisting of only the P11473 ligand binding domain . The P11473 ligand binding domain bound [ 3H ] DB00136 as effectively as wild type P11473 but did not induce vitamin D response element - mediated transcription . The anti - apoptotic effects of DB00136 and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors : Src kinase inhibitor 4 - amino - 5 -( 4 - methylphenyl )- 7 -( t - butyl ) pyrazolo [ 3 , 4 - d ] pyrimidine ( P50391 ) , phosphatidylinositol 3 kinase inhibitor Wortmannin , and the JNK kinase inhibitor SP600125 . However , inhibition of p38 with SB203580 or P29323 with either U0126 or a transfected dominant negative MEK did not interfere with these anti - apoptotic actions . Further , DB00136 induced rapid ( 5 min ) association of P11473 with Src kinase in OB - 6 cells . Finally , actinomycin D or cycloheximide prevented the anti - apoptotic effect of DB00136 , indicating that transcriptional events are also required . These findings suggest that nongenotropic modulation of kinase activity is also a general property of the P11473 and that ligands that activate nongenotropic signals , but lack transcriptional activity , display different biological profiles from the steroid hormone DB00136 .\",\n \"Interactions between DB00136 and residues in the ligand - binding pocket of the vitamin D receptor : a correlated fragment molecular orbital study . To provide physicochemical insight into the role of each residue in the ligand - binding pocket ( P18428 ) of the vitamin D receptor ( P11473 ) , we evaluated the energies of the interactions between the P18428 residues and DB00136 by using an ab initio fragment molecular orbital ( FMO ) method at the Møller - Plesset second - order perturbation ( MP2 ) level . This FMO - MP2 method can be used to correctly evaluate both electrostatic and van der Waals dispersion interactions , and it affords these interaction energies separately . We deduced the nature of each interaction and determined the importance of all the P18428 residues involved in ligand recognition by the P11473 . We previously reported the results of alanine - scanning mutational analysis ( ASMA ) of all 34 non - alanine residues lining the P18428 of the human P11473 . The theoretical results in combination with the ASMA results enabled us to assign the role of each P18428 residue . We concluded that electrostatic interactions are the major determinant of the ligand - binding activity and ligand recognition specificity and that van der Waals interactions are important for protein folding and , in turn , for cofactor binding .\",\n \"Nuclear factor of activated T cells ( NFAT ) as a molecular target for 1alpha , 25 - dihydroxyvitamin D3 - mediated effects . The molecular basis of the immunomodulatory properties of 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) remains elusive . We demonstrate here that DB00136 - mediated suppressive effects on the inducible expression of cytokine genes in human T cells may , in part , be due to diminished activity of the transcription factor NFAT . The vitamin D3 receptor ( P11473 ) and its heterodimeric partner retinoid X receptor alpha ( RXR alpha ) specifically bound to the distal NFAT site in the human P60568 promoter , and this binding was abolished by mutating unique regions in the NFAT oligonucleotide . In vitro inhibition of NFAT complex formation was noted when P11473 - RXR alpha heterodimers were added to DNA binding reactions containing nuclear extracts from activated B or T cells , whereas in vitro NFkappaB complex formation was not significantly influenced . Furthermore , DB00136 treatment of activated T cells resulted in decreased formation of NFAT complexes detected upon incubation of nuclear extracts from these cells with 32P - labeled probe . Transient expression of both P11473 and RXR alpha , but not of a single component , was capable of inhibiting expression of a NFAT - driven reporter gene in stimulated jurkat cells in a ligand - dependent manner . These results suggest that NFAT plays a crucial role in DB00136 - mediated immunosuppressive activity .\",\n \"DB00091 up - regulates Krüppel - like factor - 4 ( O43474 ) in vascular smooth muscle cells and drives phenotypic modulation in vivo . DB00091 A ( Q13216 , calcineurin inhibitor ) has been shown to block both vascular smooth muscle cell ( VSMC ) proliferation in cell culture and vessel neointimal formation following injury in vivo . The purpose of this study was to determine molecular and pathological effects of Q13216 on VSMCs . Using real - time reverse transcription - polymerase chain reaction , Western blot analysis , and immunofluorescence microscopy , we show that Q13216 up - regulated the expression of Krüppel - like factor - 4 ( O43474 ) in VSMCs . O43474 plays a key role in regulating VSMC phenotypic modulation . O43474 antagonizes proliferation , facilitates migration , and down - regulates VSMC differentiation marker gene expression . We show that the VSMC differentiation marker genes smooth muscle alpha - actin ( P62736 ) , transgelin ( Q01995 ) , smoothelin ( P53814 ) , and myocardin ( Q8IZQ8 ) are all down - regulated by Q13216 in VSMC monoculture , whereas cyclin - dependent kinase inhibitor - 1A ( P38936 ) and matrix metalloproteinase - 3 ( P08254 ) are up - regulated . Q13216 did not affect the abundance of the VSMC microRNA ( MIR ) markers MIR143 and MIR145 . Administration of Q13216 to rat carotid artery in vivo resulted in acute and transient suppression of P62736 , Q01995 , P53814 , Q8IZQ8 , and smooth muscle myosin heavy chain ( P35749 ) mRNA levels . The tumor suppressor genes O43474 , p53 , and P38936 , however , were up - regulated , as well as P08254 , P14780 , and collagen - VIII . Q13216 - treated arteries showed remarkable remodeling , including breakdown of the internal elastic lamina and reorientation of VSMCs , as well as increased O43474 immunostaining in VSMCs and endothelial cells . Altogether , these data show that cyclosporin up - regulates O43474 expression and promotes phenotypic modulation of VSMCs .\",\n \"The human peroxisome proliferator - activated receptor delta gene is a primary target of 1alpha , 25 - dihydroxyvitamin D3 and its nuclear receptor . Peroxisome proliferator - activated receptor ( Q07869 ) delta is the most widely expressed member of the Q07869 family of nuclear receptor fatty acid sensors . Real - time PCR analysis of breast and prostate cancer cell lines demonstrated that PPARdelta expression was increased 1 . 5 to 3 . 2 - fold after three hours stimulation with the natural vitamin D receptor ( P11473 ) agonist , 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . In silico analysis of the 20 kb of the human PPARdelta promoter revealed a Q93038 - type DB00136 response element approximately 350 bp upstream of the transcription start site , which was able to bind P11473 - retinoid X receptor ( RXR ) heterodimers and mediate a DB00136 - dependent upregulation of reporter gene activity . Chromatin immuno - precipitation assays demonstrated that a number of proteins representative for DB00136 - mediated gene activation , such as P11473 , RXR and RNA polymerase II , displayed a DB00136 - dependent association with a region of the proximal PPARdelta promoter that contained the putative Q93038 - type VDRE . This was also true for other proteins that are involved in or are the subject of chromatin modification , such as the histone acetyltransferase CBP and histone 4 , which displayed ligand - dependent association and acetylation , respectively . Finally , real - time PCR analysis demonstrated that DB00136 and the synthetic PPARdelta ligand L783483 show a cell and time - dependent interference in each other ' s effects on P11473 mRNA expression , so that their combined application shows complex effects on the induction of P11473 target genes , such as Q07973 . Taken together , we conclude that PPARdelta is a primary DB00136 - responding gene and that P11473 and PPARdelta signaling pathways are interconnected at the level of cross - regulation of their respective transcription factor mRNA levels .\",\n \"Genetic susceptibility to aseptic loosening following total hip arthroplasty : a systematic review . Introduction Aseptic loosening is the most common cause of total hip arthroplasty ( DB00382 ) failure and revision surgery . Genetic polymorphisms could be determinant factors for implant loosening . Source of data We performed a comprehensive search of Medline , CINAHL , Googlescholar , Embase and Cochrane databases , using various combinations of the keyword terms ' aseptic loosening ' , ' gene ' , ' hip arthoplasty ' , ' genetics ' , ' loosening ' . Twelve studies detailing the genetic investigation of patients with aseptic loosening of a DB00382 were identified . Areas of agreement SNPs of GNAS1 , P01375 - 238 A allele , P01375 - α promoter ( - 308G → A ) transition , P05231 - 174 G allele , interleukin ( IL ) - 6 ( - 597 ) and ( - 572 ) , P03956 - promoting gene , C / C genotype for the P03956 , P50281 , P08253 , transforming growth factor - beta1 signal sequence ( 29T → C ) transitions , A / A genotype for the O00300 - 163 , and P11226 were overexpressed in patients with aseptic loosening and periprosthetic osteolysis . Areas of controversy Data from single centre studies do not allow one to compare the results of different studies . Conclusion Several gene pathways and genes contribute to the genetic susceptibility to aseptic loosening following DB00382 . Further studies will enhance the understanding of prosthesis failure , and may inform and direct pharmaceutical interventions . Growing points Further multi - centre prospective studies are necessary to confirm the general validity of the findings reported . Single - centre findings should be replicated in other centres and populations to open new avenues for pre - surgical genetic testing and to investigate immune response modulation in DB00382 . Areas timely for developing research Research in this field could lead to better understanding of mechanisms behind aseptic osteolysis , and improve the results of DB00382 .\",\n \"A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor - mediated signal transduction . P14324 ( FPPS ) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways . Here we describe a novel role for this enzyme in fibroblast growth factor ( FGF ) - mediated signalling . We demonstrate the binding of FPPS to FGF receptors ( FGFRs ) using the yeast two - hybrid assay , pull - down assays and co - immunoprecipitation . The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with P09038 . Overexpression of FPPS inhibits P09038 - induced cell proliferation , accompanied by a failure of the P09038 - mediated induction of cyclins D1 and E . Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras , and temporally extends P09038 - stimulated activation of the Ras / P29323 ( extracellular - signal - regulated kinase ) cascade . These data suggest that , in addition to its role in isoprenoid biosynthesis , FPPS may function as a modulator of the cellular response to FGF treatment .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK26___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK99___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK99___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .\",\n \"Hypoxia enhances P61073 expression in human microvascular endothelial cells and human melanoma cells . The influence of environmental factors ( cytokines , matrix components , serum factors and O ( 2 ) level ) on expression of receptors for angiogenic versus angiostatic CXC chemokines in human microvascular endothelial cells has not been extensively investigated . Our semi - quantitative RT - PCR analysis demonstrated that P01375 and P01579 repressed P61073 mRNA levels in immortalized human microvascular endothelial HMEC - 1 cells after 4 h , whereas only P01375 displayed inhibitory activity in primary human microvascular endothelial cells ( HMVEC ) . P61073 mRNA expression was not affected by P15692 , GM - P04141 , IL - 1beta or various basal membrane matrix components , but was significantly up - regulated after serum starvation and / or hypoxic treatment of the microvascular endothelial cells . The alternative P48061 receptor , P25106 / RDC1 , was also up - regulated by hypoxia in HMEC - 1 cells , although less consistently than P61073 . Furthermore , hypoxia and serum starvation were required for cell surface display of P61073 and P48061 induction of P29323 activation in HMEC - 1 cells . In contrast , P25025 and P49682 mRNA levels remained , respectively , low and undetectable under all the conditions tested , and surface expression of P25025 , P49682 and P25106 on the HMEC - 1 cells could not be demonstrated by FACS . In the human SK - P61006 - 5 melanoma cell line , P61073 mRNA expression was also increased under hypoxic conditions , whereas P25025 mRNA levels remained low and levels of P49682 and P25106 were undetectable . However , immunohistochemical staining of human metastatic melanoma sections demonstrated that P25025 , P49682 , P61073 and P25106 are expressed on tumor cells and , to a lesser extent , on endothelial cells . These results demonstrate that the tumor microenvironment regulates chemokine receptor expression through both cytokine and oxygen levels .\",\n \"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK55___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .\",\n \"Q13507 - like protein and vitamin D receptor mediate DB00136 - induced Q5T124 influx in muscle cells . 1alpha , 25 - Dihydroxy - Vitamin - D3 ( 1alpha , 25 ( OH ) 2 - DB00169 ) stimulates in skeletal muscle cells Ca2 + release from inner stores and influx through both voltage - dependent and store - operated Ca2 + ( Q5T124 , CCE ) channels . We investigated the involvement of TRPC proteins and Vitamin D receptor ( P11473 ) in CCE induced by DB00136 in chick muscle cells . Two fragments were amplified by RT - PCR , exhibiting approximately 80 % sequence homology with mammalian Q13507 / 6 / 7 . Northern and Western blots employing a Q13507 - probe and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein of 140 kDa . Spectrofluorimetric measurements in Fura - 2 loaded cells showed reduced CCE and Mn2 + entry in response to either thapsigargin or DB00136 upon transfection with anti - Q13507 / 6 / 7 antisense oligodeoxynucleotides ( ODNs ) . Transfection with anti - P11473 antisense ODNs diminished DB00136 - dependent Ca2 + and Mn2 + influx . Co - immunoprecipitation of Q13507 - like protein and P11473 under non - denaturating conditions was observed . We propose that endogenous Q13507 - like proteins and the P11473 participate in the modulation of CCE by DB00136 in muscle cells , which could be mediated by an interaction between these proteins .\",\n \"The genes of the coactivator Q15596 and the corepressor Q9Y618 are primary DB00136 targets . The complex of the receptor for the hormone 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1alpha , 25 ( OH )( 2 ) D ( 3 ) ) , Vitamin D ( 3 ) receptor ( P11473 ) , the retinoid X receptor ( RXR ) and a 1alpha , 25 ( OH )( 2 ) D ( 3 ) response element ( VDRE ) is considered to be the molecular switch for nuclear 1alpha , 25 ( OH )( 2 ) D ( 3 ) signaling . In the presence of ligand the P11473 - RXR complex interacts with coactivator ( DB01992 ) proteins that in turn contact components of the basal transcriptional machinery resulting in an enhanced transcription of 1alpha , 25 ( OH )( 2 ) D ( 3 ) target genes . In the absence of ligand the P11473 remains bound to the DNA and interacts with corepressor ( CoR ) proteins that are involved in gene silencing activity . We treated MCF - 7 breast cancer cells with 1alpha , 25 ( OH )( 2 ) D ( 3 ) for increasing amounts of time , extracted mRNA and screened by real - time PCR the members of the P52701 DB01992 and NCoR CoR families . We find that of the P52701 coactivators , only Q15596 was responsive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) . Similarly Q9Y618 but not NCoR1 gene transcription was sensitive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) treatment . In silico analysis revealed that both Q15596 and Q9Y618 promoters have substantial numbers of VDREs compared to the promoters of the other family members . These VDREs are formed by direct repeats of the core binding motif RGKTCA with a three nucleotide spacing ( Q93038 ) . We suggest that some or all of these Q93038 - type VDREs are responsible for the observed responsiveness of Q15596 and Q9Y618 to 1alpha , 25 ( OH )( 2 ) D ( 3 ) .\",\n \"Expression and effect of fibroblast growth factor 9 in bovine theca cells . P31371 ( P31371 ) protein affects granulosa cell ( GC ) function but is mostly localized to theca cell ( TC ) and stromal cell of rat ovaries . The objectives of this study were to determine the 1 ) effects of P31371 on TC steroidogenesis , gene expression , and cell proliferation ; 2 ) mechanism of action of P31371 on TCs ; and 3 ) hormonal control of P31371 mRNA expression in TCs . Bovine ovaries were collected from a local slaughterhouse and TCs were collected from large ( 8 - 22 mm ) follicles and treated with various hormones in serum - free medium for 24 or 48 h . P31371 caused a dose - dependent inhibition ( P < 0 · 05 ) of LH - and LH + IGF1 - induced androstenedione and progesterone production . Also , P31371 inhibited ( P < 0 · 05 ) LH + IGF1 - induced expression of P22888 , P05108 , and P05093 mRNA ( via real - time RT - PCR ) in TCs . P31371 had no effect ( P > 0 · 10 ) on STAR mRNA abundance . Furthermore , P31371 inhibited dibutyryl DB02527 - induced progesterone and androstenedione production in LH + IGF1 - treated TCs . By contrast , P31371 increased ( P < 0 · 05 ) the number of bovine TCs . Abundance of P31371 mRNA in GCs and TCs was several - fold greater ( P < 0 · 05 ) in small ( 1 - 5 mm ) vs large follicles . P01375 α and P41221 increased ( P < 0 · 05 ) abundance of P31371 mRNA in TCs . In summary , expression of P31371 mRNA in TCs is developmentally and hormonally regulated . P31371 may act as an autocrine regulator of ovarian function in cattle by slowing TC differentiation via inhibiting LH + IGF1 action via decreasing gonadotropin receptors and the DB02527 signaling cascade while stimulating proliferation of TCs .\",\n \"Role of transient receptor potential P01024 in P01375 - enhanced calcium influx in human airway myocytes . Previous studies have suggested that the proinflammatory cytokine , P01375 , contributes to airway hyperresponsivness by altering airway smooth muscle ( P17405 ) Ca ( 2 +) responses to agonist stimulation . The present study examined the effects of P01375 on Ca ( 2 +) influx pathways in cultured human P17405 cells ( HASMCs ) . Proteins encoded by the transient receptor potential ( TRP ) gene family function as channels through which receptor - operated and store - operated Ca ( 2 +) entry ( SOCE ) occur . In the present study , the presence of P48995 , Q13507 , Q9UBN4 , Q9UL62 , and Q9Y210 mRNA and protein expression was confirmed in cultured HASMCs using RT - PCR and Western blot analysis . P01375 treatment significantly increased Q13507 mRNA and protein levels in HASMCs as well as SOCE . P01375 treatment also increased both the peak and plateau intracellular Ca ( 2 +) concentration responses in HASMCs elicited by acetylcholine and bradykinin . The effects of P01375 treatment on SOCE and agonist - induced intracellular Ca ( 2 +) concentration responses were attenuated using small interfering RNA transfection , which knocked down Q13507 expression . Thus , in inflammatory airway diseases , P01375 treatment may result in increased myocyte activation due to altered Ca ( 2 +) influx pathways . These results suggest that Q13507 may be an important therapeutic target in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease .\",\n \"Orai proteins interact with TRPC channels and confer responsiveness to store depletion . The TRPC ( C - type transient receptor potential ) class of ion channels has been hypothesized to participate in store - operated Ca ( 2 +) entry ( SOCE ) . Recently , however , Q13586 and Orai1 proteins have been proposed to form SOCE channels . Whether TRPCs participate in SOCE that is dependent on or regulated by Orai has not been explored . Here we show that Orai1 physically interacts with the N and C termini of Q13507 and Q9Y210 , and that in cells overexpressing either Q13507 or Q9Y210 in a store - depletion insensitive manner , these TRPCs become sensitive to store depletion upon expression of an exogenous Orai . Thus , Orai - 1 , - 2 , and - 3 enhanced thapsigargin - induced calcium entry by 50 - 150 % in cells stably overexpressing either Q13507 or Q9Y210 . Orai1 expression had no significant effect on endogenous , thapsigargin - induced calcium entry in wild - type cells ( P29320 - 293 , COS1 ) , in P29320 cells expressing a thapsigargin - sensitive variant of Q13507 ( TRPC3a ) , or in P29320 cells overexpressing another membrane protein , P37288 . Single - channel cation currents present in membrane patches of Q13507 - overexpressing cells were suppressed by expression of Orai1 . We propose that Orai proteins by interacting with TRPCs act as regulatory subunits that confer Q13586 - mediated store depletion sensitivity to these channels .\",\n \"P18075 blocks the cyclosporine - A - induced epithelial - to - mesenchymal transition in renal tubular epithelial cells . AIMS : The nephrotoxic side effects of cyclosporine A ( DB00091 ) are partly due to induction of the epithelial - to - mesenchymal transition ( EMT ) , possibly through upregulation of connective tissue growth factor ( P29279 ) . Bone morphogenetic protein ( P18075 ) has been reported to protect against and reverse renal injury via its renotropic and antifibrotic effects . We therefore designed a method to investigate the mechanism by which P18075 inhibits Q13216 - induced EMT in cultured human renal proximal tubular epithelial ( HK - 2 ) cells and whether P18075 can antagonize DB00091 - induced profibrogenic effects . METHODS : Cultured HK - 2 cells were treated with DB00091 or a combination of DB00091 and P18075 for 72 h . Morphological changes were assessed by phase - contrast microscopy . The expression of alpha - smooth muscle actin ( alpha - SMA ) , P12830 , collagen type I and P29279 was analyzed by immunofluorescence , RT - PCR , and Western blot . Additionally , the effect of P29279 silencing on DB00091 - mediated gene expression was assessed . RESULTS : DB00091 - induced EMT was associated with decreased expression of P12830 , increased expression of alpha - SMA , collagen type I and P29279 , and loss of epithelial morphology . P18075 inhibited these effects in a dose - dependent manner . Using siRNA , P29279 knock - down also attenuated EMT - associated phenotypic changes induced by DB00091 . CONCLUSION : These data suggest that P18075 can block DB00091 - induced EMT by downregulating the expression of P29279 , a downstream mediator of EMT .\",\n \"An in vitro osteoclast - forming assay to measure myeloma cell - derived osteoclast - activating factors . Much of the morbidity and mortality associated with the plasma cell ( PC ) malignancy , multiple myeloma ( MM ) , is owing to the severe osteolytic bone disease seen in patients with this disease . Although the molecular mechanisms responsible for osteolysis remain to be fully elucidated , it is clear from numerous studies that it is owing , in part , to an increase in osteoclastic bone resorption . Several known osteoclast ( OC ) - activating factors ( OAFs ) are produced by myeloma PCs ( MPCs ) , or by stromal cells in response to MPCs and include interleukin - 1beta ( IL - 1beta ) ; tumor necrosis factor - alpha ( P01375 ) ; P05231 ; parathyroid hormone - related protein ; macrophage inflammatory protein - 1alpha ; and , most recently , the P01375 - ligand family member receptor activator of nuclear factor - kappaB ligand ( O14788 ) . The identification and significance of any one of these myeloma - derived OAFs is dependent on robust and reliable assays that measure the de novo formation and activation of OCs . A number of in vitro assay systems have been described that examine the requirements for normal OC formation and are easily adaptable for examining which MM - derived Q86UD1 and to what extent it is responsible for the bone loss observed in individuals with myeloma . This chapter describes one such in vitro model system .\",\n \"P12004 D - 1 , interleukin - 6 , HER - 2 / neu , transforming growth factor receptor - II and prediction of relapse in women with early stage , hormone receptor - positive breast cancer treated with tamoxifen . We hypothesized that amplification or overexpression of HER - 2 ( c - erbB - 2 ) , the Ki - 67 antigen ( Mib1 ) , cyclin D - 1 ( CD1 ) , interleukin - 6 ( P05231 ) , or the transforming growth factor beta II receptor , ( TGFbetaRII ) , would predict relapse in women with early stage , estrogen ( ER ) and / or progesterone receptor ( PR ) positive breast cancer treated with tamoxifen . Conditional logistic regression models and a new novel analytic method - support vector machines ( SVM ) were used to assess the effect of multiple variables on treatment outcome . All patients had stage I - IIIa breast cancer ( AJCC version 5 ) . We paired 63 patients who were disease - free on or after tamoxifen with 63 patients who had relapsed ( total 126 ) ; both disease - free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence . These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM . In a multivariate analysis , larger tumor size , increasing extent of lymph node involvement , and poorer tumor grade were significant predictors of relapse . When HER - 2 or CD1 were added to the model both were borderline significant predictors of relapse . The SVM model , after including all of the clinical and marker variables in the 126 patients as a training set , correctly predicted relapse in 78 % of the 18 patient validation samples . In this trial , HER - 2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen . An SVM model that included all clinical and biologic variables correctly predicted relapse in > 75 % of patients .\",\n \"Increased serum osteoprotegerin in patients with primary adrenal insufficiency receiving conventional hydrocortisone substitution . Patients treated for primary adrenal insufficiency ( P05121 ) are at risk of steroid over - replacement , which may affect their skeleton . The study was aimed to investigate the effect of steroid substitution on serum osteoprotegerin and receptor activator of nuclear factor kappa - beta ligand ( O14788 ) levels in relation to bone mineral density ( BMD ) in P05121 . Eighty patients ( mean age 47 . 2 ± 14 . 5 years , mean hydrocortisone dose 0 . 49 ± 0 . 14 mg / kg / day ) and 63 healthy subjects were included . Serum osteoprotegerin , O14788 , 25 - hydroxyvitamin D₃ , calcium , phosphate , alkaline phosphatase , intact parathormone , and dehydroepiandrosterone - sulfate levels were evaluated in patients and controls . BMD was assessed in affected subjects using dual - energy X - ray absorptiometry . Mean osteoprotegerin concentration in P05121 patients appeared significantly higher vs . controls ( p = 0 . 002 ) , while O14788 levels were similar ( p = 0 . 430 ) . Serum osteoprotegerin increased with age ( p < 0 . 001 ) , but showed no correlation with daily hydrocortisone dose . O00300 was negatively correlated with serum dehydroepiandrosterone - sulfate ( p = 0 . 008 ) and with BMD at the lumbar spine ( p < 0 . 001 ) and femoral neck ( p = 0 . 003 ) . O14788 correlated negatively with P05121 duration ( p = 0 . 029 ) and positively with daily hydrocortisone dose ( p = 0 . 018 ) . Lumbar spine osteoporosis and osteopenia were found in 12 and 31 patients , respectively , whereas in femoral neck : in 5 and 33 individuals . Patients with osteoporosis displayed higher osteoprotegerin levels , but after the age - adjustment the correlation was lost . In conclusion , increased osteoprotegerin in P05121 might reflect a compensatory response to enhanced bone resorption due to exogenous steroid excess and / or result from a deficit in adrenal androgens . O14788 levels remain within normal range on standard steroid replacement .\",\n \"Polymorphisms in genes implicated in dopamine , serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis . BACKGROUND : Homovanillic acid ( HVA ) , 5 - hydroxyindoleacetic acid ( 5 - HIAA ) and 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) are the major monoamine metabolites in the central nervous system ( CNS ) . Their cerebrospinal fluid ( P04141 ) concentrations , reflecting the monoamine turnover rates in CNS , are partially under genetic influence and have been associated with schizophrenia . We have hypothesized that P04141 monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms ( SNPs ) in genes implicated in monoaminergic pathways and psychosis . METHODS : We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [ tryptophan hydroxylase 1 ( P17752 ) , Q8IWU9 , tyrosine hydroxylase ( TH ) , P20711 ( DDC ) , dopamine beta - hydroxylase ( P09172 ) , catechol - O - methyltransferase ( P21964 ) , monoamine oxidase A ( P21397 ) and P27338 ] and monoamine metabolite concentrations in P04141 in 74 patients with psychotic disorder . RESULTS : There were 42 nominally significant associations between SNPs and P04141 monoamine metabolite concentrations , which exceeded the expected number ( 20 ) of nominal associations given the total number of tests performed . The strongest association ( p = 0 . 0004 ) was found between P27338 rs5905512 , a SNP previously reported to be associated with schizophrenia in men , and MHPG concentrations in men with psychotic disorder . Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls . CONCLUSIONS : The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis .\",\n \"Osteoclast progenitors from cats with and without tooth resorption respond differently to 1 , 25 - dihydroxyvitamin D and interleukin - 6 . Both vitamin D and inflammatory cytokines can stimulate osteoclast formation and activity . We studied the effect of DB00136 ( 1 , 25 ( OH )( 2 ) D ) , and interleukin - 6 ( P05231 ) , on the formation and activity of feline osteoclasts , using peripheral blood mononuclear cells ( PBMCs ) from cats with and without tooth resorption ( TR (+) and TR (-) ) as a source of osteoclast precursors . The formation of osteoclast - like cells ( defined as multinucleated , tartrate - resistant acid phosphatase - positive cells ) was assessed at 7 and 14 days . In the presence of P09603 and O14788 , with and without P05231 , more osteoclasts were formed from TR (-) PBMCs than from TR (+) PBMCs on plastic . More osteoclasts were formed from TR (+) PBMCs on bone slices in the presence of P09603 / O14788 with 1 , 25 ( OH )( 2 ) D . This opposite effect may be due to a higher expression of the vitamin D receptor ( P11473 ) in TR (+) osteoclasts and precursors on bone . Formation of resorption pits was analyzed and confirmed with scanning electron microscopy . In conclusion , we propose that TR (+) PBMCs when cultured on bone are sensitive to 1 , 25 ( OH )( 2 ) D , whereas the differentiation of TR (-) PMBCs on bone seem more sensitive to P05231 , suggesting that osteoclast precursors from cats with and without tooth resorption respond differently to osteoclast stimulating factors .\",\n \"1 , 25 - Dihydroxycholecalciferol enhances butyrate - induced P38936 ( Waf1 / Cip1 ) expression . Butyrate , a short - chain fatty acid produced in the colon , as well as its prodrug tributyrin , reduce proliferation and increase differentiation of colon cancer cells . P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) are negative regulators of cell cycle and are thought to have a key function in the differentiation of various cell lines . We studied the effects of butyrate on differentiation , P11473 expression , as well as on P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) expression in human colon cancer cells ( Caco - 2 ) . Butyrate induced cell differentiation , which was further enhanced after addition of DB00136 . Synergistic effect of butyrate and dihydroxycholecalciferol in Caco - 2 cells was due to butyrate - induced overexpression of P11473 . While butyrate as well as dihydroxycholecalciferol increased P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) expression , in contrast combined exposure of butyrate and dihydroxycholecalciferol resulted in a synergistic amplification of P38936 ( Waf1 / Cip1 ) , but not of p27 ( Kip1 ) expression . These data imply that butyrate selectively increases P38936 ( Waf1 / Cip1 ) expression via upregulation of P11473 in Caco - 2 cells .\",\n \"Inhibition by 1alpha , 25 - dihydroxyvitamin D3 of activin A - induced differentiation of murine erythroleukemic P12259 - 5 cells . DB00136 ( 1alpha , 25 -( OH ) 2D3 ) and other vitamin D3 ( VD3 ) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia ( P61006 ) cell proliferation and differentiation in a dose - dependent manner . 1alpha , 25 -( OH ) 2D3 inhibited differentiation more potently than proliferation by one order of magnitude . The VD3 analog study demonstrated either effect of VD3 on P61006 cells via vitamin D receptor ( P11473 ) , as evidenced from the close relationship with the reported affinities for P11473 . The effects of 1alpha , 25 -( OH ) 2D3 were preceded by the suppression of ornithine decarboxylase ( ODC ) activity , a rate - limiting enzyme in polyamine metabolism . Difluoromethylornithine ( DB06243 ) , an inhibitor of ODC , inhibited P61006 cell proliferation , which was reversed by the simultaneous addition of putrescine , a product of ODC , but did not affect differentiation . 1alpha , 25 -( OH ) 2D3 inhibited cell differentiation during the phenotype - expression stage as reflected by the inhibition of beta - globin gene expression , while it inhibited proliferation in the commitment stage . Furthermore , it seems unlikely that the different effects of VD3 on proliferation and differentiation may be a result of upregulation of P11473 or nongenomic action . In summary , it was suggested that 1alpha , 25 -( OH ) 2D3 inhibited Activin A - induced P61006 cell proliferation and differentiation by distinct mechanisms and inhibited the proliferation by inhibiting ODC activity . We demonstrated the presence of 1alpha , 25 -( OH ) 2D3 action on leukemic cells at physiological concentration , which was distinct from the pharmacological effect of VD3 reported thus far .\",\n \"Nuclear translocation of Q02750 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor . Q02750 phosphorylates P27361 / 2 and regulates T cell generation , differentiation , and function . Q02750 has recently been shown to translocate to the nucleus . Its nuclear function is largely unknown . By studying human P01730 T cells , we demonstrate that a low level of Q02750 is present in the nucleus of P01730 T cells under basal conditions . T cell activation further increases the nuclear translocation of Q02750 . Q02750 interacts with the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptor ( Q9Y618 ) . Q02750 reduces the nuclear level of Q9Y618 in an activation - dependent manner . Q02750 is recruited to the promoter of c - Fos upon TCR stimulation . Conversely , Q9Y618 is bound to the c - Fos promoter under basal conditions and is removed upon TCR stimulation . We examined the role of Q9Y618 in regulation of T cell function . Small interfering RNA - mediated knockdown of Q9Y618 results in a biphasic effect on cytokine production . The production of the cytokines P60568 , P05112 , P22301 , and IFN - γ increases in the early phase ( 8 h ) and then decreases in the late phase ( 48 h ) . The late - phase decrease is associated with inhibition of T cell proliferation . The late - phase inhibition of T cell activation is , in part , mediated by P22301 that is produced in the early phase and , in part , by β - catenin signaling . Thus , we have identified a novel nuclear function of Q02750 . Q02750 triggers a complex pattern of early T cell activation , followed by a late inhibition through its interaction with Q9Y618 . This biphasic dual effect most likely reflects a homeostatic regulation of T cell function by Q02750 .\",\n \"P12259 Q506 mutation and the low prevalence of cardiovascular disease in Canadian Inuit . BACKGROUND : The Keewatin Inuit have a very low age - adjusted mortality rate from vascular diseases compared to the general population of Canada . Interethnic differences in both genetic and lifestyle factors have been offered as explanations for this observation . We previously found that compared to white subjects , the Inuit had a significantly increased prevalence of 4 candidate alleles for atherosclerosis - related phenotypes , namely AGT T235 , P12104 Q92917 , PONI R192 , and P02649 E4 , and a significantly decreased prevalence of 2 candidate alleles for atherosclerosis - related phenotypes , namely P12821 D and P42898 677T . METHODS : We tested the hypothesis that 165 Canadian Inuit would have a significantly different frequency of the thrombosis - associated P12259 Q506 allele compared with reference controls . RESULTS : We found a complete absence of P12259 Q506 in 165 Inuit , which was significantly different from the frequency of 3 . 92 % observed in regional control White subjects . CONCLUSIONS : The aggregate of results from our studies in Inuit to date suggests that the beneficial influence of the low prevalence of any or all of the P12821 D , P42898 677T and P12259 Q506 outweighs the deleterious influence of the high prevalence of any or all of the other disease - associated alleles . However , it remains possible that other genetic and / or environmental factors determine the low susceptibility to vascular disease in the Inuit .\",\n \"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK30___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK30___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .\",\n \"Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate - induced colitis . The active form of vitamin D [ DB00136 , 1 , 25 ( OH ) 2D3 ] and the vitamin D receptor ( P11473 ) regulate susceptibility to experimental colitis . The effect of the bacterial microflora on the susceptibility of C57BL / 6 mice to dextran sodium sulfate - induced colitis was determined . Mice that can not produce 1 , 25 ( OH ) 2D3 [ Cyp27b1 ( Cyp ) knockout ( KO ) ] , P11473 KO as well as their wild - type littermates were used . Cyp KO and P11473 KO mice had more bacteria from the Bacteroidetes and Proteobacteria phyla and fewer bacteria from the Firmicutes and Deferribacteres phyla in the feces compared with wild - type . In particular , there were more beneficial bacteria , including the Lactobacillaceae and Lachnospiraceae families , in feces from Cyp KO and P11473 KO mice than in feces from wild - type . Helicobacteraceae family member numbers were elevated in Cyp KO compared with wild - type mice . Depletion of the gut bacterial flora using antibiotics protected mice from colitis . 1 , 25 ( OH ) 2D3 treatment ( 1 . 25 μg / 100 g diet ) of Cyp KO mice decreased colitis severity and reduced the numbers of Helicobacteraceae in the feces compared with the numbers in the feces of untreated Cyp KO mice . The mechanisms by which the dysbiosis occurs in P11473 KO and Cyp KO mice included lower expression of P12830 on gut epithelial and immune cells and fewer tolerogenic dendritic cells that resulted in more gut inflammation in P11473 and Cyp KO mice compared with wild - type mice . Increased host inflammation has been shown to provide pathogens with substrates to out - compete more beneficial bacterial species . Our data demonstrate that vitamin D regulates the gut microbiome and that 1 , 25 ( OH ) 2D3 or P11473 deficiency results in dysbiosis , leading to greater susceptibility to injury in the gut .\",\n \"Microarray analysis revealed different gene expression patterns in HepG2 cells treated with low and high concentrations of the extracts of Anacardium occidentale shoots . In this study , the effects of low and high concentrations of the Anacardium occidentale shoot extracts on gene expression in liver HepG2 cells were investigated . From MTT assays , the concentration of the shoot extracts that maintained 50 % cell viability ( IC ( 50 ) ) was 1 . 7 mg / ml . Cell viability was kept above 90 % at both 0 . 4 mg / ml and 0 . 6 mg / ml of the extracts . The three concentrations were subsequently used for the gene expression analysis using Affymetrix Human Genome 1 . 0 S . T arrays . The microarray data were validated using real - time qRT - PCR . A total of 246 , 696 and 4503 genes were significantly regulated ( P < 0 . 01 ) by at least 1 . 5 - fold in response to 0 . 4 , 0 . 6 and 1 . 7 mg / ml of the extracts , respectively . Mutually regulated genes in response to the three concentrations included CDKN3 , LOC100289612 , P00374 , Q99986 , Q99741 , Q96GD4 and P78334 . Genes like Q07973 , P38398 , O14965 , P06493 , P24941 , P11802 and P06213 were significantly regulated at 0 . 6 mg / ml and 1 . 7 mg but not at 0 . 4 mg / ml . However , the expression of genes including O75473 , P17936 , P06400 , P14735 , P01130 , P55157 , P04114 , MTIX , P04179 and P08294 were exclusively regulated at the IC ( 50 ) concentration . In conclusion , low concentrations of the extracts were able to significantly regulate a sizable number of genes . The type of genes that were expressed was highly dependent on the concentration of the extracts used .\",\n \"DB01373 as a mediator between erythropoietin and protein tyrosine phosphatase 1B . Erythropoietin ( Epo ) is crucial for promoting the survival , proliferation , and differentiation of mammalian erythroid progenitors . The central role played by tyrosine phosphorylation of erythropoietin receptor ( EpoR ) in Epo - cell activation has focused attention on protein tyrosine phosphatases ( PTPs ) as candidates implicated in the pathogenesis of the resistance to therapy with human recombinant Epo . Prototypic member of the PTP family is P18031 , which has been implicated in the regulation of EpoR signaling pathways . In previous reports we have shown that P18031 is reciprocally modulated by Epo in undifferentiated UT - 7 cell line . However , no information is available with respect to the modulation of this phosphatase in non - Epo depending cells or at late stages of erythroid differentiation . In order to investigate these issues we induced UT - 7 cells to differentiate and studied their P18031 expression pattern . Simultaneous observations were performed in TF - 1 cells which can be cultured either with GM - P04141 , P08700 or Epo . We found that Epo induced P18031 cleaveage in TF - 1 and differentiated UT - 7 cells . This pattern of P18031 modulation may be due to an increased Q13507 / Q9Y210 expression ratio which could explain the larger and sustained calcium response to Epo and calpain activation in Epo treated TF - 1 and differentiated UT - 7 cells .\",\n \"Association of novel SNPs in the candidate genes affecting caprine milk fatty acids related to human health . In the present investigation , 618 milk samples of Sirohi breed of goat were collected , and analyzed for conjugated linoleic acid ( DB01211 , C18 : 2 ) and other fatty acids . The DB01211 in studied goat milk samples was 4 . 87 mg / g of milk fat and C18 : 2 cis - 9 , trans - 11 contributes 2 . 9 mg / g of milk fat and trans10 cis12 contributes 0 . 82 mg / g of milk fat . The saturated fatty acids in the milk accounted for 69 . 55 % and unsaturated fatty acid accounted for 28 . 50 % . The unsaturated fatty acid was constituted by monounsaturated fatty acid ( 24 . 57 % ) and polyunsaturated fatty acids ( 3 . 96 % . ) . The major contribution ( 45 . 56 % ) in total fatty acid was of C12 : 0 , C14 : 0 and C16 : 0 . C18 : 0 and short chain ones ( C4 : 0 , P13671 : 0 , Q99618 : 0 , and Q99622 : 0 ) have a neutral or cholesterol - decreasing effect . The DNA sequence analysis of the genes ( O75907 , SCAP , P37231 , OLR , P05413 and PRL ) in a random panel of 8 Sirohi goats revealed 38 SNPs across the targeted regions . Out of the studied SNPs ( 38 ) across these genes , 22 SNPs had significant effect on one or a group of fatty acids including DB01211 . The genotypes at these loci showed significant differences in the least square means of a particular fatty acid or a group of fatty acids including DB01211 and its isomers .\",\n \"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .\",\n \"c - Fos protein as a target of anti - osteoclastogenic action of vitamin D , and synthesis of new analogs . Although active vitamin D drugs have been used for the treatment of osteoporosis , how the vitamin D receptor ( P11473 ) regulates bone cell function remains largely unknown . Using osteoprotegerin - deficient mice , which exhibit severe osteoporosis due to excessive receptor activator of NF - kappaB ligand / receptor activator of NF - kappaB ( O14788 / Q9Y6Q6 ) stimulation , we show herein that oral treatment of these mice with 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] inhibited bone resorption and prevented bone loss , suggesting that P11473 counters O14788 / Q9Y6Q6 signaling . In P09603 - dependent osteoclast precursor cells isolated from mouse bone marrow , DB00136 potently and dose - dependently inhibited their differentiation into multinucleate osteoclasts induced by O14788 . Among signaling molecules downstream of Q9Y6Q6 , DB00136 inhibited the induction of c - Fos protein after O14788 stimulation , and retroviral expression of c - Fos protein abrogated the suppressive effect of DB00136 on osteoclast development . By screening vitamin D analogs based on their c - Fos - suppressing activity , we identified a new analog , named DD281 , that inhibited bone resorption and prevented bone loss in ovariectomized mice , more potently than DB00136 , with similar levels of calcium absorption . Thus , c - Fos protein is an important target of the skeletal action of P11473 - based drugs , and DD281 is a bone - selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK29___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"DB00136 induces capacitative calcium entry involving a Q13507 protein in skeletal muscle and osteoblastic cells . This work describes the involvement of TRPC proteins in capacitative calcium entry ( CCE ) induced by 1alpha , 25 - dihydroxy - vitamin - D3 [ DB00136 ] in chick skeletal muscle and in rat osteoblast - like cells ( ROS 17 / 2 . 8 ) and the role of the vitamin D receptor ( P11473 ) in this non - genomic rapid response mediated by the hormone . We propose that an endogenous Q13507 protein mediates DB00136 modulation of CCE in these cells , which seems to implicate P11473 - Q13507 association and the participation of an INAD - like scaffold protein .\",\n \"Stimulation of the peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy . Monocytes and macrophages play a key role in the progression of atheromatous changes . The peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) can limit macroangiopathy through the control of cytokine transcription . The objectives of this study were to examine the influence of Q07869 gamma and its agonist ( rosiglitazone ) on the TNFalpha , P05231 , P10145 and P22301 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion . TNFalpha , P05231 , P10145 , P22301 and Q07869 gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy ( real - time PCR [ Applied Biosystems ] ) . As indicators of endothelial lesion , concentration of thrombomodulin ( immunoassay [ Diagnostica Stago ] ) and amount of circulating blood endothelial cells ( immunofluorescence method with MoAb Q8N0X4 - HEC19 ) were determined . Following rosiglitazone therapy , a statistically significant downward tendency of TNFalpha ( p = 0 . 026 ) and P10145 ( p = 0 . 008 ) gene expression was noted . Before and following rosiglitazone treatment , Q07869 gamma , P05231 and P22301 gene expression was undetectable in studied monocytes in vivo . In conclusion , TNFalpha and P10145 play an important role in monocyte atherogenic activity . Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines ( Q07869 gamma - independent pathway ) .\",\n \"Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats . P14324 ( FPPS ) , an essential enzyme in the mevalonate pathway , was reported to be upregulated in young spontaneously hypertensive rats ( SHR ) when compared with Wistar - Kyoto ( WKY ) rats , and this was accompanied by development of left ventricular hypertrophy . Five - week - old rats were daily gavaged with vehicle or an FPPS inhibitor ( alendronate , 1 or 10 mg / kg ) and blood pressures was monitored by the tail - cuff method every other week . Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio ( LVW / BW ) , hydroxyproline content , collagen deposition in the interstitia , and gene expression of atrial natriuretic peptide , B - type natriuretic peptide , and procollagen type I / III in the SHR left ventricle , all of which were significantly higher in SHRs than in WKY rats . Furthermore , long - term treatment with an FPPS inhibitor significantly reduced RhoA activation , P29323 phosphorylation , and TGF - beta1 expression in the SHR left ventricle , all of which were upregulated more in SHRs than in WKY rats . In conclusion , chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis , and the suppression of P27361 / 2 phosphorylation and TGF - beta1 expression with inhibition of RhoA activation may be an important mechanism .\",\n \"Characterization of the antitumor activity of a polyantigenic immunomodulator ( P05121 ) : I -- Utilization of cimetidine and cyclosporine A . DB00501 ( CMT ) , cyclosporine A ( DB00091 ) , interleukin 2 ( IL 2 ) , were used to characterize the anticancerous effect of a polyantigenic immunodulator ( P05121 ) . P05121 consists of a mixture of inactivated bacteria and influenza virus in a peanut oil - arlacel A - aluminum monoesterate emulsion . Antitumoral activity was tested on Ehrlich ' s ascites tumor ( EAT ) implanted into Swiss - Webster ( allogeneic ) or C57BL / 6J ( syngeneic ) mice . P05121 antitumor activity was enhanced by CMT acting synergistically by reducing substantially the tumor growth and increasing the percentage of surviving mice , while DB00091 suppressed this activity . P05121 or its individual components were able to induce significant lymphocyte blastogenesis in mouse ( C57BL / 6J ) - spleen lymphocytes and P60568 enhanced considerably this lymphoproliferative response . The results suggest that P05121 acts at the level of cellular immunity .\",\n \"Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .\",\n \"[ Moclobemide ( ___MASK40___ ) , the first P21397 - inhibitor : really something new ? ] .\",\n \"Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor - derived endothelial cells and tumor angiogenesis in vivo . Calcitriol ( DB00136 ) , the major active form of vitamin D , is antiproliferative in tumor cells and tumor - derived endothelial cells ( TDEC ) . These actions of calcitriol are mediated at least in part by vitamin D receptor ( P11473 ) , which is expressed in many tissues including endothelial cells . To investigate the role of P11473 in calcitriol effects on tumor vasculature , we established TRAMP - 2 tumors subcutaneously into either P11473 wild - type ( WT ) or knockout ( KO ) mice . Within 30 days post - inoculation , tumors in KO mice were larger than those in WT ( P < 0 . 001 ) . TDEC from WT expressed P11473 and were able to transactivate a reporter gene whereas TDEC from KO mice were not . Treatment with calcitriol resulted in growth inhibition in TDEC expressing P11473 . However , TDEC from KO mice were relatively resistant , suggesting that calcitriol - mediated growth inhibition on TDEC is P11473 - dependent . Further analysis of the TRAMP - P06681 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared with WT ( P < 0 . 001 ) . Contrast - enhanced magnetic resonance imaging showed an increase in vascular volume of TRAMP tumors grown in P11473 KO mice compared with WT mice ( P < 0 . 001 ) and FITC - dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice . Using ELISA and Western blot analysis , there was an increase of hypoxia - inducible factor - 1alpha , vascular endothelial growth factor , angiopoietin 1 , and platelet - derived growth factor - BB levels observed in tumors from KO mice . These results indicate that calcitriol - mediated antiproliferative effects on TDEC are P11473 - dependent and loss of P11473 can lead to abnormal tumor angiogenesis .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK26___","___MASK29___","___MASK30___","___MASK40___","___MASK52___","___MASK55___","___MASK58___","___MASK69___","___MASK99___"],"string":"[\n \"___MASK26___\",\n \"___MASK29___\",\n \"___MASK30___\",\n \"___MASK40___\",\n \"___MASK52___\",\n \"___MASK55___\",\n \"___MASK58___\",\n \"___MASK69___\",\n \"___MASK99___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK69___"},"id":{"kind":"string","value":"MH_train_81"}}},{"rowIdx":82,"cells":{"query":{"kind":"string","value":"interacts_with DB01276?"},"supports":{"kind":"list like","value":["___MASK31___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .","DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK32___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .","The genomic organization of the human P43220 gene . The genomic organization of the human gene encoding the receptor for glucagon - like peptide - 1 ( P0C6A0 ( 7 - 37 ) /( 7 - 36 ) amide ) was analyzed to reveal the relationship to other G - protein - coupled receptors . The coding sequence of the P43220 is interrupted by 12 introns . These introns are uniformly distributed within the open reading frame . The length of the introns varies between 6 . 6 kb and 100 bp , in contrast to the relative constant length of 100 bp of the exons . All of the exon / intron splice junctions characterized followed the consensus GT - AG rule . A comparison of the genomic structure with other related receptor genes indicates that the exon / intron organization is well - conserved among the P01282 / glucagon / secretin receptor family .","[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK53___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .","Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .","P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .","HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .","New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .","Signaling and biological effects of glucagon - like peptide 1 on the differentiation of DB05914 from human bone marrow . Glucagon - like peptide 1 ( P0C6A0 ) functions as an incretin hormone with antidiabetogenic properties . However , the role of P0C6A0 in human bone marrow - derived DB05914 ( hMSCs ) , if any , remains unknown . The effects of P0C6A0 on hMSCs were tested with regard to cell proliferation , cytoprotection , and cell differentiation into adipocytes . The signaling pathways involved in these processes were also analyzed . Cells were characterized with biochemical and morphological approaches before and after being induced to differentiate into adipocytes . P12004 protein levels were used as a proliferation index , whereas cell apoptosis was studied by deprivation of fetal bovine serum . Isolated hMSCs expressed stem cell markers as well as mRNA and P43220 protein . P0C6A0 increased the proliferation of hMSCs , which decreased when they were induced to differentiate into adipocytes . This process produced biochemical and morphological changes in cells expressing PPARgamma , C / EBPbeta , AP2 , and P06858 in a time - dependent pattern . Notably , P0C6A0 significantly reduced the expression of PPARgamma , C / EBPbeta , and P06858 . These effects were exerted at least through the MEK and PKC signaling pathways . In addition , P0C6A0 significantly reduced cell apoptosis . Our data indicate that , in hMSCs , P0C6A0 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes . These latter findings underscore the potential therapeutic role of P0C6A0 in preventing the adipocyte hyperplasia associated with obesity and , additionally , could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC .","___MASK79___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .","Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .","Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53 - deficient HT29 human colon cancer cell line . Mutations in the tumor - suppressor gene p53 have been associated with advanced colorectal cancer ( CRC ) . ___MASK80___ ( CPT - 11 ) , a P11387 inhibitor , has been recently incorporated to the adjuvant therapy . Since the DNA - damage checkpoint depends on p53 activation , the status of p53 might critically influence the response to CPT - 11 . We analysed the sensitivity to CPT - 11 in the human colon cancer cell line HT29 ( mut p53 ) and its wild - type ( wt )- p53 stably transfected subclone HT29 - A4 . Cell - cycle analysis in synchronised cells demonstrated the activation of transfected wt - p53 and a P38936 ( P38936 / CIP1 )- dependent cell - cycle blockage in the S phase . Activated wt - p53 increased apoptosis and enhanced sensitivity to CPT - 11 . In p53 - deficient cells , cDNA - macroarray analysis and western blotting showed an accumulation of the cyclin - dependent kinase ( cdk ) 1 / cyclin B complex . Subsequent p53 - independent activation of the cdk - inhibitor ( cdk - I ) P38936 ( P38936 / CIP1 ) prevented cell - cycle progression . Cdk1 induction was exploited in vivo to improve the sensitivity to CPT - 11 by additional treatment with the cdk - I P99999 - 202 . We demonstrate a gain of sensitivity to CPT - 11 in a p53 - mutated colon cancer model either by restoring wild - type p53 function or by sequential treatment with cdk - Is . Considering that mutations in p53 are among the most common genetic alterations in CRC , a therapeutic approach specifically targeting p53 - deficient tumors could greatly improve the treatment outcomes .","Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .","[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK21___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK21___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .","Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .","A Short - activating RNA Oligonucleotide Targeting the Islet β - cell Transcriptional Factor MafA in P28906 (+) Cells . Upon functional loss of insulin producing islet β - cells , some patients with diabetes become dependent on life - long insulin supplementation therapy . Bioengineering surrogate insulin producing cells is an alternative replacement strategy . We have developed a novel approach using short - activating RNA oligonucleotides to differentiate adult human P28906 (+) cells into insulin - secreting cells . By transfecting RNA to increase transcript levels of the master regulator of insulin biosynthesis , v - maf musculoaponeurotic fibrosarcoma oncogene homolog A ( MafA ) , several pancreatic endodermal genes were upregulated during the differentiation procedure . These included Pancreatic and duodenal homeobox gene - 1 ( PDX1 ) , Neurogenin 3 , Q13562 , and NK6 homeobox 1 ( NKx6 - 1 ) . Differentiated P28906 (+) cells also expressed glucokinase , glucagon - like peptide 1 receptor ( P43220 ) , sulfonylurea receptor - 1 ( Q09428 ) and phogrin - all essential for glucose sensitivity and insulin secretion . The differentiated cells appropriately processed C - peptide and insulin in response to increasing glucose stimulation as shown by enzyme - linked immunosorbent assay ( ELISA ) , fluorescence - activated cell sorting analysis , western blotting , and immunofluorescence staining . We provide a new approach using short - activating RNA in developing insulin producing surrogate cells for treating diabetes . Molecular Therapy - Nucleic Acids ( 2013 ) 2 , e97 ; doi : 10 . 1038 / mtna . 2013 . 23 ; advance online publication 4 June 2013 .","Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .","Concurrent pharmacological modification of cannabinoid - 1 and glucagon - like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free - choice , high - carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free - choice , high - carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high - sucrose chow . After 4 days of the high - calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 receptor antagonist ) or 1 mg / kg Q08050 55 , 212 - 2 ( a P21554 receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 agonist ) or 160 µg / kg exendin ( 9 - 39 ) [ Ex ( 9 - 39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 55 , 212 - 2 compared with either of the drugs injected alone and the saline - injected controls . Both drug combinations selectively inhibited ingestion of the high - sucrose chow . Although Ex ( 9 - 39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 55 , 212 - 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high - sugar food .","Exendin - 4 alleviates angiotensin II - induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . Vascular aging has been implicated in the progression of diabetes and age - related cardiovascular disorders . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone capable of cytoprotective actions in addition to its glucose - lowering effect . The present study was undertaken to examine whether Exendin - 4 , a specific ligand for the P43220 , could prevent angiotensin ( P03950 ) II - induced premature senescence in vascular smooth muscle cells ( VSMCs ) and to determine the underlying mechanism involved . Senescence - associated β - galactosidase ( SA β - gal ) assay showed that P03950 II induced premature senescence of VSMCs . Pretreatment with Exendin - 4 significantly attenuated P03950 II - induced generation of H2O2 and the subsequent VSMC senescence . These effects were , however , reversed in the presence of exendin fragment 9 - 39 , a P43220 antagonist , or PKI14 - 22 . Moreover , a marked increase in the levels of p53 and P38936 induced by P03950 II was blunted by the treatment with Exendin - 4 . Nevertheless , Exendin - 4 failed to decrease P03950 II - induced expression of NAD ( P ) H oxidase 1 ( Nox1 ) , NAD ( P ) H oxidase 4 ( Nox4 ) , O75935 ( phox ) , or p47 ( phox ) in VSMCs . Mechanistically , Exendin - 4 blocked P03950 II - induced Rac1 activation through the DB02527 / PKA signaling cascade . Specifically , NSC23766 , a Rac1 inhibitor , abrogated the suppressive effects of Exendin - 4 on P03950 II - induced premature senescence and H2O2 generation , respectively . Thus Exendin - 4 confers resistance to P03950 II - induced superoxide anion generation from NAD ( P ) H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . These findings demonstrate that P0C6A0 as well as its analogs ( P0C6A0 - related reagents ) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease .","Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .","[ ___MASK60___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .","Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .","17 ___MASK63___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .","Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .","[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .","Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK28___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK28___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction ."],"string":"[\n \"___MASK31___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .\",\n \"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK32___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .\",\n \"The genomic organization of the human P43220 gene . The genomic organization of the human gene encoding the receptor for glucagon - like peptide - 1 ( P0C6A0 ( 7 - 37 ) /( 7 - 36 ) amide ) was analyzed to reveal the relationship to other G - protein - coupled receptors . The coding sequence of the P43220 is interrupted by 12 introns . These introns are uniformly distributed within the open reading frame . The length of the introns varies between 6 . 6 kb and 100 bp , in contrast to the relative constant length of 100 bp of the exons . All of the exon / intron splice junctions characterized followed the consensus GT - AG rule . A comparison of the genomic structure with other related receptor genes indicates that the exon / intron organization is well - conserved among the P01282 / glucagon / secretin receptor family .\",\n \"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK53___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .\",\n \"Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .\",\n \"P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .\",\n \"HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .\",\n \"New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .\",\n \"Signaling and biological effects of glucagon - like peptide 1 on the differentiation of DB05914 from human bone marrow . Glucagon - like peptide 1 ( P0C6A0 ) functions as an incretin hormone with antidiabetogenic properties . However , the role of P0C6A0 in human bone marrow - derived DB05914 ( hMSCs ) , if any , remains unknown . The effects of P0C6A0 on hMSCs were tested with regard to cell proliferation , cytoprotection , and cell differentiation into adipocytes . The signaling pathways involved in these processes were also analyzed . Cells were characterized with biochemical and morphological approaches before and after being induced to differentiate into adipocytes . P12004 protein levels were used as a proliferation index , whereas cell apoptosis was studied by deprivation of fetal bovine serum . Isolated hMSCs expressed stem cell markers as well as mRNA and P43220 protein . P0C6A0 increased the proliferation of hMSCs , which decreased when they were induced to differentiate into adipocytes . This process produced biochemical and morphological changes in cells expressing PPARgamma , C / EBPbeta , AP2 , and P06858 in a time - dependent pattern . Notably , P0C6A0 significantly reduced the expression of PPARgamma , C / EBPbeta , and P06858 . These effects were exerted at least through the MEK and PKC signaling pathways . In addition , P0C6A0 significantly reduced cell apoptosis . Our data indicate that , in hMSCs , P0C6A0 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes . These latter findings underscore the potential therapeutic role of P0C6A0 in preventing the adipocyte hyperplasia associated with obesity and , additionally , could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC .\",\n \"___MASK79___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .\",\n \"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .\",\n \"Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53 - deficient HT29 human colon cancer cell line . Mutations in the tumor - suppressor gene p53 have been associated with advanced colorectal cancer ( CRC ) . ___MASK80___ ( CPT - 11 ) , a P11387 inhibitor , has been recently incorporated to the adjuvant therapy . Since the DNA - damage checkpoint depends on p53 activation , the status of p53 might critically influence the response to CPT - 11 . We analysed the sensitivity to CPT - 11 in the human colon cancer cell line HT29 ( mut p53 ) and its wild - type ( wt )- p53 stably transfected subclone HT29 - A4 . Cell - cycle analysis in synchronised cells demonstrated the activation of transfected wt - p53 and a P38936 ( P38936 / CIP1 )- dependent cell - cycle blockage in the S phase . Activated wt - p53 increased apoptosis and enhanced sensitivity to CPT - 11 . In p53 - deficient cells , cDNA - macroarray analysis and western blotting showed an accumulation of the cyclin - dependent kinase ( cdk ) 1 / cyclin B complex . Subsequent p53 - independent activation of the cdk - inhibitor ( cdk - I ) P38936 ( P38936 / CIP1 ) prevented cell - cycle progression . Cdk1 induction was exploited in vivo to improve the sensitivity to CPT - 11 by additional treatment with the cdk - I P99999 - 202 . We demonstrate a gain of sensitivity to CPT - 11 in a p53 - mutated colon cancer model either by restoring wild - type p53 function or by sequential treatment with cdk - Is . Considering that mutations in p53 are among the most common genetic alterations in CRC , a therapeutic approach specifically targeting p53 - deficient tumors could greatly improve the treatment outcomes .\",\n \"Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .\",\n \"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK21___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK21___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .\",\n \"Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .\",\n \"A Short - activating RNA Oligonucleotide Targeting the Islet β - cell Transcriptional Factor MafA in P28906 (+) Cells . Upon functional loss of insulin producing islet β - cells , some patients with diabetes become dependent on life - long insulin supplementation therapy . Bioengineering surrogate insulin producing cells is an alternative replacement strategy . We have developed a novel approach using short - activating RNA oligonucleotides to differentiate adult human P28906 (+) cells into insulin - secreting cells . By transfecting RNA to increase transcript levels of the master regulator of insulin biosynthesis , v - maf musculoaponeurotic fibrosarcoma oncogene homolog A ( MafA ) , several pancreatic endodermal genes were upregulated during the differentiation procedure . These included Pancreatic and duodenal homeobox gene - 1 ( PDX1 ) , Neurogenin 3 , Q13562 , and NK6 homeobox 1 ( NKx6 - 1 ) . Differentiated P28906 (+) cells also expressed glucokinase , glucagon - like peptide 1 receptor ( P43220 ) , sulfonylurea receptor - 1 ( Q09428 ) and phogrin - all essential for glucose sensitivity and insulin secretion . The differentiated cells appropriately processed C - peptide and insulin in response to increasing glucose stimulation as shown by enzyme - linked immunosorbent assay ( ELISA ) , fluorescence - activated cell sorting analysis , western blotting , and immunofluorescence staining . We provide a new approach using short - activating RNA in developing insulin producing surrogate cells for treating diabetes . Molecular Therapy - Nucleic Acids ( 2013 ) 2 , e97 ; doi : 10 . 1038 / mtna . 2013 . 23 ; advance online publication 4 June 2013 .\",\n \"Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .\",\n \"Concurrent pharmacological modification of cannabinoid - 1 and glucagon - like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free - choice , high - carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free - choice , high - carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high - sucrose chow . After 4 days of the high - calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 receptor antagonist ) or 1 mg / kg Q08050 55 , 212 - 2 ( a P21554 receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 agonist ) or 160 µg / kg exendin ( 9 - 39 ) [ Ex ( 9 - 39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 55 , 212 - 2 compared with either of the drugs injected alone and the saline - injected controls . Both drug combinations selectively inhibited ingestion of the high - sucrose chow . Although Ex ( 9 - 39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 55 , 212 - 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high - sugar food .\",\n \"Exendin - 4 alleviates angiotensin II - induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . Vascular aging has been implicated in the progression of diabetes and age - related cardiovascular disorders . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone capable of cytoprotective actions in addition to its glucose - lowering effect . The present study was undertaken to examine whether Exendin - 4 , a specific ligand for the P43220 , could prevent angiotensin ( P03950 ) II - induced premature senescence in vascular smooth muscle cells ( VSMCs ) and to determine the underlying mechanism involved . Senescence - associated β - galactosidase ( SA β - gal ) assay showed that P03950 II induced premature senescence of VSMCs . Pretreatment with Exendin - 4 significantly attenuated P03950 II - induced generation of H2O2 and the subsequent VSMC senescence . These effects were , however , reversed in the presence of exendin fragment 9 - 39 , a P43220 antagonist , or PKI14 - 22 . Moreover , a marked increase in the levels of p53 and P38936 induced by P03950 II was blunted by the treatment with Exendin - 4 . Nevertheless , Exendin - 4 failed to decrease P03950 II - induced expression of NAD ( P ) H oxidase 1 ( Nox1 ) , NAD ( P ) H oxidase 4 ( Nox4 ) , O75935 ( phox ) , or p47 ( phox ) in VSMCs . Mechanistically , Exendin - 4 blocked P03950 II - induced Rac1 activation through the DB02527 / PKA signaling cascade . Specifically , NSC23766 , a Rac1 inhibitor , abrogated the suppressive effects of Exendin - 4 on P03950 II - induced premature senescence and H2O2 generation , respectively . Thus Exendin - 4 confers resistance to P03950 II - induced superoxide anion generation from NAD ( P ) H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . These findings demonstrate that P0C6A0 as well as its analogs ( P0C6A0 - related reagents ) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease .\",\n \"Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .\",\n \"[ ___MASK60___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .\",\n \"Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .\",\n \"17 ___MASK63___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .\",\n \"Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .\",\n \"[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .\",\n \"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK28___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK28___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK21___","___MASK28___","___MASK31___","___MASK32___","___MASK53___","___MASK60___","___MASK63___","___MASK79___","___MASK80___"],"string":"[\n \"___MASK21___\",\n \"___MASK28___\",\n \"___MASK31___\",\n \"___MASK32___\",\n \"___MASK53___\",\n \"___MASK60___\",\n \"___MASK63___\",\n \"___MASK79___\",\n \"___MASK80___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK32___"},"id":{"kind":"string","value":"MH_train_82"}}},{"rowIdx":83,"cells":{"query":{"kind":"string","value":"interacts_with DB01064?"},"supports":{"kind":"list like","value":["P25021 activation exacerbates myocardial ischemia / reperfusion injury by disturbing mitochondrial and endothelial function . There is evidence that P25021 blockade improves ischemia / reperfusion ( I / R ) injury , but the underlying cellular mechanisms remain unclear . DB11320 is known to increase vascular permeability and induce apoptosis , and these effects are closely associated with endothelial and mitochondrial dysfunction , respectively . Here , we investigated whether activation of the histamine H2 receptor ( P25021 ) exacerbates myocardial I / R injury by increasing mitochondrial and endothelial permeability . Serum histamine levels were measured in patients with coronary heart disease , while the influence of P25021 activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells , and myocardial I / R injury in mice . The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls . In neonatal rat cardiomyocytes , histamine dose - dependently reduced viability and induced apoptosis . Mitochondrial permeability and the levels of p - P27361 / 2 , Bax , p - Q9UIK4 , and caspase 3 were increased by P25021 agonists . In cultured human umbilical vein endothelial cells ( HUVECs ) , P25021 activation increased p - P27361 / 2 and p - moesin levels and also enhanced permeability of HUVEC monolayer . All of these effects were abolished by the P25021 blocker famotidine or the P29323 inhibitor U0126 . After I / R injury or permanent ischemia , the infarct size was reduced by famotidine and increased by an P25021 agonist in wild - type mice . In P25021 KO mice , the infarct size was smaller ; myocardial p - P27361 / 2 , p - Q9UIK4 , and mitochondrial Bax were downregulated . These findings indicate that P25021 activation exaggerates myocardial I / R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability .","Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .","P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .","Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK12___ ( ___MASK12___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK12___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK12___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .","Selective cyclooxygenase - 2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration - triggered c - DB00134 / hepatocyte growth factor receptor induction and extracellular signal - regulated kinase 2 activation . Nonsteroidal anti - inflammatory drugs , both nonselective and cyclooxygenase - 2 ( P35354 ) selective , delay gastric ulcer healing . Whether they affect esophageal ulcer healing remains unexplored . We studied the effects of the P35354 selective inhibitor , celecoxib , on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process . Esophageal ulcers were induced in rats by focal application of acetic acid . Rats with esophageal ulcers were treated intragastrically with either celecoxib ( 10 mg / kg , once daily ) or vehicle for 2 or 4 days . Esophageal ulceration triggered increases in : esophageal epithelial cell proliferation ; expression of P35354 ( but not P23219 ) ; hepatocyte growth factor ( P14210 ) and its receptor , c - DB00134 ; and activation of extracellular signal - regulated kinase 2 ( P28482 ) . Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration - triggered increases in esophageal epithelial cell proliferation , c - DB00134 mRNA and protein expression , and P28482 activity . In an ex vivo organ - culture system , exogenous P14210 significantly increased P28482 phosphorylation levels in esophageal mucosa . A structural analog of celecoxib , SC - 236 , completely prevented this effect . These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration - induced esophageal epithelial cell proliferation . These actions are associated with , and likely mediated by , down - regulation of the P14210 / c - DB00134 - P28482 signaling pathway .","No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK87___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK87___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK87___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK87___ among adults with ADHD .","Phosphorylation of beta - arrestin2 regulates its function in internalization of beta ( 2 )- adrenergic receptors . Beta - arrestins mediate agonist - dependent desensitization and internalization of G protein - coupled receptors . Previously , we have shown that phosphorylation of beta - arrestin1 by ERKs at DB00133 - 412 regulates its association with clathrin and its function in promoting clathrin - mediated internalization of the receptor . In this paper we report that beta - arrestin2 is also phosphorylated , predominantly at residues DB00156 - 383 and DB00133 - 361 . DB01064 stimulation of the beta ( 2 )- adrenergic receptor promotes dephosphorylation of beta - arrestin2 . Mutation of beta - arrestin2 phosphorylation sites to aspartic acid decreases the association of beta - arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta ( 2 )- adrenergic receptor . Its ability to bind and desensitize the beta ( 2 )- adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta - arrestin1 , phosphorylation / dephosphorylation of beta - arrestin2 regulates clathrin - mediated internalization of the beta ( 2 )- adrenergic receptor . In contrast to beta - arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta - arrestin2 at DB00156 - 383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 - 366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein - coupled receptors is regulated by distinct phosphorylation / dephosphorylation mechanisms .","Regulation of extracellular signal - regulated kinase 1 / 2 influences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia . Activation of extracellular signal - regulated kinase 1 / 2 has been demonstrated in acute brain ischemia . We hypothesized that activated extracellular signal - regulated kinase 1 / 2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia / reperfusion . In this study , transient whole - brain ischemia was induced by four - vessel occlusion in normal and diabetic rats , and extracellular signal - regulated kinase 1 / 2 inhibitor ( U0126 ) was administered into diabetic rats 30 minutes before ischemia as a pretreatment . Results showed that the number of surviving neurons in the hippocampal P00915 region was reduced , extracellular signal - regulated kinase 1 / 2 phosphorylation and P12956 activity were decreased , and pro - apoptotic Bax expression was upregulated after intervention using U0126 . These findings demonstrate that inhibition of extracellular signal - regulated kinase 1 / 2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia / reperfusion , further decreased DNA repairing ability and accelerated apoptosis in hippocampal neurons . P27361 / 2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia / reperfusion .","Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .","DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK35___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .","DB01064 inhibits fibroblast growth factor - 2 - induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen - activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8 - bromo - DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin - Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8 - bromo - DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8 - bromo - DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 / 2 ) , blocked the P09038 mitogenic effects , but did not affect the 8 - bromo - DB02527 - induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth - promoting effects of P09038 in RTEc via MEK - dependent and - independent pathways .","Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK36___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .","Differential functional activity of 5 - hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5 - hydroxytryptamine1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5 - hydroxytryptamine ( 5 - HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin - stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin - induced cyclic AMP formation and their potency to potentiate P09038 - induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5 - methoxy - 3 , 1 , 2 , 3 , 6 - tetrahydro - 4 - pyidinyl - 1H - indole ( RU 24 , 969 ) , 5 - carboxamidotryptamine ( 5 - CT ) , 3 -( 1 , 2 , 5 , 6 )- tetrahydro - 4 - pyridyl - 5 - pyrrolo ( 3 , 2 - b ) pyril - 5 - one ( CP 93 , 129 ) and 5 - HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor - mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4 -( 3 - tert - butyl - amino - 2 - hydroxypropoxy )- indole - 2 carbonic acid isopropyl ester ( SDZ 21 , 009 ) , isamoltane , (-)- propranolol and (-)- pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor - mediated responses although the antagonist effect was more pronounced in CHL fibroblasts . ( ABSTRACT TRUNCATED AT 250 WORDS )","Inhibition of P29323 activation enhances the repair of double - stranded breaks via non - homologous end joining by increasing P78527 activation . Non - homologous end joining ( NHEJ ) is one of the major pathways that repairs double - stranded DNA breaks ( DSBs ) . Activation of DNA - PK is required for NHEJ . However , the mechanism leading to P78527 activation remains incompletely understood . We provide evidence here that the MEK - P29323 pathway plays a role in P78527 - mediated NHEJ . In comparison to the vehicle control ( DB01093 ) , etoposide ( ETOP ) - induced DSBs in MCF7 cells were more rapidly repaired in the presence of U0126 , a specific MEK inhibitor , based on the reduction of γ P16104 and tail moments . Additionally , U0126 increased reactivation of luciferase activity , which resulted from the repair of restriction enzyme - cleaved DSBs . Furthermore , while inhibition of P29323 activation using the dominant - negative MEK1K97M accelerated the repair of DSBs , enforcing P29323 activation with the constitutively active MEK1Q56P reduced DSB repair . In line with MEK activating P27361 and P28482 kinases , knockdown of either P27361 or P28482 increased DSB repair . Consistent with the activation of P78527 being required for NHEJ , we demonstrated that inhibition of P29323 activation using U0126 , MEK1K97M , and knockdown of P27361 or P28482 enhanced ETOP - induced activation of P78527 . Conversely , enforcing P29323 activation by MEK1Q56P reduced ETOP - initiated P78527 activation . Taken together , we demonstrate that P29323 reduces NHEJ - mediated repair of DSBs via attenuation of P78527 activation .","Class I histone deacetylase - mediated repression of the proximal promoter of the activity - regulated cytoskeleton - associated protein gene regulates its response to brain - derived neurotrophic factor . We examined the transcriptional regulation of the activity - regulated cytoskeleton - associated protein gene ( Arc ) , focusing on P23560 - induced Arc expression in cultured rat cortical cells . Although the synaptic activity - responsive element ( SARE ) , located - 7 kbp upstream of the Arc transcription start site , responded to DB01221 , P23560 , or P09038 , the proximal region of the promoter ( Arc /- 1679 ) was activated by P23560 or P09038 , but not by DB01221 , suggesting the presence of at least two distinct Arc promoter regions , distal and proximal , that respond to extracellular stimuli . Specificity protein 4 ( Q02446 ) and early growth response 1 ( P18146 ) controlled Arc /- 1679 transcriptional activity via the region encompassing - 169 to - 37 of the Arc promoter . We found that trichostatin A ( P32119 ) , a histone deacetylase ( HDAC ) inhibitor , significantly enhanced the inductive effects of P23560 or P09038 , but not those of DB01221 on Arc expression . Inhibitors of class I / IIb HDACs , ___MASK12___ , and class I HDACs , MS - 275 , but not of class II HDACs , MC1568 , enhanced P23560 - induced Arc expression . The enhancing effect of P32119 was mediated by the region from - 1027 to - 1000 bp , to which serum response factor ( P11831 ) and Q13547 bound . The binding of Q13547 to this region was reduced by P32119 . Thus , Arc expression was suppressed by class I HDAC - mediated mechanisms via chromatin modification of the proximal promoter whereas the inhibition of HDAC allowed Arc expression to be markedly enhanced in response to P23560 or P09038 . These results contribute to our understanding of the physiological role of Arc expression in neuronal functions such as memory consolidation .","Extracellular signal - regulated kinase and the small GTP - binding protein , Rac , contribute to the effects of transforming growth factor - beta1 on gene expression . The kinases and regulatory proteins that convey signals initiated by transforming growth factor - beta ( TGF - beta ) to the nucleus are poorly characterized . To study the role of the extracellular signal - regulated kinase ( P29323 ) pathway in this process , we transiently transfected NIH 3T3 fibroblasts with TGF - beta - responsive luciferase reporter genes and expression vectors designed to interrupt this kinase cascade . Mitogen - activated protein ( Q96HU1 ) kinase phosphatase - 1 and a dominant negative Q96HU1 / P29323 kinase 1 mutant reduced stimulation of plasminogen activator inhibitor - 1 ( P05121 ) promoter activity by TGF - beta1 from 11 . 5 - to 4 - fold and 4 . 9 - fold , respectively . Similar results were observed with the type I collagen promoters . TGF - beta1 increased P27361 activity 4 . 5 - fold at 5 min and 3 . 1 - fold at 3 h , while Jun kinase and p38 activity were not affected . Cotransfection of a dominant negative mutant of the small G protein , Rac , but not dominant negative Ras , Cdc42 , or Rho mutants , reduced the effects of TGF - beta1 on the P05121 promoter by approximately half . In support of a role for Rac in signaling by TGF - beta , GTP binding to Rac was increased 3 . 7 - fold following exposure of NIH 3T3 cells to TGF - beta1 for 3 min . These findings indicate that TGF - beta1 modulates gene expression partly through P29323 and Rac in NIH 3T3 cells .","Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen - activated protein kinases ( MAPK ) [ extracellular signal - regulated kinase - 2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng / mL ) induced a significant 4 - fold increase in P28482 activity and [ 3H ] - thymidine incorporation ( 6 - fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10 (- 6 ) M ) induced a more modest increase in P28482 activity ( 2 - fold ) and [ 3H ] - thymidine incorporation ( 35 +/- 4 % ) . The mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 - induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . DB01064 inhibited the basal and P09038 - induced proliferation of HFMc through a MEK - 1 / 2 - independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK - 1 / 2 - dependent and independent signaling pathways . Activation of MEK - 1 / 2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK - 1 / 2 - independent pathway .","Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK58___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK58___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK58___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK58___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK58___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK58___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK58___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK58___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK58___ in the treatment of changes in hypervigilance following severe stress .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK84___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK70___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .","Downregulation of angiotensin converting enzyme II is associated with pacing - induced sustained atrial fibrillation . Atrial fibrillation ( AF ) , the most common cardiac arrhythmia , is frequently accompanied by atrial interstitial fibrosis . Angiotensin II ( Ang II ) dependent signaling pathways have been implicated in interstitial fibrosis during the development of AF . However , Ang II could be further degraded by angiotensin converting enzyme II ( Q9BYF1 ) . We examined expression of Q9BYF1 in the fibrillating atria of pigs and its involvement in fibrotic pathogenesis during AF . Nine adult pigs underwent continuous rapid atrial pacing to induce sustained AF and six pigs were sham controls ( i . e . , sinus rhythm ; SR ) . In the histological examinations , extensive accumulation of extracellular matrix in the interstitial space of the atria , as evidenced by Masson ' s trichrome stain , were found in fibrillating atria . The relative amount of collagen type I in the atria with AF was significantly increased as compared with that in the SR . Local P12821 activity in the fibrillating atria was also markedly higher than that in the SR subjects . Q9BYF1 gene and protein expression in the AF subjects were significantly decreased compared with those in the SR subjects , whereas expression of mitogen - activated / P29323 kinase 1 / 2 ( Q02750 / 2 ) , extracellular signal - regulated protein kinase 2 ( P28482 ) , and activated P28482 were significantly greater in the AF subjects . We propose that decreasing Q9BYF1 expression during AF may affect the Ang II - dependent signaling pathway . In addition , our results suggest that atrial fibrosis in AF may be induced by antagonistic regulation between P12821 and Q9BYF1 expression .","The use of IRES - based bicistronic vectors allows the stable expression of recombinant G - protein coupled receptors such as NPY5 and histamine 4 . Stable expression of G protein coupled receptors in cell lines is a crucial tool for the characterization of the molecular pharmacology of receptors and the screening for new antagonists . However , in some instances , many difficulties have been encountered to obtain stable cell lines expressing functional receptors . Here , we addressed the question of vector optimization to establish cell lines expressing the human neuropeptide Y receptor 5 ( Q15761 ) or histamine receptor 4 ( Q9H3N8 ) . We have compared bicistronic vectors containing viral or cellular internal ribosome entry sites ( IRES ) , co - expressing the receptor and the neomycine resistance gene from a single mRNA , to a bigenic vector containing two distinct promoters upstream each different genes . This study is the first one to validate the use of three cellular IRESs for long - term transgene expression . Our results demonstrate for both Q15761 and Q9H3N8 that the bicistronic vectors with EMCV , P15692 , FGF1A or P09038 IRES provide clones expressing functional receptors with yields between 25 % and 100 % . In contrast , the bigenic vector provided no functional clones , related to a low expression of Q15761 mRNA . The cell lines expressing active receptor were stable after more than 50 passages . These data indicate that IRES - based bicistronic vectors are particularly appropriate to establish cell clones expressing active G - coupled protein receptors with a high yield . In the case of NPY5 , it was a new way to produce such a stable cell line . Furthermore , the characteristics - presented herein - of this receptor pharmacological property are perfectly in line with those reported in the literature .","Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK27___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK27___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .","P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK90___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study ."],"string":"[\n \"P25021 activation exacerbates myocardial ischemia / reperfusion injury by disturbing mitochondrial and endothelial function . There is evidence that P25021 blockade improves ischemia / reperfusion ( I / R ) injury , but the underlying cellular mechanisms remain unclear . DB11320 is known to increase vascular permeability and induce apoptosis , and these effects are closely associated with endothelial and mitochondrial dysfunction , respectively . Here , we investigated whether activation of the histamine H2 receptor ( P25021 ) exacerbates myocardial I / R injury by increasing mitochondrial and endothelial permeability . Serum histamine levels were measured in patients with coronary heart disease , while the influence of P25021 activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells , and myocardial I / R injury in mice . The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls . In neonatal rat cardiomyocytes , histamine dose - dependently reduced viability and induced apoptosis . Mitochondrial permeability and the levels of p - P27361 / 2 , Bax , p - Q9UIK4 , and caspase 3 were increased by P25021 agonists . In cultured human umbilical vein endothelial cells ( HUVECs ) , P25021 activation increased p - P27361 / 2 and p - moesin levels and also enhanced permeability of HUVEC monolayer . All of these effects were abolished by the P25021 blocker famotidine or the P29323 inhibitor U0126 . After I / R injury or permanent ischemia , the infarct size was reduced by famotidine and increased by an P25021 agonist in wild - type mice . In P25021 KO mice , the infarct size was smaller ; myocardial p - P27361 / 2 , p - Q9UIK4 , and mitochondrial Bax were downregulated . These findings indicate that P25021 activation exaggerates myocardial I / R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability .\",\n \"Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .\",\n \"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .\",\n \"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK12___ ( ___MASK12___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK12___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK12___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .\",\n \"Selective cyclooxygenase - 2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration - triggered c - DB00134 / hepatocyte growth factor receptor induction and extracellular signal - regulated kinase 2 activation . Nonsteroidal anti - inflammatory drugs , both nonselective and cyclooxygenase - 2 ( P35354 ) selective , delay gastric ulcer healing . Whether they affect esophageal ulcer healing remains unexplored . We studied the effects of the P35354 selective inhibitor , celecoxib , on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process . Esophageal ulcers were induced in rats by focal application of acetic acid . Rats with esophageal ulcers were treated intragastrically with either celecoxib ( 10 mg / kg , once daily ) or vehicle for 2 or 4 days . Esophageal ulceration triggered increases in : esophageal epithelial cell proliferation ; expression of P35354 ( but not P23219 ) ; hepatocyte growth factor ( P14210 ) and its receptor , c - DB00134 ; and activation of extracellular signal - regulated kinase 2 ( P28482 ) . Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration - triggered increases in esophageal epithelial cell proliferation , c - DB00134 mRNA and protein expression , and P28482 activity . In an ex vivo organ - culture system , exogenous P14210 significantly increased P28482 phosphorylation levels in esophageal mucosa . A structural analog of celecoxib , SC - 236 , completely prevented this effect . These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration - induced esophageal epithelial cell proliferation . These actions are associated with , and likely mediated by , down - regulation of the P14210 / c - DB00134 - P28482 signaling pathway .\",\n \"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK87___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK87___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK87___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK87___ among adults with ADHD .\",\n \"Phosphorylation of beta - arrestin2 regulates its function in internalization of beta ( 2 )- adrenergic receptors . Beta - arrestins mediate agonist - dependent desensitization and internalization of G protein - coupled receptors . Previously , we have shown that phosphorylation of beta - arrestin1 by ERKs at DB00133 - 412 regulates its association with clathrin and its function in promoting clathrin - mediated internalization of the receptor . In this paper we report that beta - arrestin2 is also phosphorylated , predominantly at residues DB00156 - 383 and DB00133 - 361 . DB01064 stimulation of the beta ( 2 )- adrenergic receptor promotes dephosphorylation of beta - arrestin2 . Mutation of beta - arrestin2 phosphorylation sites to aspartic acid decreases the association of beta - arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta ( 2 )- adrenergic receptor . Its ability to bind and desensitize the beta ( 2 )- adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta - arrestin1 , phosphorylation / dephosphorylation of beta - arrestin2 regulates clathrin - mediated internalization of the beta ( 2 )- adrenergic receptor . In contrast to beta - arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta - arrestin2 at DB00156 - 383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 - 366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein - coupled receptors is regulated by distinct phosphorylation / dephosphorylation mechanisms .\",\n \"Regulation of extracellular signal - regulated kinase 1 / 2 influences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia . Activation of extracellular signal - regulated kinase 1 / 2 has been demonstrated in acute brain ischemia . We hypothesized that activated extracellular signal - regulated kinase 1 / 2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia / reperfusion . In this study , transient whole - brain ischemia was induced by four - vessel occlusion in normal and diabetic rats , and extracellular signal - regulated kinase 1 / 2 inhibitor ( U0126 ) was administered into diabetic rats 30 minutes before ischemia as a pretreatment . Results showed that the number of surviving neurons in the hippocampal P00915 region was reduced , extracellular signal - regulated kinase 1 / 2 phosphorylation and P12956 activity were decreased , and pro - apoptotic Bax expression was upregulated after intervention using U0126 . These findings demonstrate that inhibition of extracellular signal - regulated kinase 1 / 2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia / reperfusion , further decreased DNA repairing ability and accelerated apoptosis in hippocampal neurons . P27361 / 2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia / reperfusion .\",\n \"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .\",\n \"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK35___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .\",\n \"DB01064 inhibits fibroblast growth factor - 2 - induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen - activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8 - bromo - DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin - Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8 - bromo - DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8 - bromo - DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 / 2 ) , blocked the P09038 mitogenic effects , but did not affect the 8 - bromo - DB02527 - induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth - promoting effects of P09038 in RTEc via MEK - dependent and - independent pathways .\",\n \"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK36___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .\",\n \"Differential functional activity of 5 - hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5 - hydroxytryptamine1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5 - hydroxytryptamine ( 5 - HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin - stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin - induced cyclic AMP formation and their potency to potentiate P09038 - induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5 - methoxy - 3 , 1 , 2 , 3 , 6 - tetrahydro - 4 - pyidinyl - 1H - indole ( RU 24 , 969 ) , 5 - carboxamidotryptamine ( 5 - CT ) , 3 -( 1 , 2 , 5 , 6 )- tetrahydro - 4 - pyridyl - 5 - pyrrolo ( 3 , 2 - b ) pyril - 5 - one ( CP 93 , 129 ) and 5 - HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor - mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4 -( 3 - tert - butyl - amino - 2 - hydroxypropoxy )- indole - 2 carbonic acid isopropyl ester ( SDZ 21 , 009 ) , isamoltane , (-)- propranolol and (-)- pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor - mediated responses although the antagonist effect was more pronounced in CHL fibroblasts . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Inhibition of P29323 activation enhances the repair of double - stranded breaks via non - homologous end joining by increasing P78527 activation . Non - homologous end joining ( NHEJ ) is one of the major pathways that repairs double - stranded DNA breaks ( DSBs ) . Activation of DNA - PK is required for NHEJ . However , the mechanism leading to P78527 activation remains incompletely understood . We provide evidence here that the MEK - P29323 pathway plays a role in P78527 - mediated NHEJ . In comparison to the vehicle control ( DB01093 ) , etoposide ( ETOP ) - induced DSBs in MCF7 cells were more rapidly repaired in the presence of U0126 , a specific MEK inhibitor , based on the reduction of γ P16104 and tail moments . Additionally , U0126 increased reactivation of luciferase activity , which resulted from the repair of restriction enzyme - cleaved DSBs . Furthermore , while inhibition of P29323 activation using the dominant - negative MEK1K97M accelerated the repair of DSBs , enforcing P29323 activation with the constitutively active MEK1Q56P reduced DSB repair . In line with MEK activating P27361 and P28482 kinases , knockdown of either P27361 or P28482 increased DSB repair . Consistent with the activation of P78527 being required for NHEJ , we demonstrated that inhibition of P29323 activation using U0126 , MEK1K97M , and knockdown of P27361 or P28482 enhanced ETOP - induced activation of P78527 . Conversely , enforcing P29323 activation by MEK1Q56P reduced ETOP - initiated P78527 activation . Taken together , we demonstrate that P29323 reduces NHEJ - mediated repair of DSBs via attenuation of P78527 activation .\",\n \"Class I histone deacetylase - mediated repression of the proximal promoter of the activity - regulated cytoskeleton - associated protein gene regulates its response to brain - derived neurotrophic factor . We examined the transcriptional regulation of the activity - regulated cytoskeleton - associated protein gene ( Arc ) , focusing on P23560 - induced Arc expression in cultured rat cortical cells . Although the synaptic activity - responsive element ( SARE ) , located - 7 kbp upstream of the Arc transcription start site , responded to DB01221 , P23560 , or P09038 , the proximal region of the promoter ( Arc /- 1679 ) was activated by P23560 or P09038 , but not by DB01221 , suggesting the presence of at least two distinct Arc promoter regions , distal and proximal , that respond to extracellular stimuli . Specificity protein 4 ( Q02446 ) and early growth response 1 ( P18146 ) controlled Arc /- 1679 transcriptional activity via the region encompassing - 169 to - 37 of the Arc promoter . We found that trichostatin A ( P32119 ) , a histone deacetylase ( HDAC ) inhibitor , significantly enhanced the inductive effects of P23560 or P09038 , but not those of DB01221 on Arc expression . Inhibitors of class I / IIb HDACs , ___MASK12___ , and class I HDACs , MS - 275 , but not of class II HDACs , MC1568 , enhanced P23560 - induced Arc expression . The enhancing effect of P32119 was mediated by the region from - 1027 to - 1000 bp , to which serum response factor ( P11831 ) and Q13547 bound . The binding of Q13547 to this region was reduced by P32119 . Thus , Arc expression was suppressed by class I HDAC - mediated mechanisms via chromatin modification of the proximal promoter whereas the inhibition of HDAC allowed Arc expression to be markedly enhanced in response to P23560 or P09038 . These results contribute to our understanding of the physiological role of Arc expression in neuronal functions such as memory consolidation .\",\n \"Extracellular signal - regulated kinase and the small GTP - binding protein , Rac , contribute to the effects of transforming growth factor - beta1 on gene expression . The kinases and regulatory proteins that convey signals initiated by transforming growth factor - beta ( TGF - beta ) to the nucleus are poorly characterized . To study the role of the extracellular signal - regulated kinase ( P29323 ) pathway in this process , we transiently transfected NIH 3T3 fibroblasts with TGF - beta - responsive luciferase reporter genes and expression vectors designed to interrupt this kinase cascade . Mitogen - activated protein ( Q96HU1 ) kinase phosphatase - 1 and a dominant negative Q96HU1 / P29323 kinase 1 mutant reduced stimulation of plasminogen activator inhibitor - 1 ( P05121 ) promoter activity by TGF - beta1 from 11 . 5 - to 4 - fold and 4 . 9 - fold , respectively . Similar results were observed with the type I collagen promoters . TGF - beta1 increased P27361 activity 4 . 5 - fold at 5 min and 3 . 1 - fold at 3 h , while Jun kinase and p38 activity were not affected . Cotransfection of a dominant negative mutant of the small G protein , Rac , but not dominant negative Ras , Cdc42 , or Rho mutants , reduced the effects of TGF - beta1 on the P05121 promoter by approximately half . In support of a role for Rac in signaling by TGF - beta , GTP binding to Rac was increased 3 . 7 - fold following exposure of NIH 3T3 cells to TGF - beta1 for 3 min . These findings indicate that TGF - beta1 modulates gene expression partly through P29323 and Rac in NIH 3T3 cells .\",\n \"Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen - activated protein kinases ( MAPK ) [ extracellular signal - regulated kinase - 2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng / mL ) induced a significant 4 - fold increase in P28482 activity and [ 3H ] - thymidine incorporation ( 6 - fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10 (- 6 ) M ) induced a more modest increase in P28482 activity ( 2 - fold ) and [ 3H ] - thymidine incorporation ( 35 +/- 4 % ) . The mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 - induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . DB01064 inhibited the basal and P09038 - induced proliferation of HFMc through a MEK - 1 / 2 - independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK - 1 / 2 - dependent and independent signaling pathways . Activation of MEK - 1 / 2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK - 1 / 2 - independent pathway .\",\n \"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK58___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK58___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK58___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK58___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK58___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK58___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK58___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK58___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK58___ in the treatment of changes in hypervigilance following severe stress .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK84___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK70___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .\",\n \"Downregulation of angiotensin converting enzyme II is associated with pacing - induced sustained atrial fibrillation . Atrial fibrillation ( AF ) , the most common cardiac arrhythmia , is frequently accompanied by atrial interstitial fibrosis . Angiotensin II ( Ang II ) dependent signaling pathways have been implicated in interstitial fibrosis during the development of AF . However , Ang II could be further degraded by angiotensin converting enzyme II ( Q9BYF1 ) . We examined expression of Q9BYF1 in the fibrillating atria of pigs and its involvement in fibrotic pathogenesis during AF . Nine adult pigs underwent continuous rapid atrial pacing to induce sustained AF and six pigs were sham controls ( i . e . , sinus rhythm ; SR ) . In the histological examinations , extensive accumulation of extracellular matrix in the interstitial space of the atria , as evidenced by Masson ' s trichrome stain , were found in fibrillating atria . The relative amount of collagen type I in the atria with AF was significantly increased as compared with that in the SR . Local P12821 activity in the fibrillating atria was also markedly higher than that in the SR subjects . Q9BYF1 gene and protein expression in the AF subjects were significantly decreased compared with those in the SR subjects , whereas expression of mitogen - activated / P29323 kinase 1 / 2 ( Q02750 / 2 ) , extracellular signal - regulated protein kinase 2 ( P28482 ) , and activated P28482 were significantly greater in the AF subjects . We propose that decreasing Q9BYF1 expression during AF may affect the Ang II - dependent signaling pathway . In addition , our results suggest that atrial fibrosis in AF may be induced by antagonistic regulation between P12821 and Q9BYF1 expression .\",\n \"The use of IRES - based bicistronic vectors allows the stable expression of recombinant G - protein coupled receptors such as NPY5 and histamine 4 . Stable expression of G protein coupled receptors in cell lines is a crucial tool for the characterization of the molecular pharmacology of receptors and the screening for new antagonists . However , in some instances , many difficulties have been encountered to obtain stable cell lines expressing functional receptors . Here , we addressed the question of vector optimization to establish cell lines expressing the human neuropeptide Y receptor 5 ( Q15761 ) or histamine receptor 4 ( Q9H3N8 ) . We have compared bicistronic vectors containing viral or cellular internal ribosome entry sites ( IRES ) , co - expressing the receptor and the neomycine resistance gene from a single mRNA , to a bigenic vector containing two distinct promoters upstream each different genes . This study is the first one to validate the use of three cellular IRESs for long - term transgene expression . Our results demonstrate for both Q15761 and Q9H3N8 that the bicistronic vectors with EMCV , P15692 , FGF1A or P09038 IRES provide clones expressing functional receptors with yields between 25 % and 100 % . In contrast , the bigenic vector provided no functional clones , related to a low expression of Q15761 mRNA . The cell lines expressing active receptor were stable after more than 50 passages . These data indicate that IRES - based bicistronic vectors are particularly appropriate to establish cell clones expressing active G - coupled protein receptors with a high yield . In the case of NPY5 , it was a new way to produce such a stable cell line . Furthermore , the characteristics - presented herein - of this receptor pharmacological property are perfectly in line with those reported in the literature .\",\n \"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK27___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK27___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .\",\n \"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK90___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK12___","___MASK27___","___MASK35___","___MASK36___","___MASK58___","___MASK70___","___MASK84___","___MASK87___","___MASK90___"],"string":"[\n \"___MASK12___\",\n \"___MASK27___\",\n \"___MASK35___\",\n \"___MASK36___\",\n \"___MASK58___\",\n \"___MASK70___\",\n \"___MASK84___\",\n \"___MASK87___\",\n \"___MASK90___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK87___"},"id":{"kind":"string","value":"MH_train_83"}}},{"rowIdx":84,"cells":{"query":{"kind":"string","value":"interacts_with DB00669?"},"supports":{"kind":"list like","value":["How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .","DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .","Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .","Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .","Possible involvement of endocannabinoids in the increase of morphine consumption in maternally deprived rat . Whether adolescent exposure to chronic DB00470 ( THC ) facilitates progression to opioid consumption is still controversial . In a maternal deprivation model ( 3 h daily from postnatal day 1 - 14 ) , we previously reported that adolescent exposure to chronic THC blocks morphine dependence in maternally deprived ( D ) rats . Owing to the existence of a functional cross - interaction between the opioid and cannabinoid systems in reward , we evaluated if the vulnerability to opiate reward in D rats , may involve an alteration of the endocannabinoid system . Anandamide and 2 - arachidonoylglycerol ( 2 - AG ) , were quantified in the striatum and mesencephalon of adolescent and adult D and non - deprived ( animal facility rearing , AFR ) rats by isotope dilution liquid chromatography - mass spectrometry . Oral morphine self - administration behavior was analyzed for 14 weeks , 24 days after chronic injection of the cannabinoid P21554 receptor antagonist / inverse agonist , SR141716A ( 3 mg / kg ) for 2 weeks during adolescence ( P01160 35 - 48 ) . Adolescent D rats exhibited higher basal levels of anandamide than adolescent AFR rats in the nucleus accumbens ( 38 % ) , the caudate - putamen nucleus ( 62 % ) and the mesencephalon ( 320 % ) , whereas adult D rats showed an increase of anandamide and 2 - AG levels in the nucleus accumbens ( 50 % and 24 % , respectively ) and of 2 - AG in the caudate - putamen nucleus ( 48 % ) , compared to adult AFR rats . Chronic administration of SR141716A to adolescent D rats blocked the escalation behavior in the morphine consumption test . Our data suggest that altered brain endocannabinoid levels may contribute to the escalation behavior in the morphine consumption test in a maternal deprivation model .","The pipeline in headache therapy . Migraine is a common , disabling , neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms . The advent of the DB00669 class of medication in the 1990s revolutionized the acute treatment of migraine , but many migraineurs do not respond optimally or at all to triptans , have intolerable adverse effects , or have contraindications to their use . Preventive pharmacotherapy has advanced mostly through serendipity , with new drugs being found effective while being used for other indications . There remains a significant need for new medications and devices that can provide effective , rapid , and sustained pain relief without adverse effects or recurrence . Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation . This article covers innovative delivery mechanisms , calcitonin gene - related peptide receptor antagonists , antibodies to calcitonin gene - related peptide and its receptor , P30939 receptor agonists , transient receptor potential vanilloid receptor modulators , orexin receptor antagonists , glial cell modulators , and neurostimulation .","The pharmacological profile and clinical prospects of the oral P30939 receptor agonist lasmiditan in the acute treatment of migraine . More than 20 years have passed without the launch of a new substance class for acute migraine therapy . Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile . New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who can not tolerate triptans for attack treatment . Lasmiditan is a novel highly specific P30939 receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay . In both phase II randomized , placebo - controlled trials in acute migraine the primary endpoint was met . For the intravenous formulation a clear dose - dependent effect on headaches could be determined . Lasmiditan tablets in doses of 50 - 400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms . This substance is chemically clearly different from other antimigraine drugs , which is also reflected by its dose - dependent adverse event profile chiefly including dizziness , vertigo , paresthesia and fatigue . Adverse events are usually linked to the central nervous system . Future phase III clinical trials with an active DB00669 comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans . They will also determine whether lasmiditan will become available to the migraine patient .","Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )","[ Pathophysiological basis of 3 subtypes in ganfeng neidong syndrome ] . The multiple parameters of 3 Subtypes : Ganyang Huafeng Syndrome ( GYHFS ) , Xuexu Shengfeng Syndrome and Yinxu Fengdong Syndrome of Ganfeng Neidong Syndrome were determined for the 1st time . It was found that there were several characteristics in GYHFS . ( 1 ) Disturbance of the cerebral blood flow and the damage of brain tissue was manifested by the abnormality of the bulbar conjunctival microcirculation , carotid Doppler ultrasonic determination and brainstem auditory and visual pathway , high blood viscosity , dysmnesia , free radical and lipid peroxidation injury and the changes of Zn , Cu , K and Mg after brain damage . ( 2 ) Stress status were expressed by the high plasma levels of cortisol , norepinephrine and epinephrine , decreased serum triiodothyronine level and hyperfunction of sympathetic nerve . ( 3 ) The marked changes of the regulating substance of the vessel smooth muscle function including the increased plasma levels of TXB2 , TXB2 / 6 - k - PGF1 alpha , and calmodulin , as well as decreased SP , P01160 , P80511 . Other 2 subtypes had about the same changes of these parameters , but of milder disorders .","Genomic organization , expression and evolution of porcine Q15648 , 2 , and 3 . Recently we identified and characterized porcine calcitonin receptor - stimulating peptide ( CRSP ) 1 , O60244 and Q9ULK4 as members of the calcitonin / calcitonin gene - related peptide ( CT / P80511 ) family . In the present study , the genomic sequences and organization of Q15648 , 2 , and 3 were determined , and the expression of the genes in the porcine brain was investigated using in situ hybridization . Analysis of 5 '- upstream regions of the three CRSPs demonstrated that Q15648 and O60244 have almost identical sequences ( > 98 % similarity ) and high sequence similarities including functional transcription binding sites with the corresponding region of human CALCA ( CT / alpha P80511 ) , whereas Q9ULK4 retains less similarity with the above genes . RH mapping of CRSPs demonstrated that they resided in a region of swine chromosome 2 ( Q9NXB9 ) . The arrangement of the genes in the region was found to be conserved in corresponding human and mouse regions . In situ hybridization demonstrated sense transcripts of the three genes in cerebrum , hippocampus , hypothalamus , pons / midbrain , and thalamus of 3 - month - old pigs , and O60244 sense transcripts additionally in tractus opticus . The sense transcripts of alpha P80511 and P10092 ( beta P80511 ) were detected in cerebrum , hippocampus , and pons / midbrain of newborn mice , and to a lesser extent in pons / midbrain of 8 - week - old mice . These results taken together with the chromosomal conservation and phylogenetic clustering of CT / P80511 family indicate that Q15648 , 2 , and 3 may be functionally different from alpha P80511 and beta P80511 , though they are indicated to have a common progenitor gene .","The search for novel migraine therapies : experimental models . The identification and development of the potent P28222 / 1D agonist , sumatriptan has resulted in new therapeutic opportunities for the treatment of migraine and a number of chemically novel agents with a similar mechanism of action have been identified . Whilst these agents are optimised to enhance the therapeutic effect of sumatriptan , development of mechanistically novel therapies may provide new directions for the care of migraine sufferers . To develop new treatment paradigms , novel chemical entities should be evaluated in animal models which are predictive of therapeutic efficacy e . g . : in animal models where sumatriptan has shown activity , or the pathophysiological processes involved in the disease must be targeted . Therefore , investigation of mechanisms underlying cortical activity and its involvement in the activation of trigeminal vascular pathways may allow better understanding of the disease and result in the identification of new non - DB00669 - like therapies .","Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK12___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK12___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .","Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK20___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .","[ The cluster headache : a clinical model of immunologic receptor pathology ? ] . It is well established that cluster headache shows impaired functions at their neuroimmunomodulatory system level . Defect in receptor expression for 5 - HT , IL - 1 and P60568 have been found in these patients . Sumatriptan , a molecule with agonistic activity for P28221 receptor , truncates cluster headache attacks in 74 % of patients . Flow cytometric analysis of monocytes expressing 5 - HT receptor in cluster headache patients showed different trends clearly correlated with the clinical response to sumatriptan . Our findings strongly support the concept that cluster headache patients who are non responders to sumatriptan could present a block in their 5 - HT receptor possibly due to specific autoantibodies for this receptor site .","P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK94___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK94___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK94___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK94___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .","[ Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine . Current hypotheses ] . The study of the mechanisms of action of the DB00669 group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine . In this context , two discoveries have been especially important : 1 ) these anti - migraine drugs are specifically recognized by three main types of serotonin receptors ( P28222 , P28221 , and P30939 ) ; and 2 ) these receptors are present in the meninges , where they are expressed by both smooth muscle cells and / or endothelial cells of the vascular wall and / or the perivascular trigeminal to be deleted axon terminals . These two findings have led to the most currently accepted physiopathogenic hypothesis , whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers , which would then trigger the release of vasoactive peptides ( DB05875 , calcitonin gene - related peptide / P80511 ) within the dura mater . Locally , i . e . , in the dura mater in particular , these substances can provoke vasodilatation ( P80511 ) and plasmatic extravasation ( DB05875 ) with platelet lysis and mast cell degranulation , thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers , and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole . This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex , where it is integrated and expressed as migraine pain . The aim of this article was to report the main findings on endogenous substances ( serotonin , peptides , nitric oxide [ NO ] , etc . ) which appear to play a key role in this physiopathogenic sequence .","Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .","[ Effects of P80511 on the P12830 expression in human bronchial epithelial cells ] . OBJECTIVE : To discuss the effect of calcitonin gene - related peptides ( P80511 ) on epithelial cadherin ( E - cd ) expression in human bronchial epithelial cells ( HBECs ) in vitro . METHODS : The effect of P80511 on E - cd protein and mRNA expression in both normal and O3 - challenged HBECs were determined by immunocytochemistry and RT - PCR . The signal transduction pathways of P80511 were observed by using protein kinase C ( PKC ) inhibitor ( H - 7 ) , calmodulin ( P62158 ) inhibitor ( W - 7 ) and PKA inhibitor ( H - 89 ) . RESULTS : P80511 increased E - cd mRNA and protein expressions of normal and O3 - challenged HBECs in a dose - dependent manner . P80511 had no effect on cytoplasm E - cd expression . Pre - treatment with H - 89 , H - 7 and W - 7 , the up - regulatory effect of P80511 on E - cd expression was partly abolished . CONCLUSION : P80511 increased in cytomembrane E - cd expression of normal and O3 - challenged HBECs in a dose - dependent manner . E - cd expression on HBECs was strengthened by P80511 via PKA , PKC and P62158 pathways .","Rare human nicotinic acetylcholine receptor α4 subunit ( P43681 ) variants affect expression and function of high - affinity nicotinic acetylcholine receptors . ___MASK29___ , the primary psychoactive component in tobacco smoke , produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors ( nAChRs ) . α4β2 nAChRs are the most abundant in mammalian brain , and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine . A number of rare variants in the P43681 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers . We compared three of these variants ( α4R336C , α4P451L , and α4R487Q ) to the common variant to determine their effects on α4β2 nAChR pharmacology . We examined [( 3 ) H ] epibatidine binding , interacting proteins , and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry ( LC - MS / MS ) in P29320 293 cells and voltage - clamp electrophysiology in Xenopus laevis oocytes . We observed significant effects of the α4 variants on nAChR expression , subcellular distribution , and sensitivity to nicotine - induced receptor upregulation . Proteomic analysis of immunopurified α4β2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions . Electrophysiological characterization in X . laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants , as well as shifts in receptor function after incubation with nicotine . Taken together , these experiments suggest that genetic variation at P43681 alters the assembly and expression of human α4β2 nAChRs , resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant . The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants .","[ Migraine - established concepts and new developments ] . Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering . Despite extensive research efforts in the recent years , many pathophysiological aspects remain unclear . An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a ( silent ) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache . Numerous studies in the last years have examined somatic , especially cerebrovascular and also psychological comorbidities . For attack therapy , P80511 antagonists have emerged as promising non - vasoconstrictive acting alternatives for triptans . However , they were so far not approved due to liver enzyme elevations in safety studies . Another new approach without vasoconstrictive action are the selective P30939 agonists ( especially Lasmiditan ) . Large placebo - controlled and DB00669 - controlled trials need to be awaited . For migraine prophylaxis , a comparable effect of sports and pharmacological prophylaxis using topiramate could be found . Particularly the combination of drug and non - drug therapies ( such as the combination of stress management training with a beta - blocker treatment ) achieves high efficacy . Also interdisciplinary , multimodal treatment approaches are important options . Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine . Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine .","Curcumin inhibits the metastasis of P04264 papillary thyroid cancer cells via modulating P12830 and matrix metalloproteinase - 9 expression . The anti - metastatic effect of curcumin on papillary thyroid cancer P04264 cells and its underlying mechanisms were investigated . Curcumin at 12 . 5 , 25 and 50 μM promoted mesenchymal - epithelial transition and decreased the migration rate of P04264 cells by 24 - 87 % . Its mechanism may involve the up - regulation of P12830 expression levels and down - regulation of the activity and expression of matrix metalloproteinase - 9 .","Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .","Migraine in the DB00669 era : progresses achieved , lessons learned and future developments . Triptans , serotonin P28222 / 1D receptor agonists , more than revolutionizing the treatment of migraine , stimulated also ground breaking research that provided insights into the anatomy , physiology , and molecular pharmacology of migraine . This knowledge , in turn , is stimulating research on new mechanisms of action for the treatment of migraine . Accordingly , it is opportune to critically review the main advances in migraine science that happened in the DB00669 era . Herein we first review and conceptualize some of the progresses achieved in migraine science during the DB00669 era . We then review the class of the triptans -- mechanism of action and clinical evidence . We close by briefly discussing the class of P80511 receptor antagonists , which is currently being developed for the acute treatment of migraine .","Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK13___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .","Small - dose capsaicin reduces systemic inflammatory responses in septic rats . We investigated the influence of small - and large - dose capsaicin in modulating systemic inflammatory responses during different stages of sepsis in rats . Rats were divided into six groups : group C , control ; group S , sepsis ; group CLC , small dose of capsaicin ( 1 mg / kg subcutaneously ) ; group O00585 , small dose of capsaicin plus sepsis ; group CHC , large dose of capsaicin ( 150 mg / kg subcutaneously ) ; group P29353 , large dose of capsaicin plus sepsis . Rats were made septic by cecal ligation and puncture ( CLP ) . Each group was subdivided into two subgroups . The animals were killed at 9 or 18 h after CLP . Plasma concentrations of calcitonin gene - related peptide ( P80511 ) , tumor necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 6 , P22301 , and total nitrite / nitrate ( NOx ) were measured . Superoxide dismutase and malondialdehyde ( MDA ) were determined in liver , lung , and heart tissues . P80511 was increased in groups S , CLC , and O00585 when compared with the other groups . In the O00585 group , plasma concentrations of P01375 , P05231 , NOx , and tissue MDA levels were reduced and P22301 level was increased when compared with groups S and P29353 18 h after CLP ( P < 0 . 05 ) . Small - dose capsaicin treatment increased antiinflammatory P22301 levels and attenuated the increases in proinflammatory cytokines , NOx , and tissue MDA in septic rats .","Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 / 1D receptor agonists , the triptans . P01258 gene - related peptide ( P80511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P80511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 and P28221 receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 receptors . Development of one or more such compound offers the exciting prospect of new non - vasoconstrictor treatments for migraine and cluster headache .","Triptan use preceding life - threatening arrhythmias in charcot - marie - tooth : a case report and review of the literature . Charcot - Marie - Tooth ( CMT ) identifies a rare group of inherited disorders of the peripheral nervous system that share clinical features of sensory and motor defects , but rarely affect cardiac function . The few references that relate CMT to cardiac pathology of any sort are so rare that their finding was considered either fortuitous or suggestive of an erroneous diagnosis . The P28222 / 1D agonists or DB00669 drug class was introduced to the clinical practice arena in the early 1990s , and since then several cardiac adverse events have been associated with its use . The authors report the case of a 41 - year - old white woman with CMT who had been recently prescribed sumatriptan and who presented with sudden loss of consciousness associated with ventricular fibrillation . These findings have been reported in the literature , but the association of DB00669 - induced arrhythmias and degenerative neuropathies remains to be established . The authors propose , through this case report and review , that the relative rarity of CMT coupled with the lack of further investigation of their association with conduction abnormalities might have set the stage for underestimation of the potentially synergistic effect with triptans in their capacity to generate life - threatening arrhythmias .","Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .","Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .","Characterization of the 3p12 . 3 - pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer . The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV - 90 ovarian cancer cell line identified the 3p12 . 3 - pcen region as a candidate tumor suppressor gene ( Q9GZX9 ) locus . In the present study , polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12 . 3 - pcen interval to a 16 . 1 Mb common region containing 12 known or hypothetical genes : 3ptel - Q9HCK4 - Q9Y6N7 - Q04446 - Q8N3J6 - A8MV65 - Q9UQN3 - P28069 - P30939 - Q9UFW8 - Q8IZM8 - Q5JPI3 - P29320 - 3pcen . Seven of these genes , Q9Y6N7 , Q04446 , A8MV65 , Q9UQN3 , Q9UFW8 , Q8IZM8 , and Q5JPI3 , exhibited gene expression in the hybrids , placing them as top Q9GZX9 candidates for further analysis . The expression of all but one ( A8MV65 ) of these genes was also detected in the parental OV - 90 cell line . Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV - 90 and donor normal chromosome 3 contig . However , the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for Q9Y6N7 , A8MV65 , Q9UQN3 , and Q9UFW8 and cDNA sequencing of the hybrids revealed biallelic expression of these genes . Interestingly , underexpression of A8MV65 and Q8IZM8 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors , and this occurred regardless of allelic content of 3p12 . 3 - pcen . The results taken together suggest that dysregulation of A8MV65 and / or Q8IZM8 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV - 90 , a cell line hemizygous for 3p .","___MASK13___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK13___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK13___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .","Individual DB00669 selection in migraine attack therapy . About 6 % of men and 18 % of women suffer migraine attacks . Migraine can induce a great impact in the quality of life of the patient and the costs of medical care and lost productivity can be also high . There are two therapeutic approaches in the treatment of migraine : preventive therapy and acute treatment of migraine attack . Immediate treatment with selective serotonin [ P28222 / 1T ] receptor agonists ( so - called triptans ) is the first - line option in the acute treatment of moderate - severe migraine attacks . The introduction in early nineties of triptans was a revolution in migraine therapy and evidences about their efficacy are at present irrefutable . At the moment , there are seven marketed molecules : sumatriptan , rizatriptan , zolmitriptan , eletriptan , naratriptan , almotriptan and frovatriptan . Obviously , every molecule has different pharmacokinetic and pharmacodinamic properties and , moreover , some triptans have several formulations : tablets , dissolvable tablets , nasal and injections . The prescription of one of these seven triptans for a specified patient is based in the drug profile : efficacy , safety , pharmacokinetics and pharmacodynamics . Despite there are a lot of published studies using triptans , no clinical trial has analyzed all the molecules at the same time . Other data to take account in the final prescription are clinical characteristics of the migraine attack and patient characteristics : labour aspects , style of life and the patient medical history . We present a state - of - the - art of the DB00669 selection in treatment of moderate - severe migraine attacks .","Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK62___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .","Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via P21554 and \" DB00669 \" receptors : implications in migraine . Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine . Endocannabinoids , as well as being physiologically analgesic , are known to inhibit dural trigeminovascular nociceptive responses . They are also involved in the descending modulation of cutaneous - evoked C - fiber spinal nociceptive responses from the brainstem . The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and / or cutaneous facial trigeminovascular nociceptive responses , from the brainstem ventrolateral periaqueductal gray ( vlPAG ) . P21554 receptor activation in the vlPAG attenuated dural - evoked Aδ - fiber neurons ( maximally by 19 % ) and basal spontaneous activity ( maximally by 33 % ) in the rat trigeminocervical complex , but there was no effect on cutaneous facial receptive field responses . This inhibitory vlPAG - mediated modulation was inhibited by specific P21554 receptor antagonism , given via the vlPAG , and with a P28222 / 1D receptor antagonist , given either locally in the vlPAG or systemically . These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ - fiber dural - nociceptive responses , which differs from the way the brainstem modulates spinal nociceptive transmission . Furthermore , our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information , suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG .","Sumatriptan ( P28221 receptor agonist ) does not exacerbate symptoms in obsessive compulsive disorder . The non - selective serotonin ( 5 - HT ) receptor agonist meta - chlorophenylpiperazine ( mCPP ) has been reported to elicit symptoms in patients with obsessive compulsive disorder ( OCD ) . MK - 212 , another non - selective 5 - HT receptor agonist , does not seem to induce obsessive compulsive symptoms in OCD patients . The major pharmacological difference between mCPP and MK - 212 is their affinity for the 5 - HT ( ID ) receptor . The aim of this study was to explore the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD , by using a challenge paradigm with the selective 5 - HT ( ID ) receptor agonist sumatriptan ( DB00669 ) . A randomized , double - blind , placebo - controlled crossover challenge with sumatriptan ( 100 mg PO ) was performed in 15 OCD patients . Neither the obsessive compulsive symptoms nor mood or anxiety symptoms changed significantly following sumatriptan administration as compared to placebo . Sumatriptan did induce a significant increase in plasma growth hormone ( GH ) levels . In the present study , no indication were found for the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD . It should be noted , however , that sumatriptan does not readily pass the blood - brain barrier . Selective 5 - HT ( ID ) receptors with better brain penetrating properties may shed more light on the role of this 5 - HT receptor subtype in OCD .","[ Triptans and calcitonin gene - related peptide ( P80511 ) receptor antagonists ] . While triptans , the P28222 / 1D agonists , are effective and generally well - tolerated in many patients up to one - third of migraine patients either may not respond well to triptans , may not tolerate their side effects , or may have contraindications that preclude their use . Recurrence , DB00669 - related side effects , and cardiovascular constriction effects are demerits for acute migraine treatment . P80511 receptor antagonists , the so - called gepants , were clearely designed and expected to be better than triptans . P80511 is located in sensory nerve endings around cranial blood vessels . P80511 is a strong dilator of cerebral arteries and intravenous infusion of P80511 cause a migraine attack . DB04869 is the first selective P80511 receptor antagonist of proven efficacy in migraine . DB04869 could only be administered intravenously and never taken beyond Phase II . Telcagepant is orally available and several completed Phase III trials have revealed positive results . In several comparative studies of telcagepant and triptans , telcegepant did not appeared more effective than zolmitriptan or rizatriptan , although it had fewer DB00669 - related adverse events and drug - related adverse enents . A small number of patients taking olcegepant showed marked elevation in liver transaminase levels . It was decided to discontinue development of olcegepant . New P80511 receptor antagonists would be expected for acute migraine treatment .","___MASK48___ treatment ameliorates murine chronic graft - versus - host disease . Chronic graft - versus - host disease ( cGVHD ) is a life - threatening impediment to allogeneic hematopoietic stem cell transplantation , and current therapies do not completely prevent and / or treat cGVHD . P01730 + T cells and B cells mediate cGVHD ; therefore , targeting these populations may inhibit cGVHD pathogenesis . ___MASK48___ is an FDA - approved irreversible inhibitor of Bruton ' s tyrosine kinase ( Q06187 ) and P60568 inducible T cell kinase ( Q08881 ) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity . Here , we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models , a model interrogating T cell - driven sclerodermatous cGVHD and an alloantibody - driven multiorgan system cGVHD model that induces bronchiolar obliterans ( BO ) . In the T cell - mediated sclerodermatous cGVHD model , ibrutinib treatment delayed progression , improved survival , and ameliorated clinical and pathological manifestations . In the alloantibody - driven cGVHD model , ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition . Animals lacking Q06187 and Q08881 did not develop cGVHD , indicating that these molecules are critical to cGVHD development . Furthermore , ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD . Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent , warranting consideration for cGVHD clinical trials .","A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK94___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK94___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK94___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK94___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Rizatriptan in migraineurs with unilateral cranial autonomic symptoms : a double - blind trial . The objective and background is to confirm in a double - blind , placebo - controlled study the high DB00669 response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms . In this randomized , double - blind , placebo - controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo ( ratio 1 : 1 ) and treated for a single moderate or severe migraine attack . The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h . Secondary endpoints included pain relief , no associated symptoms and sustained pain freedom or relief . Significantly more patients reported pain freedom at 2 h after taking rizatriptan ( 54 % ) than after placebo ( 8 % ) ( therapeutic gain 46 % [ 28 % ; 64 % ] ; P < 0 . 001 ) . Similarly , significantly more patients reported total migraine freedom at 2 h after rizatriptan ( 51 % ) than after placebo ( 8 % ) ( therapeutic gain 43 % [ 26 % ; 61 % ] ; P < 0 . 001 ) . Rizatriptan was also more effective than placebo on most secondary endpoints . We confirm in a placebo - controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans , probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular P28222 / 1D receptors . Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients .","A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .","UV - induced but P04637 independent apoptotic death in CHO . P04264 cells is promoted by M phase inhibitors .","Colocalization of P80511 with P28222 / 1D receptors and DB05875 in trigeminal ganglion neurons in rats . Vasodilatation in the dura mater has been implicated in migraine pathogenesis . Anti - migraine DB00669 drugs block vasodilatation by binding to P28222 / 1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles . Previous studies suggest that calcitonin gene - related peptide ( P80511 ) released from Adelta - fibres plays a more important role than DB05875 ( SP ) released from C - fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of DB00669 drugs is inhibiting P80511 release . In the present study , the relationship between P80511 and P28222 / 1D receptors , and between P80511 and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining . P80511 , P28222 , P28221 and SP - positive trigeminal ganglion neurons were all predominantly small and medium - sized . In the trigeminal ganglia , approximately 50 % of P80511 - positive neurons were P28222 positive . Similarly , approximately 55 % of P80511 - positive neurons were P28221 immunoreactive . Approximately 50 % of P80511 - positive neurons were SP - positive , while 93 % of SP - positive neurons were P80511 - positive , suggesting that nearly all SP - positive neurons also contain P80511 . The fibre types of the P28222 - and P28221 - positive neurons were further investigated with an antibody against the A - fibre marker 200 - kDa neurofilaments ( NF200 ) . Approximately 46 % of the P28222 - positive and 43 % of the P28221 - positive trigeminal ganglion neurons were also NF200 positive , indicating that many A - fibre trigeminal neurons express P28222 or P28221 receptors . These results support the hypothesis that one important action of antimigraine drugs is the inhibition of P80511 release and that Adelta - fibres may play an important role in migraine pathogenesis .","Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .","Migraine : current concepts and emerging therapies . Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . Migraine affects a substantial fraction of world population and is a major cause of disability in the work place . Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular ( due to cerebral vasodilatation ) , neurological ( abnormal neurological firing which causes the spreading depression and migraine ) and neurogenic dural inflammation ( release of inflammatory neuropeptides ) . The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder . The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention . The last decade has witnessed the advent of Sumatriptan and the ' DB00669 ' class of P28222 / 1D receptor agonists which have well established efficacy in treating migraine . Currently prophylactic treatments for migraine include calcium channel blockers , 5 - HT2 receptor antagonists , beta adrenoceptor blockers and gamma - amino butyric acid ( GABA ) agonists . Unfortunately , many of these treatments are non specific and not always effective . Despite such progress , in view of the complexity of the etiology of migraine , it still remains undiagnosed and available therapies are underused . In this article , the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed . Furthermore , the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine , with a special emphasis to calcitonin gene - related peptide , are critically evaluated .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super - families have been identified : DB00171 - binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system ( s ) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules .","[ Treatments of migraine ] . During the 1980s , a new class of drugs for the acute treatment of migraine attacks was developed , the triptans . These agents are selective P28222 / 1D serotonin receptor agonists , and were developed in order to address the underlying biological mechanism of the migraine attack . French guidelines in migraine are available since 2002 . It is recommended to use a stratified treatment approach during the first consultation with the use of NSAID in first line acute treatment and DB00669 in second line . It is also recommended to use prophylactic treatment when the patient experience frequent and / or severe migraine attack with a bad quality of life and a real impairment .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","The biology of serotonin receptors : focus on migraine pathophysiology and treatment . Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families ( 5 - HT1 - P34969 ) . With the exception of the 5 - Q9H205 which is a ligand - gated ion channel , all others are G - protein coupled receptors with each family sharing structural , pharmacological and transductional characteristics . 5 - HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission , and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache . In this respect , activation of vascular P41595 and / or P34969 receptors , possibly as a consequence of the sudden rise in 5 - HT levels reported at the onset of a migraine attack , would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents , hence initiating the manifestation of head pain . At this stage in the migraine process , activation of specific subtypes of 5 - HT1 receptors has proven clinically effective in relieving migraine pain . Neural P28221 and / or P30939 receptors localized pre - junctionally on trigeminovascular afferents appear to mediate the DB00669 - induced inhibition of the neurogenic inflammatory response , with possible additional sites of action for brain penetrant 5 - HT1 receptor agonists in inhibiting the transmission of pain centrally . In contrast , activation of vascular P28222 receptors would constrict meningeal vessels hence recovering their pre - migraine diameter . The recent availability of subtype selective P28221 and P30939 receptor agonists should allow a further test of the neural / vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile .","No contractile effect for P28221 and P30939 receptor agonists in human and bovine cerebral arteries : similarity with human coronary artery . 1 . Using subtype - selective 5 - HT1 receptor agonists and / or the 5 - HT1 receptor antagonist GR127935 , we characterized in vitro the 5 - HT receptor that mediates the contraction of human and bovine cerebral arteries . Further , we investigated which sumatriptan - sensitive receptors are present in human coronary artery by reverse - transcriptase polymerase chain reaction ( RT - PCR ) . 2 . Agonists with affinity at the P28222 receptor , such as sumatriptan , alniditan and / or IS - 159 , elicited dose - dependent contraction in both human and bovine cerebral arteries . They behaved as full agonists at the sumatriptan - sensitive 5 - HT1 receptors in both species . In contrast , PNU - 109291 and LY344864 , selective agonists at P28221 and P30939 receptors , respectively , were devoid of any significant vasocontractile activity in cerebral arteries , or did not affect the sumatriptan - induced vasocontraction . The rank order of agonist potency was similar in both species and could be summarized as 5 - HT = alniditan > sumatriptan = IS - 159 >>> PNU - 109291 = LY344864 . 3 . In bovine cerebral arteries , the 5 - HT1 receptor antagonist GR127935 dose - dependently inhibited the vasoconstrictions elicited by both 5 - HT and sumatriptan , with respective pA2 values of 8 . 0 and 8 . 6 . 4 . RT - PCR studies in human coronary arteries showed a strong signal for the P28222 receptor while message for the P30939 receptor was weak and less frequently detected . Expression of P28221 receptor mRNA was not detected in any sample . 5 . The present results demonstrate that the DB00669 - induced contraction in brain vessels is mediated exclusively by the P28222 receptor , which is also present in a majority of human coronary arteries . These results suggest that selective P28221 and P30939 receptor agonists might represent new antimigraine drugs devoid of cerebro - and cardiovascular effects .","Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK26___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK26___ who were treated with a single dose of mifepristone .","[ ___MASK48___ : A new drug of B - cell malignancies ] . ___MASK48___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK48___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK48___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .","[ Rizatriptan : experience after 15 years of clinical use ] . We review the development of rizatriptan , one of the seven P28222 / 1D agonists available for the symptomatic treatment of migraine , emphasizing the most relevant contributions carried out from our country . Rizatriptan has shown the quickest onset of action , both in controlled studies and in the different metaanalyses , which translates in high efficacy levels at two hours . Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group . Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this DB00669 . Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents . This global profile places rizatriptan as a DB00669 of first choice for any kind of migraine attacks .","Tissue injury regulates serotonin 1D receptor expression : implications for the control of migraine and inflammatory pain . The anti - migraine action of \" DB00669 \" drugs involves the activation of serotonin subtype 1D ( P28221 ) receptors expressed on \" pain - responsive \" trigeminal primary afferents . In the central terminals of these nociceptors , the receptor is concentrated on peptidergic dense core vesicles ( DCVs ) and is notably absent from the plasma membrane . Based on this arrangement , we hypothesized that in the resting state the receptor is not available for binding by a DB00669 , but that noxious stimulation of these afferents could trigger vesicular release of DCVs , thus externalizing the receptor . Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat , there is a significant increase of P28221 - immunoreactivity ( IR ) in the ipsilateral dorsal horn of the spinal cord . We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane , where it is more readily detected . We also observed divergent changes in P28221 - IR in inflammatory and nerve - injury models of persistent pain , occurring at least in part through the regulation of P28221 - receptor gene expression . Finally , we found that P28221 - IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide DB05875 . This result differs from that reported for the partial differential - opioid receptor , which is also sorted to DCVs , but is greatly reduced in preprotachykinin mutant mice . We suggest that a \" pain \" - triggered regulation of P28221 - receptor expression underlies the effectiveness of triptans for the treatment of migraine . Moreover , the widespread expression of P28221 receptor in somatic nociceptive afferents suggests that triptans could , in certain circumstances , treat pain in nontrigeminal regions of the body .","___MASK29___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .","Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .","Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK43___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients ."],"string":"[\n \"How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .\",\n \"DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .\",\n \"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .\",\n \"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .\",\n \"Possible involvement of endocannabinoids in the increase of morphine consumption in maternally deprived rat . Whether adolescent exposure to chronic DB00470 ( THC ) facilitates progression to opioid consumption is still controversial . In a maternal deprivation model ( 3 h daily from postnatal day 1 - 14 ) , we previously reported that adolescent exposure to chronic THC blocks morphine dependence in maternally deprived ( D ) rats . Owing to the existence of a functional cross - interaction between the opioid and cannabinoid systems in reward , we evaluated if the vulnerability to opiate reward in D rats , may involve an alteration of the endocannabinoid system . Anandamide and 2 - arachidonoylglycerol ( 2 - AG ) , were quantified in the striatum and mesencephalon of adolescent and adult D and non - deprived ( animal facility rearing , AFR ) rats by isotope dilution liquid chromatography - mass spectrometry . Oral morphine self - administration behavior was analyzed for 14 weeks , 24 days after chronic injection of the cannabinoid P21554 receptor antagonist / inverse agonist , SR141716A ( 3 mg / kg ) for 2 weeks during adolescence ( P01160 35 - 48 ) . Adolescent D rats exhibited higher basal levels of anandamide than adolescent AFR rats in the nucleus accumbens ( 38 % ) , the caudate - putamen nucleus ( 62 % ) and the mesencephalon ( 320 % ) , whereas adult D rats showed an increase of anandamide and 2 - AG levels in the nucleus accumbens ( 50 % and 24 % , respectively ) and of 2 - AG in the caudate - putamen nucleus ( 48 % ) , compared to adult AFR rats . Chronic administration of SR141716A to adolescent D rats blocked the escalation behavior in the morphine consumption test . Our data suggest that altered brain endocannabinoid levels may contribute to the escalation behavior in the morphine consumption test in a maternal deprivation model .\",\n \"The pipeline in headache therapy . Migraine is a common , disabling , neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms . The advent of the DB00669 class of medication in the 1990s revolutionized the acute treatment of migraine , but many migraineurs do not respond optimally or at all to triptans , have intolerable adverse effects , or have contraindications to their use . Preventive pharmacotherapy has advanced mostly through serendipity , with new drugs being found effective while being used for other indications . There remains a significant need for new medications and devices that can provide effective , rapid , and sustained pain relief without adverse effects or recurrence . Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation . This article covers innovative delivery mechanisms , calcitonin gene - related peptide receptor antagonists , antibodies to calcitonin gene - related peptide and its receptor , P30939 receptor agonists , transient receptor potential vanilloid receptor modulators , orexin receptor antagonists , glial cell modulators , and neurostimulation .\",\n \"The pharmacological profile and clinical prospects of the oral P30939 receptor agonist lasmiditan in the acute treatment of migraine . More than 20 years have passed without the launch of a new substance class for acute migraine therapy . Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile . New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who can not tolerate triptans for attack treatment . Lasmiditan is a novel highly specific P30939 receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay . In both phase II randomized , placebo - controlled trials in acute migraine the primary endpoint was met . For the intravenous formulation a clear dose - dependent effect on headaches could be determined . Lasmiditan tablets in doses of 50 - 400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms . This substance is chemically clearly different from other antimigraine drugs , which is also reflected by its dose - dependent adverse event profile chiefly including dizziness , vertigo , paresthesia and fatigue . Adverse events are usually linked to the central nervous system . Future phase III clinical trials with an active DB00669 comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans . They will also determine whether lasmiditan will become available to the migraine patient .\",\n \"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"[ Pathophysiological basis of 3 subtypes in ganfeng neidong syndrome ] . The multiple parameters of 3 Subtypes : Ganyang Huafeng Syndrome ( GYHFS ) , Xuexu Shengfeng Syndrome and Yinxu Fengdong Syndrome of Ganfeng Neidong Syndrome were determined for the 1st time . It was found that there were several characteristics in GYHFS . ( 1 ) Disturbance of the cerebral blood flow and the damage of brain tissue was manifested by the abnormality of the bulbar conjunctival microcirculation , carotid Doppler ultrasonic determination and brainstem auditory and visual pathway , high blood viscosity , dysmnesia , free radical and lipid peroxidation injury and the changes of Zn , Cu , K and Mg after brain damage . ( 2 ) Stress status were expressed by the high plasma levels of cortisol , norepinephrine and epinephrine , decreased serum triiodothyronine level and hyperfunction of sympathetic nerve . ( 3 ) The marked changes of the regulating substance of the vessel smooth muscle function including the increased plasma levels of TXB2 , TXB2 / 6 - k - PGF1 alpha , and calmodulin , as well as decreased SP , P01160 , P80511 . Other 2 subtypes had about the same changes of these parameters , but of milder disorders .\",\n \"Genomic organization , expression and evolution of porcine Q15648 , 2 , and 3 . Recently we identified and characterized porcine calcitonin receptor - stimulating peptide ( CRSP ) 1 , O60244 and Q9ULK4 as members of the calcitonin / calcitonin gene - related peptide ( CT / P80511 ) family . In the present study , the genomic sequences and organization of Q15648 , 2 , and 3 were determined , and the expression of the genes in the porcine brain was investigated using in situ hybridization . Analysis of 5 '- upstream regions of the three CRSPs demonstrated that Q15648 and O60244 have almost identical sequences ( > 98 % similarity ) and high sequence similarities including functional transcription binding sites with the corresponding region of human CALCA ( CT / alpha P80511 ) , whereas Q9ULK4 retains less similarity with the above genes . RH mapping of CRSPs demonstrated that they resided in a region of swine chromosome 2 ( Q9NXB9 ) . The arrangement of the genes in the region was found to be conserved in corresponding human and mouse regions . In situ hybridization demonstrated sense transcripts of the three genes in cerebrum , hippocampus , hypothalamus , pons / midbrain , and thalamus of 3 - month - old pigs , and O60244 sense transcripts additionally in tractus opticus . The sense transcripts of alpha P80511 and P10092 ( beta P80511 ) were detected in cerebrum , hippocampus , and pons / midbrain of newborn mice , and to a lesser extent in pons / midbrain of 8 - week - old mice . These results taken together with the chromosomal conservation and phylogenetic clustering of CT / P80511 family indicate that Q15648 , 2 , and 3 may be functionally different from alpha P80511 and beta P80511 , though they are indicated to have a common progenitor gene .\",\n \"The search for novel migraine therapies : experimental models . The identification and development of the potent P28222 / 1D agonist , sumatriptan has resulted in new therapeutic opportunities for the treatment of migraine and a number of chemically novel agents with a similar mechanism of action have been identified . Whilst these agents are optimised to enhance the therapeutic effect of sumatriptan , development of mechanistically novel therapies may provide new directions for the care of migraine sufferers . To develop new treatment paradigms , novel chemical entities should be evaluated in animal models which are predictive of therapeutic efficacy e . g . : in animal models where sumatriptan has shown activity , or the pathophysiological processes involved in the disease must be targeted . Therefore , investigation of mechanisms underlying cortical activity and its involvement in the activation of trigeminal vascular pathways may allow better understanding of the disease and result in the identification of new non - DB00669 - like therapies .\",\n \"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK12___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK12___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .\",\n \"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK20___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .\",\n \"[ The cluster headache : a clinical model of immunologic receptor pathology ? ] . It is well established that cluster headache shows impaired functions at their neuroimmunomodulatory system level . Defect in receptor expression for 5 - HT , IL - 1 and P60568 have been found in these patients . Sumatriptan , a molecule with agonistic activity for P28221 receptor , truncates cluster headache attacks in 74 % of patients . Flow cytometric analysis of monocytes expressing 5 - HT receptor in cluster headache patients showed different trends clearly correlated with the clinical response to sumatriptan . Our findings strongly support the concept that cluster headache patients who are non responders to sumatriptan could present a block in their 5 - HT receptor possibly due to specific autoantibodies for this receptor site .\",\n \"P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK94___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK94___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK94___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK94___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .\",\n \"[ Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine . Current hypotheses ] . The study of the mechanisms of action of the DB00669 group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine . In this context , two discoveries have been especially important : 1 ) these anti - migraine drugs are specifically recognized by three main types of serotonin receptors ( P28222 , P28221 , and P30939 ) ; and 2 ) these receptors are present in the meninges , where they are expressed by both smooth muscle cells and / or endothelial cells of the vascular wall and / or the perivascular trigeminal to be deleted axon terminals . These two findings have led to the most currently accepted physiopathogenic hypothesis , whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers , which would then trigger the release of vasoactive peptides ( DB05875 , calcitonin gene - related peptide / P80511 ) within the dura mater . Locally , i . e . , in the dura mater in particular , these substances can provoke vasodilatation ( P80511 ) and plasmatic extravasation ( DB05875 ) with platelet lysis and mast cell degranulation , thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers , and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole . This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex , where it is integrated and expressed as migraine pain . The aim of this article was to report the main findings on endogenous substances ( serotonin , peptides , nitric oxide [ NO ] , etc . ) which appear to play a key role in this physiopathogenic sequence .\",\n \"Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .\",\n \"[ Effects of P80511 on the P12830 expression in human bronchial epithelial cells ] . OBJECTIVE : To discuss the effect of calcitonin gene - related peptides ( P80511 ) on epithelial cadherin ( E - cd ) expression in human bronchial epithelial cells ( HBECs ) in vitro . METHODS : The effect of P80511 on E - cd protein and mRNA expression in both normal and O3 - challenged HBECs were determined by immunocytochemistry and RT - PCR . The signal transduction pathways of P80511 were observed by using protein kinase C ( PKC ) inhibitor ( H - 7 ) , calmodulin ( P62158 ) inhibitor ( W - 7 ) and PKA inhibitor ( H - 89 ) . RESULTS : P80511 increased E - cd mRNA and protein expressions of normal and O3 - challenged HBECs in a dose - dependent manner . P80511 had no effect on cytoplasm E - cd expression . Pre - treatment with H - 89 , H - 7 and W - 7 , the up - regulatory effect of P80511 on E - cd expression was partly abolished . CONCLUSION : P80511 increased in cytomembrane E - cd expression of normal and O3 - challenged HBECs in a dose - dependent manner . E - cd expression on HBECs was strengthened by P80511 via PKA , PKC and P62158 pathways .\",\n \"Rare human nicotinic acetylcholine receptor α4 subunit ( P43681 ) variants affect expression and function of high - affinity nicotinic acetylcholine receptors . ___MASK29___ , the primary psychoactive component in tobacco smoke , produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors ( nAChRs ) . α4β2 nAChRs are the most abundant in mammalian brain , and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine . A number of rare variants in the P43681 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers . We compared three of these variants ( α4R336C , α4P451L , and α4R487Q ) to the common variant to determine their effects on α4β2 nAChR pharmacology . We examined [( 3 ) H ] epibatidine binding , interacting proteins , and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry ( LC - MS / MS ) in P29320 293 cells and voltage - clamp electrophysiology in Xenopus laevis oocytes . We observed significant effects of the α4 variants on nAChR expression , subcellular distribution , and sensitivity to nicotine - induced receptor upregulation . Proteomic analysis of immunopurified α4β2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions . Electrophysiological characterization in X . laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants , as well as shifts in receptor function after incubation with nicotine . Taken together , these experiments suggest that genetic variation at P43681 alters the assembly and expression of human α4β2 nAChRs , resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant . The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants .\",\n \"[ Migraine - established concepts and new developments ] . Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering . Despite extensive research efforts in the recent years , many pathophysiological aspects remain unclear . An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a ( silent ) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache . Numerous studies in the last years have examined somatic , especially cerebrovascular and also psychological comorbidities . For attack therapy , P80511 antagonists have emerged as promising non - vasoconstrictive acting alternatives for triptans . However , they were so far not approved due to liver enzyme elevations in safety studies . Another new approach without vasoconstrictive action are the selective P30939 agonists ( especially Lasmiditan ) . Large placebo - controlled and DB00669 - controlled trials need to be awaited . For migraine prophylaxis , a comparable effect of sports and pharmacological prophylaxis using topiramate could be found . Particularly the combination of drug and non - drug therapies ( such as the combination of stress management training with a beta - blocker treatment ) achieves high efficacy . Also interdisciplinary , multimodal treatment approaches are important options . Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine . Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine .\",\n \"Curcumin inhibits the metastasis of P04264 papillary thyroid cancer cells via modulating P12830 and matrix metalloproteinase - 9 expression . The anti - metastatic effect of curcumin on papillary thyroid cancer P04264 cells and its underlying mechanisms were investigated . Curcumin at 12 . 5 , 25 and 50 μM promoted mesenchymal - epithelial transition and decreased the migration rate of P04264 cells by 24 - 87 % . Its mechanism may involve the up - regulation of P12830 expression levels and down - regulation of the activity and expression of matrix metalloproteinase - 9 .\",\n \"Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .\",\n \"Migraine in the DB00669 era : progresses achieved , lessons learned and future developments . Triptans , serotonin P28222 / 1D receptor agonists , more than revolutionizing the treatment of migraine , stimulated also ground breaking research that provided insights into the anatomy , physiology , and molecular pharmacology of migraine . This knowledge , in turn , is stimulating research on new mechanisms of action for the treatment of migraine . Accordingly , it is opportune to critically review the main advances in migraine science that happened in the DB00669 era . Herein we first review and conceptualize some of the progresses achieved in migraine science during the DB00669 era . We then review the class of the triptans -- mechanism of action and clinical evidence . We close by briefly discussing the class of P80511 receptor antagonists , which is currently being developed for the acute treatment of migraine .\",\n \"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK13___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .\",\n \"Small - dose capsaicin reduces systemic inflammatory responses in septic rats . We investigated the influence of small - and large - dose capsaicin in modulating systemic inflammatory responses during different stages of sepsis in rats . Rats were divided into six groups : group C , control ; group S , sepsis ; group CLC , small dose of capsaicin ( 1 mg / kg subcutaneously ) ; group O00585 , small dose of capsaicin plus sepsis ; group CHC , large dose of capsaicin ( 150 mg / kg subcutaneously ) ; group P29353 , large dose of capsaicin plus sepsis . Rats were made septic by cecal ligation and puncture ( CLP ) . Each group was subdivided into two subgroups . The animals were killed at 9 or 18 h after CLP . Plasma concentrations of calcitonin gene - related peptide ( P80511 ) , tumor necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 6 , P22301 , and total nitrite / nitrate ( NOx ) were measured . Superoxide dismutase and malondialdehyde ( MDA ) were determined in liver , lung , and heart tissues . P80511 was increased in groups S , CLC , and O00585 when compared with the other groups . In the O00585 group , plasma concentrations of P01375 , P05231 , NOx , and tissue MDA levels were reduced and P22301 level was increased when compared with groups S and P29353 18 h after CLP ( P < 0 . 05 ) . Small - dose capsaicin treatment increased antiinflammatory P22301 levels and attenuated the increases in proinflammatory cytokines , NOx , and tissue MDA in septic rats .\",\n \"Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 / 1D receptor agonists , the triptans . P01258 gene - related peptide ( P80511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P80511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 and P28221 receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 receptors . Development of one or more such compound offers the exciting prospect of new non - vasoconstrictor treatments for migraine and cluster headache .\",\n \"Triptan use preceding life - threatening arrhythmias in charcot - marie - tooth : a case report and review of the literature . Charcot - Marie - Tooth ( CMT ) identifies a rare group of inherited disorders of the peripheral nervous system that share clinical features of sensory and motor defects , but rarely affect cardiac function . The few references that relate CMT to cardiac pathology of any sort are so rare that their finding was considered either fortuitous or suggestive of an erroneous diagnosis . The P28222 / 1D agonists or DB00669 drug class was introduced to the clinical practice arena in the early 1990s , and since then several cardiac adverse events have been associated with its use . The authors report the case of a 41 - year - old white woman with CMT who had been recently prescribed sumatriptan and who presented with sudden loss of consciousness associated with ventricular fibrillation . These findings have been reported in the literature , but the association of DB00669 - induced arrhythmias and degenerative neuropathies remains to be established . The authors propose , through this case report and review , that the relative rarity of CMT coupled with the lack of further investigation of their association with conduction abnormalities might have set the stage for underestimation of the potentially synergistic effect with triptans in their capacity to generate life - threatening arrhythmias .\",\n \"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .\",\n \"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .\",\n \"Characterization of the 3p12 . 3 - pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer . The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV - 90 ovarian cancer cell line identified the 3p12 . 3 - pcen region as a candidate tumor suppressor gene ( Q9GZX9 ) locus . In the present study , polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12 . 3 - pcen interval to a 16 . 1 Mb common region containing 12 known or hypothetical genes : 3ptel - Q9HCK4 - Q9Y6N7 - Q04446 - Q8N3J6 - A8MV65 - Q9UQN3 - P28069 - P30939 - Q9UFW8 - Q8IZM8 - Q5JPI3 - P29320 - 3pcen . Seven of these genes , Q9Y6N7 , Q04446 , A8MV65 , Q9UQN3 , Q9UFW8 , Q8IZM8 , and Q5JPI3 , exhibited gene expression in the hybrids , placing them as top Q9GZX9 candidates for further analysis . The expression of all but one ( A8MV65 ) of these genes was also detected in the parental OV - 90 cell line . Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV - 90 and donor normal chromosome 3 contig . However , the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for Q9Y6N7 , A8MV65 , Q9UQN3 , and Q9UFW8 and cDNA sequencing of the hybrids revealed biallelic expression of these genes . Interestingly , underexpression of A8MV65 and Q8IZM8 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors , and this occurred regardless of allelic content of 3p12 . 3 - pcen . The results taken together suggest that dysregulation of A8MV65 and / or Q8IZM8 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV - 90 , a cell line hemizygous for 3p .\",\n \"___MASK13___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK13___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK13___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .\",\n \"Individual DB00669 selection in migraine attack therapy . About 6 % of men and 18 % of women suffer migraine attacks . Migraine can induce a great impact in the quality of life of the patient and the costs of medical care and lost productivity can be also high . There are two therapeutic approaches in the treatment of migraine : preventive therapy and acute treatment of migraine attack . Immediate treatment with selective serotonin [ P28222 / 1T ] receptor agonists ( so - called triptans ) is the first - line option in the acute treatment of moderate - severe migraine attacks . The introduction in early nineties of triptans was a revolution in migraine therapy and evidences about their efficacy are at present irrefutable . At the moment , there are seven marketed molecules : sumatriptan , rizatriptan , zolmitriptan , eletriptan , naratriptan , almotriptan and frovatriptan . Obviously , every molecule has different pharmacokinetic and pharmacodinamic properties and , moreover , some triptans have several formulations : tablets , dissolvable tablets , nasal and injections . The prescription of one of these seven triptans for a specified patient is based in the drug profile : efficacy , safety , pharmacokinetics and pharmacodynamics . Despite there are a lot of published studies using triptans , no clinical trial has analyzed all the molecules at the same time . Other data to take account in the final prescription are clinical characteristics of the migraine attack and patient characteristics : labour aspects , style of life and the patient medical history . We present a state - of - the - art of the DB00669 selection in treatment of moderate - severe migraine attacks .\",\n \"Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK62___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .\",\n \"Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via P21554 and \\\" DB00669 \\\" receptors : implications in migraine . Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine . Endocannabinoids , as well as being physiologically analgesic , are known to inhibit dural trigeminovascular nociceptive responses . They are also involved in the descending modulation of cutaneous - evoked C - fiber spinal nociceptive responses from the brainstem . The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and / or cutaneous facial trigeminovascular nociceptive responses , from the brainstem ventrolateral periaqueductal gray ( vlPAG ) . P21554 receptor activation in the vlPAG attenuated dural - evoked Aδ - fiber neurons ( maximally by 19 % ) and basal spontaneous activity ( maximally by 33 % ) in the rat trigeminocervical complex , but there was no effect on cutaneous facial receptive field responses . This inhibitory vlPAG - mediated modulation was inhibited by specific P21554 receptor antagonism , given via the vlPAG , and with a P28222 / 1D receptor antagonist , given either locally in the vlPAG or systemically . These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ - fiber dural - nociceptive responses , which differs from the way the brainstem modulates spinal nociceptive transmission . Furthermore , our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information , suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG .\",\n \"Sumatriptan ( P28221 receptor agonist ) does not exacerbate symptoms in obsessive compulsive disorder . The non - selective serotonin ( 5 - HT ) receptor agonist meta - chlorophenylpiperazine ( mCPP ) has been reported to elicit symptoms in patients with obsessive compulsive disorder ( OCD ) . MK - 212 , another non - selective 5 - HT receptor agonist , does not seem to induce obsessive compulsive symptoms in OCD patients . The major pharmacological difference between mCPP and MK - 212 is their affinity for the 5 - HT ( ID ) receptor . The aim of this study was to explore the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD , by using a challenge paradigm with the selective 5 - HT ( ID ) receptor agonist sumatriptan ( DB00669 ) . A randomized , double - blind , placebo - controlled crossover challenge with sumatriptan ( 100 mg PO ) was performed in 15 OCD patients . Neither the obsessive compulsive symptoms nor mood or anxiety symptoms changed significantly following sumatriptan administration as compared to placebo . Sumatriptan did induce a significant increase in plasma growth hormone ( GH ) levels . In the present study , no indication were found for the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD . It should be noted , however , that sumatriptan does not readily pass the blood - brain barrier . Selective 5 - HT ( ID ) receptors with better brain penetrating properties may shed more light on the role of this 5 - HT receptor subtype in OCD .\",\n \"[ Triptans and calcitonin gene - related peptide ( P80511 ) receptor antagonists ] . While triptans , the P28222 / 1D agonists , are effective and generally well - tolerated in many patients up to one - third of migraine patients either may not respond well to triptans , may not tolerate their side effects , or may have contraindications that preclude their use . Recurrence , DB00669 - related side effects , and cardiovascular constriction effects are demerits for acute migraine treatment . P80511 receptor antagonists , the so - called gepants , were clearely designed and expected to be better than triptans . P80511 is located in sensory nerve endings around cranial blood vessels . P80511 is a strong dilator of cerebral arteries and intravenous infusion of P80511 cause a migraine attack . DB04869 is the first selective P80511 receptor antagonist of proven efficacy in migraine . DB04869 could only be administered intravenously and never taken beyond Phase II . Telcagepant is orally available and several completed Phase III trials have revealed positive results . In several comparative studies of telcagepant and triptans , telcegepant did not appeared more effective than zolmitriptan or rizatriptan , although it had fewer DB00669 - related adverse events and drug - related adverse enents . A small number of patients taking olcegepant showed marked elevation in liver transaminase levels . It was decided to discontinue development of olcegepant . New P80511 receptor antagonists would be expected for acute migraine treatment .\",\n \"___MASK48___ treatment ameliorates murine chronic graft - versus - host disease . Chronic graft - versus - host disease ( cGVHD ) is a life - threatening impediment to allogeneic hematopoietic stem cell transplantation , and current therapies do not completely prevent and / or treat cGVHD . P01730 + T cells and B cells mediate cGVHD ; therefore , targeting these populations may inhibit cGVHD pathogenesis . ___MASK48___ is an FDA - approved irreversible inhibitor of Bruton ' s tyrosine kinase ( Q06187 ) and P60568 inducible T cell kinase ( Q08881 ) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity . Here , we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models , a model interrogating T cell - driven sclerodermatous cGVHD and an alloantibody - driven multiorgan system cGVHD model that induces bronchiolar obliterans ( BO ) . In the T cell - mediated sclerodermatous cGVHD model , ibrutinib treatment delayed progression , improved survival , and ameliorated clinical and pathological manifestations . In the alloantibody - driven cGVHD model , ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition . Animals lacking Q06187 and Q08881 did not develop cGVHD , indicating that these molecules are critical to cGVHD development . Furthermore , ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD . Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent , warranting consideration for cGVHD clinical trials .\",\n \"A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK94___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK94___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK94___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK94___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Rizatriptan in migraineurs with unilateral cranial autonomic symptoms : a double - blind trial . The objective and background is to confirm in a double - blind , placebo - controlled study the high DB00669 response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms . In this randomized , double - blind , placebo - controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo ( ratio 1 : 1 ) and treated for a single moderate or severe migraine attack . The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h . Secondary endpoints included pain relief , no associated symptoms and sustained pain freedom or relief . Significantly more patients reported pain freedom at 2 h after taking rizatriptan ( 54 % ) than after placebo ( 8 % ) ( therapeutic gain 46 % [ 28 % ; 64 % ] ; P < 0 . 001 ) . Similarly , significantly more patients reported total migraine freedom at 2 h after rizatriptan ( 51 % ) than after placebo ( 8 % ) ( therapeutic gain 43 % [ 26 % ; 61 % ] ; P < 0 . 001 ) . Rizatriptan was also more effective than placebo on most secondary endpoints . We confirm in a placebo - controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans , probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular P28222 / 1D receptors . Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients .\",\n \"A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .\",\n \"UV - induced but P04637 independent apoptotic death in CHO . P04264 cells is promoted by M phase inhibitors .\",\n \"Colocalization of P80511 with P28222 / 1D receptors and DB05875 in trigeminal ganglion neurons in rats . Vasodilatation in the dura mater has been implicated in migraine pathogenesis . Anti - migraine DB00669 drugs block vasodilatation by binding to P28222 / 1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles . Previous studies suggest that calcitonin gene - related peptide ( P80511 ) released from Adelta - fibres plays a more important role than DB05875 ( SP ) released from C - fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of DB00669 drugs is inhibiting P80511 release . In the present study , the relationship between P80511 and P28222 / 1D receptors , and between P80511 and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining . P80511 , P28222 , P28221 and SP - positive trigeminal ganglion neurons were all predominantly small and medium - sized . In the trigeminal ganglia , approximately 50 % of P80511 - positive neurons were P28222 positive . Similarly , approximately 55 % of P80511 - positive neurons were P28221 immunoreactive . Approximately 50 % of P80511 - positive neurons were SP - positive , while 93 % of SP - positive neurons were P80511 - positive , suggesting that nearly all SP - positive neurons also contain P80511 . The fibre types of the P28222 - and P28221 - positive neurons were further investigated with an antibody against the A - fibre marker 200 - kDa neurofilaments ( NF200 ) . Approximately 46 % of the P28222 - positive and 43 % of the P28221 - positive trigeminal ganglion neurons were also NF200 positive , indicating that many A - fibre trigeminal neurons express P28222 or P28221 receptors . These results support the hypothesis that one important action of antimigraine drugs is the inhibition of P80511 release and that Adelta - fibres may play an important role in migraine pathogenesis .\",\n \"Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .\",\n \"Migraine : current concepts and emerging therapies . Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . Migraine affects a substantial fraction of world population and is a major cause of disability in the work place . Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular ( due to cerebral vasodilatation ) , neurological ( abnormal neurological firing which causes the spreading depression and migraine ) and neurogenic dural inflammation ( release of inflammatory neuropeptides ) . The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder . The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention . The last decade has witnessed the advent of Sumatriptan and the ' DB00669 ' class of P28222 / 1D receptor agonists which have well established efficacy in treating migraine . Currently prophylactic treatments for migraine include calcium channel blockers , 5 - HT2 receptor antagonists , beta adrenoceptor blockers and gamma - amino butyric acid ( GABA ) agonists . Unfortunately , many of these treatments are non specific and not always effective . Despite such progress , in view of the complexity of the etiology of migraine , it still remains undiagnosed and available therapies are underused . In this article , the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed . Furthermore , the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine , with a special emphasis to calcitonin gene - related peptide , are critically evaluated .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super - families have been identified : DB00171 - binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system ( s ) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules .\",\n \"[ Treatments of migraine ] . During the 1980s , a new class of drugs for the acute treatment of migraine attacks was developed , the triptans . These agents are selective P28222 / 1D serotonin receptor agonists , and were developed in order to address the underlying biological mechanism of the migraine attack . French guidelines in migraine are available since 2002 . It is recommended to use a stratified treatment approach during the first consultation with the use of NSAID in first line acute treatment and DB00669 in second line . It is also recommended to use prophylactic treatment when the patient experience frequent and / or severe migraine attack with a bad quality of life and a real impairment .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"The biology of serotonin receptors : focus on migraine pathophysiology and treatment . Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families ( 5 - HT1 - P34969 ) . With the exception of the 5 - Q9H205 which is a ligand - gated ion channel , all others are G - protein coupled receptors with each family sharing structural , pharmacological and transductional characteristics . 5 - HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission , and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache . In this respect , activation of vascular P41595 and / or P34969 receptors , possibly as a consequence of the sudden rise in 5 - HT levels reported at the onset of a migraine attack , would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents , hence initiating the manifestation of head pain . At this stage in the migraine process , activation of specific subtypes of 5 - HT1 receptors has proven clinically effective in relieving migraine pain . Neural P28221 and / or P30939 receptors localized pre - junctionally on trigeminovascular afferents appear to mediate the DB00669 - induced inhibition of the neurogenic inflammatory response , with possible additional sites of action for brain penetrant 5 - HT1 receptor agonists in inhibiting the transmission of pain centrally . In contrast , activation of vascular P28222 receptors would constrict meningeal vessels hence recovering their pre - migraine diameter . The recent availability of subtype selective P28221 and P30939 receptor agonists should allow a further test of the neural / vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile .\",\n \"No contractile effect for P28221 and P30939 receptor agonists in human and bovine cerebral arteries : similarity with human coronary artery . 1 . Using subtype - selective 5 - HT1 receptor agonists and / or the 5 - HT1 receptor antagonist GR127935 , we characterized in vitro the 5 - HT receptor that mediates the contraction of human and bovine cerebral arteries . Further , we investigated which sumatriptan - sensitive receptors are present in human coronary artery by reverse - transcriptase polymerase chain reaction ( RT - PCR ) . 2 . Agonists with affinity at the P28222 receptor , such as sumatriptan , alniditan and / or IS - 159 , elicited dose - dependent contraction in both human and bovine cerebral arteries . They behaved as full agonists at the sumatriptan - sensitive 5 - HT1 receptors in both species . In contrast , PNU - 109291 and LY344864 , selective agonists at P28221 and P30939 receptors , respectively , were devoid of any significant vasocontractile activity in cerebral arteries , or did not affect the sumatriptan - induced vasocontraction . The rank order of agonist potency was similar in both species and could be summarized as 5 - HT = alniditan > sumatriptan = IS - 159 >>> PNU - 109291 = LY344864 . 3 . In bovine cerebral arteries , the 5 - HT1 receptor antagonist GR127935 dose - dependently inhibited the vasoconstrictions elicited by both 5 - HT and sumatriptan , with respective pA2 values of 8 . 0 and 8 . 6 . 4 . RT - PCR studies in human coronary arteries showed a strong signal for the P28222 receptor while message for the P30939 receptor was weak and less frequently detected . Expression of P28221 receptor mRNA was not detected in any sample . 5 . The present results demonstrate that the DB00669 - induced contraction in brain vessels is mediated exclusively by the P28222 receptor , which is also present in a majority of human coronary arteries . These results suggest that selective P28221 and P30939 receptor agonists might represent new antimigraine drugs devoid of cerebro - and cardiovascular effects .\",\n \"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK26___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK26___ who were treated with a single dose of mifepristone .\",\n \"[ ___MASK48___ : A new drug of B - cell malignancies ] . ___MASK48___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK48___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK48___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .\",\n \"[ Rizatriptan : experience after 15 years of clinical use ] . We review the development of rizatriptan , one of the seven P28222 / 1D agonists available for the symptomatic treatment of migraine , emphasizing the most relevant contributions carried out from our country . Rizatriptan has shown the quickest onset of action , both in controlled studies and in the different metaanalyses , which translates in high efficacy levels at two hours . Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group . Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this DB00669 . Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents . This global profile places rizatriptan as a DB00669 of first choice for any kind of migraine attacks .\",\n \"Tissue injury regulates serotonin 1D receptor expression : implications for the control of migraine and inflammatory pain . The anti - migraine action of \\\" DB00669 \\\" drugs involves the activation of serotonin subtype 1D ( P28221 ) receptors expressed on \\\" pain - responsive \\\" trigeminal primary afferents . In the central terminals of these nociceptors , the receptor is concentrated on peptidergic dense core vesicles ( DCVs ) and is notably absent from the plasma membrane . Based on this arrangement , we hypothesized that in the resting state the receptor is not available for binding by a DB00669 , but that noxious stimulation of these afferents could trigger vesicular release of DCVs , thus externalizing the receptor . Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat , there is a significant increase of P28221 - immunoreactivity ( IR ) in the ipsilateral dorsal horn of the spinal cord . We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane , where it is more readily detected . We also observed divergent changes in P28221 - IR in inflammatory and nerve - injury models of persistent pain , occurring at least in part through the regulation of P28221 - receptor gene expression . Finally , we found that P28221 - IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide DB05875 . This result differs from that reported for the partial differential - opioid receptor , which is also sorted to DCVs , but is greatly reduced in preprotachykinin mutant mice . We suggest that a \\\" pain \\\" - triggered regulation of P28221 - receptor expression underlies the effectiveness of triptans for the treatment of migraine . Moreover , the widespread expression of P28221 receptor in somatic nociceptive afferents suggests that triptans could , in certain circumstances , treat pain in nontrigeminal regions of the body .\",\n \"___MASK29___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .\",\n \"Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .\",\n \"Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK43___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK12___","___MASK13___","___MASK20___","___MASK26___","___MASK29___","___MASK43___","___MASK48___","___MASK62___","___MASK94___"],"string":"[\n \"___MASK12___\",\n \"___MASK13___\",\n \"___MASK20___\",\n \"___MASK26___\",\n \"___MASK29___\",\n \"___MASK43___\",\n \"___MASK48___\",\n \"___MASK62___\",\n \"___MASK94___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK20___"},"id":{"kind":"string","value":"MH_train_84"}}},{"rowIdx":85,"cells":{"query":{"kind":"string","value":"interacts_with DB00744?"},"supports":{"kind":"list like","value":["Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK38___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .","Exploring the roles of P22309 and P35503 in oral clearance of GSK2190915 , a P09917 - activating protein inhibitor . Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders . Substantial variability in the oral clearance of GSK2190915 , a P09917 - activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes , is largely unaccounted for by clinical variables . A study of 41 patients , 78 % ( 32 / 41 ) of whom were non - Hispanic whites , with mild to moderate asthma identified an association of P22309 * 28 and P35503 * 2 with the oral clearance of GSK2190915 ( P = 3 . 8 × 10 ⁻ ⁴ and 1 . 2 × 10 ⁻ ⁵ , respectively ) . However , in a subsequent replication study of 403 non - Hispanic white patients with asthma , we failed to observe a statistically significant association between oral clearance of GSK2190915 and either P22309 * 28 or P35503 * 2 ( P > 0 . 05 ) . Therefore , genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified .","Effects of DB00482 and DB00744 on liver metastasis and lipidperoxidation in pancreatic cancer in Syrian hamsters . Selective inhibition of eicosanoid synthesis is thought to have effects on carcinogenesis in lung and colon cancer . However , it is still unknown whether pancreatic cancer might also be influenced . Therefore we evaluated the impact of selective cyclooxygenase - 2 inhibitor DB00482 and selective P09917 inhibitor DB00744 on liver metastasis in a solid model of pancreatic adenocarcinoma in Syrian hamster . In week 33 , the animals were sacrificed and incidence of pancreatic carcinomas and number and size of liver metastases were determined . Activities of antioxidative enzymes ( GSHPX / SOD ) and concentrations of products of lipidperoxidation were measured in liver metastases and non - metastatic hepatic tissue . The incidence ( 54 . 5 vs . 100 % ) , number ( 3 . 17 +/- 0 . 98 vs . 6 . 75 +/- 0 . 71 ) and size ( 2 . 67 +/- 1 . 97 vs . 11 . 75 +/- 1 . 98 mm2 ) of liver metastases were decreased by combined therapy of DB00744 and DB00482 ( P < 0 . 05 ) . Furthermore , activities of GSHPX ( [ 73 . 77 +/- 5 . 67 ] * 10 ( 5 ) vs . [ 15 . 49 +/- 4 . 02 ] * 10 ( 5 ) U / mg prot . ; P < 0 . 05 ) and SOD ( 474 . 92 +/- 108 . 8 vs . 127 . 89 +/- 38 . 75 U / mg prot . ; P < 0 . 05 ) were increased , while lipidperoxidation ( 0 . 31 +/- 0 . 08 nmol / mg prot . vs . 1 . 54 +/- 0 . 55 nmol / mg prot . ; P < 0 . 05 ) was decreased by combination therapy , in non - metastatic hepatic tissue . Moreover , combined therapy increased lipidperoxidation in liver metastases ( 0 . 47 +/- 0 . 09 vs . 1 . 95 +/- 0 . 12 nmol / mg prot . ; P < 0 . 05 ) . Thus , a combination of DB00482 and DB00744 might be a new concept to decrease tumour growth in liver metastases in advanced pancreatic cancer .","Preliminary assessment of differential expression of candidate genes associated with atherosclerosis . Identifying susceptible genes associated with the pathogenesis of atherosclerosis ( ATH ) may contribute toward better management of this condition . This preliminary study was aimed at assessing the expression levels of 11 candidate genes , namely tumor protein ( P04637 ) , transforming growth factor , beta receptor II ( P37173 ) , cysthathionenine - beta - synthase ( P35520 ) , insulin receptor substrate 1 ( P35568 ) , lipoprotein lipase ( P06858 ) , methylenetetrahydrofolate reductase ( P42898 ) , thrombomodulin ( P07204 ) , lecithin - cholesterol acyltransferase ( P04180 ) , matrix metallopeptidase 9 ( P14780 ) , low density lipoprotein receptor ( P01130 ) , and arachidonate P09917 - activating protein ( P20292 ) genes associated with ATH . Twelve human coronary artery tissues ( HCATs ) were obtained from deceased subjects who underwent post - mortem procedures . Six atherosclerotic coronary artery tissue ( ACAT ) samples representing the cases and non - atherosclerotic coronary artery tissue ( NCAT ) samples as controls were gathered based on predetermined inclusion and exclusion criteria . Gene expression levels were assessed using the GenomeLab Genetic Analysis System ( GeXP ) . The results showed that P01130 , P04637 , and P14780 expression levels were significantly increased in ACAT compared to NCAT samples ( p < 0 . 05 ) . Thus , P01130 , P04637 , and P14780 genes may play important roles in the development of ATH in a Malaysian study population .","___MASK68___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .","Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation : a novel role of the cysteinyl LT - 1 receptor . Inflammatory mediators and drugs which affect inflammation can influence the healing of injured tissues . Leukotrienes are potent inflammatory mediators , and similar to prostaglandins , are metabolites of arachidonic acid which can have positive or negative effects on bone and cartilage tissues . Here we tested the hypothesis that blocking the negative regulation of leukotrienes , would lead to enhanced endochondral bone formation during fracture repair . A closed femoral fracture was created in mice . Animals were divided into three groups for treatment with either montelukast sodium , a cysteinyl leukotriene type 1 receptor antagonist ( trade name Singulair ) , zileuton , a P09917 enzyme inhibitor ( trade name DB00744 ) , or carrier alone . The fractures were analyzed using radiographs , quantitative gene expression , histology and histomorphometry , and immunohistochemistry . Both the montelukast sodium group and the zileuton group exhibited enhanced fracture repair when compared with controls . Both treatment groups exhibited increased callous size and earlier bone formation when compared to controls as early as day 7 . Gene expression analysis of treatment groups showed increased markers of chondrocyte proliferation and differentiation , and increased early bone formation markers when compared with controls . Treatment with montelukast sodium directly targeted the cysteinyl leukotriene type 1 receptor , leading to increased chondrocyte proliferation at early time points . These novel findings suggests a potential mechanism by which the cysteinyl leukotriene type 1 receptor acts as a negative regulator of chondrocyte proliferation , with important and previously unrecognized implications for both fracture repair , and in a broader context , systemic chondrocyte growth and differentiation .","The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .","DB04725 inhibits interleukin - 18 - induced pro - inflammatory cytokine release and cellular proliferation in human mesangial cells . DB04725 , a novel dual anti - inflammatory drug that inhibits P09917 ( 5 - P28300 ) and cyclooxygenase ( P36551 ) , has recently been defined to have therapeutic effects in osteoarthritis . Both 5 - P28300 and P36551 play functional roles in the pathogenesis of glomerulonephritis in children as well . Q14116 is a pro - inflammatory cytokine . It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells ( HMC ) exposed to interleukin - 18 . In this study , HMC were cultured and exposed to interleukin - 18 with or without pre - treatment of licofelone . P35354 and 5 - P28300 enzyme activities in mesangial cells were determined with chromometry or high - performance liquid chromatography . DB00917 , cysteinyl leukotriene , monocyte chemotactic protein - 1 and interferon - γ concentrations in culture medium were measured using an enzyme - linked immunosorbent assay . Western blotting was employed to detect phosphorylated mitogen - activated protein kinases P27361 / 2 , p38 and P45983 / 2 in HMC . It was found that licofelone attenuated interleukin - 18 - induced P35354 enzyme activity in HMC and prostaglandin E2 release in a dose - dependent manner . Similarly , licofelone inhibited interleukin - 18 - induced 5 - P28300 enzyme activity and leukotriene release . DB04725 reduced interleukin - 18 - induced phosphorylation of p38 mitogen - activated protein kinase and suppressed monocyte chemotactic protein - 1 and interferon - γ synthesis . Moreover , licofelone inhibited Q14116 - induced proliferation of mesangial cells . We conclude that licofelone inhibits interleukin - 18 - induced pro - inflammatory cytokine release and cellular proliferation in HMC , which may represent a really interesting therapeutic approach for glomerulonephritis in children .","Inhibition of a thrombin anion - binding exosite - 2 mutant by the glycosaminoglycan - dependent serpins protein C inhibitor and heparin cofactor II . Antithrombin ( P01008 ) , heparin cofactor II ( HCII ) and protein C inhibitor ( P05154 ; also named plasminogen activator inhibitor - 3 ) are serine protease inhibitors ( serpins ) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans . We compared the inhibition properties of P05154 and HCII to P01008 using R93A / R97A / R101A thrombin , an anion - binding exosite - 2 ( exosite - 2 ) mutant that has greatly reduced heparin - binding properties . ___MASK41___ - enhanced P05154 inhibition of R93A / R97A / R101A thrombin was only approximately 2 - fold compared to 40 - fold enhancement with wild - type recombinant thrombin . P07204 ( TM ) ( with or without the chondroitin sulfate moiety ) accelerated P05154 inhibition of both wild - type and R93A / R97A / R101A thrombins . HCII achieved the same maximum activity in the presence of heparin with both wild - type and R93A / R97A / R101A thrombins ; however , the optimum heparin concentration was 20 times greater than the reaction with wild - type thrombin , indicative of a decrease in heparin affinity . Dermatan sulfate ( DSO4 ) - catalyzed HCII thrombin inhibition was unchanged in R93A / R97A / R101A thrombin compared to wild - type recombinant thrombin . These results suggest that P05154 is similar to P01008 and depends upon ternary complex formation with heparin and these specific thrombin exosite - 2 residues to accelerate thrombin inhibition . In contrast , HCII does not require DB00125 ( 93 ) , DB00125 ( 97 ) and DB00125 ( 101 ) of thrombin exosite - 2 and further supports the hypothesis that HCII uses an allosteric process following glycosaminoglycan binding to inhibit thrombin .","___MASK6___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .","Leukotriene B4 amplifies NF - κB activation in mouse macrophages by reducing O15524 inhibition of MyD88 expression . Activation of NF - κB and P09917 - mediated ( P09917 - mediated ) biosynthesis of the lipid mediator leukotriene B4 ( LTB4 ) are pivotal components of host defense and inflammatory responses . However , the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and cytokines is unknown . Here we have shown that responses dependent on MyD88 ( an adaptor protein that mediates signaling through all of the known TLRs , except O15455 , as well as IL - 1β and Q14116 ) are reduced in mice lacking either P09917 or the LTB4 receptor BTL1 , and that macrophages from these mice are impaired in MyD88 - dependent activation of NF - κB . This macrophage defect was associated with lower basal and inducible expression of MyD88 and reflected impaired activation of P42224 and overexpression of the P42224 inhibitor O15524 . Expression of MyD88 and responsiveness to the O00206 ligand LPS were decreased by Stat1 siRNA silencing in WT macrophages and restored by Socs1 siRNA in P09917 - deficient macrophages . These results uncover a pivotal role in macrophages for the GPCR Q15722 in regulating activation of NF - κB through Stat1 - dependent expression of MyD88 .","___MASK49___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK49___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .","___MASK68___ - targeted liposomes loaded with CPT - 11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is a rare endocrine tumor that frequently metastasizes , but treatment with irinotecan ( CPT - 11 ) is limited because of side effects . P04629 is known to overexpress the somatostatin receptor subtype 2 ( P30874 ) . ___MASK68___ ( Oct ) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor - targeting ligand . We prepared Oct - targeted liposomes loaded with CPT - 11 using Oct - poly ( ethylene glycol ) ( PEG ) - lipid and evaluated Oct - mediated association and cytotoxicity of the liposomes with an P04629 cell line TT . The association of higher concentrations of modified Oct - targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct - targeted liposomes but not by free Oct . With exposure for 96 h , the cytotoxicity of Oct - targeted liposomal CPT - 11 ( IC50 : 1 . 05 ± 0 . 47 μM ) was higher than free CPT - 11 ( IC50 : 3 . 76 ± 0 . 61 μM ) or PEGylated liposomal CPT - 11 ( IC50 : 3 . 05 ± 0 . 28 μM ) . In addition , empty Oct - targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity , suggesting that Oct as a ligand showed cytotoxicity . Moreover , Oct - targeted liposomal CPT - 11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT - 11 at a one - third dose and lower administration times with free CPT - 11 . These findings indicated that Oct - targeted liposomes loaded with CPT - 11 may offer considerable potential for P04629 chemotherapy because cytotoxicity of both CPT - 11 and Oct was enhanced by effective cellular uptake via P30874 .","Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK31___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK31___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .","Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK23___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .","___MASK1___ induces the expression of bradykinin type 2 receptors in cultured human coronary artery endothelial cells . Cardioprotective bradykinin type - 2 receptors ( BK - 2Rs ) are downregulated in the myocardial endothelium of both human and rat failing hearts . Statins are cardioprotective drugs that reduce the level of plasma cholesterol but also exert cholesterol - independent pleiotropic effects . Here we examined the effect of lovastatin on BK - 2R expression in cultured human coronary artery endothelial cells . The effect of lovastatin on the expression of BK receptors in human coronary artery endothelial cells ( HCAECs ) was examined by real - time PCR , Western blot analysis and immunocytochemistry . ___MASK1___ induced a time - and concentration - dependent increase in both BK - 2R and BK - 1R mRNA expression in the cultured HCAECs . Also , the number of functional BK - 2Rs capable of inducing BK - mediated NO production and cGMP signaling was increased in the lovastatin - treated HCAECs . Mevalonate , the direct metabolite of P04035 , reversed the effect of lovastatin . Furthermore , lovastatin inhibited Rho activation and a selective inhibitor of Rho - associated kinases , Y - 27632 , induced a similar increase in BK - 2R expression as lovastatin . In contrast , a specific inhibitor of P35354 , NS398 , significantly inhibited the lovastatin - induced expression of BK - 2Rs . Here we show for the first time that lovastatin induces the expression of BK - 2Rs in cultured human coronary artery endothelial cells through a novel cholesterol - independent pleiotropic mechanism that involves RhoA kinase inhibition and P35354 activation . Thus , reported beneficial effects of statins in cardiovascular diseases may be partly mediated by an increased expression of cardioprotective BK - 2Rs in the endothelial cells of the coronary tree . Moreover , the use of P35354 inhibitors may affect the level of endothelial BK - 2Rs in a negative fashion .","Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .","Interaction between P20292 and P20815 gene variants significantly increases the risk for cerebral infarctions in Chinese . In this study , we investigated associations between susceptibility genes and cerebral infarctions in a Chinese population , and whether gene - gene interactions increase the risk of cerebral infarctions . Overall , 292 patients with cerebral infarctions and 259 healthy control individuals were included . Eight variants in five candidate genes were examined for the risk of stroke , including the SG13S32 ( rs9551963 ) , SG13S42 ( rs4769060 ) , SG13S89 ( rs4769874 ) , and SG13S114 ( rs10507391 ) variants of the P09917 activating protein ( P20292 ) gene , the G860A ( rs751141 ) variant of the soluble epoxide hydrolase ( P34913 ) gene , the A1075C ( rs1057910 ) variant of the P11712 * 2 gene , the C430T ( rs1799853 ) variant of the P11712 * 3 gene , and the A6986G ( rs776746 ) variant of the P20815 gene . Gene - gene interactions were explored using generalized multifactor dimensionality reduction methods . There were no statistically significant differences in the frequencies of the genotypes of the eight candidate genes . The generalized multifactor dimensionality reduction analysis showed a significant gene - gene interaction between SG13S114 and A6986G , with scores of 10 for cross - validation consistency and 9 for the sign test ( P = 0 . 0107 ) . These gene - gene interactions predicted a significantly higher risk of cerebral infarction ( adjusted for age , hypertension , and diabetes mellitus ; odds ratio = 1 . 80495 % , confidence interval : 1 . 180 - 2 . 759 , P = 0 . 006 ) . A two - loci gene interaction confers a significantly higher risk for cerebral infarction . The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases .","Cytokine - modulating activity of tepoxalin , a new potential antirheumatic . Tepoxalin is a new dual cyclooxygenase / P09917 anti - inflammatory compound currently under clinical investigation . It has been shown to possess anti - inflammatory activity in a variety of animal models and more recently to inhibit P60568 induced signal transduction . The current study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects . In human peripheral blood mononuclear cells ( PBMC ) stimulated with OKT3 / PMA , tepoxalin inhibited lymphocyte proliferation with an IC50 of 6 microM . Additionally , it inhibited the production of LTB4 ( IC50 = 0 . 5 microM ) and the cytokines P60568 , P05231 and P01375 alpha ( IC50 = 10 - 12 microM ) . Cytotoxicity was not demonstrated at these concentrations . Add - back experiments with either cytokines ( P60568 or P05231 ) , LTB4 or conditioned media failed to restore the proliferative response in the presence of tepoxalin . However , the concurrent addition of iron ( in the form of ferrous or ferric chloride and other iron salts ) reversed the inhibition of proliferation caused by tepoxalin . Tepoxalin also inhibits the activation of NF kappa B , a transcription factor which acts on several cytokine genes . Tepoxalin ' s effect on NF kappa B is also reversed by the addition of iron salts . These data suggest that the action of tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NF kappa B and subsequent inhibition of cytokine production .","Enhancement of 5 - fluorouracil efficacy on high P35354 expressing HCA - 7 cells by low dose indomethacin and NS - 398 but not on low P35354 expressing HT - 29 cells . The antiproliferative effect of 5 - fluorouracil ( ___MASK73___ ) in the presence of low dose non - steroidal anti - inflammatory drugs ( NSAIDs ) on high cyclooxygenase - 2 ( P35354 ) - expressing HCA - 7 and low P35354 - expressing HT - 29 colon carcinoma cell lines was investigated . Pharmacogenetic parameters were studied to characterize the ___MASK73___ sensitivity of the two cell lines . P04818 ( TS ) and methylenetetrahydrofolate reductase ( P42898 ) polymorphisms were determined by PCR analysis . Cell proliferation was measured by P50991 assay , cell cycle distribution and apoptosis by FACS analysis . Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy . Prostaglandin E ( 2 ) ( PGE ( 2 ) ) levels were investigated with ELISA kit . The HT - 29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for P42898 677 polymorphisms predicting high ___MASK73___ sensitivity ( IC ( 50 ) : 10 microM ) . TS 3R homozygosity , TS 1496del6 and P42898 677CT heterozygosity may explain the modest ___MASK73___ sensitivity ( IC ( 50 ) : 1 . 1 mM ) of the HCA - 7 cell line . Indomethacin and NS - 398 ( 10 microM and 1 . 77 microM , respectively ) reduced the PGE ( 2 ) level in HCA - 7 cells ( > 90 % ) . Low concentrations of NSAIDs without antiproliferative potency increased the S - phase arrest and enhanced the cytotoxic action of ___MASK73___ only in HCA - 7 cells after 48 - hours treatment . The presented data suggested that the enhancement of ___MASK73___ cytotoxicity by indomethacin or NS - 398 applied in low dose is related to the potency of NSAIDs to modulate the cell - cycle distribution and the apoptosis ; however , it seems that this effect might be dependent on cell phenotype , namely on the P35354 expression .","[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK41___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .","___MASK1___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .","___MASK23___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .","Suppression of cyclooxygenase - 2 overexpression by 15S - hydroxyeicosatrienoic acid in androgen - dependent prostatic adenocarcinoma cells . Emerging reports now implicate alterations of arachidonic acid ( AA ) metabolism with prostate carcinogenesis . To test this hypothesis , androgen - primed benign hyperplastic ( BHC ) and malignant tumorigenic ( P04629 ) cells derived from the Lobund - Wistar rat model of autochthonous prostate adenocarcinoma were incubated with ( 14 ) C - AA . Our data using MTCs revealed enhanced dual metabolism of ( 14 ) C - AA via P36551 to generate increased PGE ( 2 ) and via P09917 ( P28300 ) to generate increased 5S - HETE in tumorigenic cells . Western blot of MTCs revealed upregulation of P35354 expression . This paralleled the increased biosynthesis of PGE ( 2 ) . Since some polyunsaturated fatty acids have been reported to modulate AA metabolism and tumorigenesis , we primed the cells with either gamma - linolenic acid ( GLA ) or its in vivo metabolite , 15S - HETrE , prior to incubation with AA . Our data revealed suppression of P35354 expression / PGE ( 2 ) biosynthesis . In parallel , priming cells with 15S - HETrE resulted in greater suppression of P35354 expression / PGE ( 2 ) biosynthesis . These findings suggest that 15S - HETrE could function in vivo after dietary intake of GLA to suppress DB02901 - enhanced prostatic P35354 expression / PGE ( 2 ) biosynthesis and , thus , alleviate tumor growth and progression .","Effects of selective P35354 and 5 - P28300 inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster . Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis , however , the effect on liver metastasis in pancreatic cancer is still unknown . Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N - nitrosobis - 2 - oxopropylamine ( BOP ) in Syrian hamster . Animals received selective inhibition of cyclooxygenase - 2 ( DB00482 ) and P09917 ( DB00744 ) . In week 33 , hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined . Furthermore , size and number of liver metastases per animal were determined and concentration of PGF1alpha , DB00917 and leukotrienes was measured in hepatic and pancreatic tissue . Combined therapy ( DB00482 + DB00744 ) significantly decreased incidence , number and size of liver metastases . Furthermore extra - and intrametastatic concentration of DB00917 was reduced by this treatment in hepatic tissue . Single Cox - 2 - inhibition ( DB00482 ) decreased intrametastatic hepatic PGF1alpha and DB00917 concentration while PGF1alpha concentration was reduced in non - metastatic liver ( nml ) . Moreover 5 - P28300 - inhibition ( DB00744 ) decreased intrametastatic DB00917 concentration as well as PGF1alpha and DB00917 in nml . In pancreatic carcinomas highest LT - concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour - free tissue . Hepatic LT - concentration was significantly lower in the control groups than in nml of the tumour groups . Combination of Cox - 2 - inhibition and 5 - Lox - inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma .","Nonsteroidal anti - inflammatory drugs ( NSAID ) sparing effects of glucosamine hydrochloride through N - glycosylation inhibition ; strategy to rescue stomach from NSAID damage . Gastrointestinal or cardiovascular complications limit nonsteroidal anti - inflammatory drugs ( NSAID ) prescription . ___MASK49___ hydrochloride ( GS - HCl ) alternatively chosen , but debates still exist in its clinical efficiency . P35354 instability through inhibiting P35354 N - glycosylation of GS - HCl raised the possibility of NSAID sparing effect . Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect . IEC - 6 cells were stimulated with P01375 - α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS - HCl by Western blotting and RT - PCR . C57BL / 6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS - HCl after 3 weeks . P01375 - α increased the expression of P35354 , P35228 and inflammatory cytokines , but GS - HCl significantly attenuated P01375 - α - induced P35354 expression . Decreased P35354 after GS - HCl was caused by N - glycosylation inhibition as much as tunicamycin . Combination of reduced dose of indomethacin and GS - HCl significantly reduced the expressions of P05362 , P19320 , P10145 , IL - 1β , P08253 , P09237 , P14780 , and P24347 mRNA as well as NF - κB activation better than high dose indomethacin alone . These NSAID sparing effect of GS - HCl was further proven in collagen - induced arthritis model . Combination of GS - HCl and 2 . 5 mg / kg indomethacin showed significant protection from gastric damages as well as efficacious anti - arthritic effect . Taken together , P35354 N - glycosylation inhibition by GS - HCl led to indomethacin sparing effects , based on which combination of GS - HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID - induced gastric damage as well as excellent anti - arthritic effects .","Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .","Unfavourable expression of pharmacologic markers in mucinous colorectal cancer . Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety . The reason for this disparity is unclear , but may result from a differential response to adjuvant chemotherapy . We examined known molecular markers for response to common chemotherapy in these two histological subtypes . In all , 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome . Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed . Quantitative expression levels of drug pathway genes were determined using TaqMan RT - PCR ( 5 - fluorouracil ( ___MASK73___ ) : P04818 , Q12882 , P19971 ; oxaliplatin : P09211 ( glutathione S - transferase pi ) , P07992 and 2 ; irinotecan : P08183 , Q9UNQ0 , P08684 , P22309 , CES2 , P11387 ) . Mucinous tumours significantly overexpressed both P04818 and P09211 relative to nonmucinous tumours and patient - matched normal mucosa . No significant differences in expression of the remaining markers were found . Mean follow - up was 20 months ; 17 patients had recurrent disease . Among patients receiving ___MASK73___ , those with mucinous tumours experienced shorter disease - free survival ( DFS ) than those with nonmucinous tumours ( median DFS 13 . 8 vs 46 . 5 months , P = 0 . 053 ) . Mucinous colorectal cancer overexpresses markers of resistance to ___MASK73___ and oxaliplatin . Likewise , DFS may be decreased in patients with mucinous tumours who receive ___MASK73___ . The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer .","Novel combination treatments targeting chronic myeloid leukemia stem cells . Chronic myeloid leukemia ( CML ) is currently considered incurable in most patients . Stem cell transplantation , an accepted curative option for which extensive experience has been gained , is limited by high morbidity and mortality rates , particularly in older patients . Tyrosine kinase inhibitors targeting P11274 - P00519 are widely used and induce remission in a high proportion of patients , but resistance and incomplete response to these agents portends eventual relapse and disease progression . Although P11274 - P00519 inhibitors eradicate most CML cells , they are largely ineffective against the reservoir of quiescent leukemic stem cells ( LSCs ) . Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research . To date , evidence obtained from in vitro studies , animal models , and clinical CML specimens suggests that an effective approach may be to partner existing P11274 - P00519 inhibitors with compounds targeting key stem cell molecular effectors , including Wnt / β - catenin , hedgehog pathway components , histone deacetylase ( HDAC ) , transforming growth factor - β ( TGF - β ) , O60674 , promyelocytic leukemia protein , and arachidonate P09917 ( P09917 ) . Novel combinations may sensitize LSCs to P11274 - P00519 inhibitors , thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care .","Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .","___MASK6___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK6___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK6___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK6___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .","Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by P01375 plus cycloheximide in U937 cells . U937 human myeloid leukemia cells are induced to apoptosis by tumour necrosis factor ( P01375 ) plus cycloheximide ( CHX ) . We have analysed the effect of various inhibitors of the arachidonic acid ( AA ) metabolism on several features of this process . The formation of high molecular weight and oligonucleosomal DNA fragments as well as nuclear fragmentation were reduced by inhibitors of P09917 ( BWA4C and BWB70C ) , P09917 activating protein ( MK - 886 ) , and cytosolic P04054 ( AACOCF3 ) . None of these agents blocked the morphological changes detected by microscopy or flow cytometry , phosphatidylserine exposure on the cell surface or Caspase 3 - like activation . AA also induced nuclear fragmentation at a concentration of 1 - 20 microM . However , the mechanisms by which these inhibitors act , remain unexplained since there was no P09917 expression in the U937 cells and no AA release followed their stimulation with P01375 plus CHX ."],"string":"[\n \"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK38___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .\",\n \"Exploring the roles of P22309 and P35503 in oral clearance of GSK2190915 , a P09917 - activating protein inhibitor . Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders . Substantial variability in the oral clearance of GSK2190915 , a P09917 - activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes , is largely unaccounted for by clinical variables . A study of 41 patients , 78 % ( 32 / 41 ) of whom were non - Hispanic whites , with mild to moderate asthma identified an association of P22309 * 28 and P35503 * 2 with the oral clearance of GSK2190915 ( P = 3 . 8 × 10 ⁻ ⁴ and 1 . 2 × 10 ⁻ ⁵ , respectively ) . However , in a subsequent replication study of 403 non - Hispanic white patients with asthma , we failed to observe a statistically significant association between oral clearance of GSK2190915 and either P22309 * 28 or P35503 * 2 ( P > 0 . 05 ) . Therefore , genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified .\",\n \"Effects of DB00482 and DB00744 on liver metastasis and lipidperoxidation in pancreatic cancer in Syrian hamsters . Selective inhibition of eicosanoid synthesis is thought to have effects on carcinogenesis in lung and colon cancer . However , it is still unknown whether pancreatic cancer might also be influenced . Therefore we evaluated the impact of selective cyclooxygenase - 2 inhibitor DB00482 and selective P09917 inhibitor DB00744 on liver metastasis in a solid model of pancreatic adenocarcinoma in Syrian hamster . In week 33 , the animals were sacrificed and incidence of pancreatic carcinomas and number and size of liver metastases were determined . Activities of antioxidative enzymes ( GSHPX / SOD ) and concentrations of products of lipidperoxidation were measured in liver metastases and non - metastatic hepatic tissue . The incidence ( 54 . 5 vs . 100 % ) , number ( 3 . 17 +/- 0 . 98 vs . 6 . 75 +/- 0 . 71 ) and size ( 2 . 67 +/- 1 . 97 vs . 11 . 75 +/- 1 . 98 mm2 ) of liver metastases were decreased by combined therapy of DB00744 and DB00482 ( P < 0 . 05 ) . Furthermore , activities of GSHPX ( [ 73 . 77 +/- 5 . 67 ] * 10 ( 5 ) vs . [ 15 . 49 +/- 4 . 02 ] * 10 ( 5 ) U / mg prot . ; P < 0 . 05 ) and SOD ( 474 . 92 +/- 108 . 8 vs . 127 . 89 +/- 38 . 75 U / mg prot . ; P < 0 . 05 ) were increased , while lipidperoxidation ( 0 . 31 +/- 0 . 08 nmol / mg prot . vs . 1 . 54 +/- 0 . 55 nmol / mg prot . ; P < 0 . 05 ) was decreased by combination therapy , in non - metastatic hepatic tissue . Moreover , combined therapy increased lipidperoxidation in liver metastases ( 0 . 47 +/- 0 . 09 vs . 1 . 95 +/- 0 . 12 nmol / mg prot . ; P < 0 . 05 ) . Thus , a combination of DB00482 and DB00744 might be a new concept to decrease tumour growth in liver metastases in advanced pancreatic cancer .\",\n \"Preliminary assessment of differential expression of candidate genes associated with atherosclerosis . Identifying susceptible genes associated with the pathogenesis of atherosclerosis ( ATH ) may contribute toward better management of this condition . This preliminary study was aimed at assessing the expression levels of 11 candidate genes , namely tumor protein ( P04637 ) , transforming growth factor , beta receptor II ( P37173 ) , cysthathionenine - beta - synthase ( P35520 ) , insulin receptor substrate 1 ( P35568 ) , lipoprotein lipase ( P06858 ) , methylenetetrahydrofolate reductase ( P42898 ) , thrombomodulin ( P07204 ) , lecithin - cholesterol acyltransferase ( P04180 ) , matrix metallopeptidase 9 ( P14780 ) , low density lipoprotein receptor ( P01130 ) , and arachidonate P09917 - activating protein ( P20292 ) genes associated with ATH . Twelve human coronary artery tissues ( HCATs ) were obtained from deceased subjects who underwent post - mortem procedures . Six atherosclerotic coronary artery tissue ( ACAT ) samples representing the cases and non - atherosclerotic coronary artery tissue ( NCAT ) samples as controls were gathered based on predetermined inclusion and exclusion criteria . Gene expression levels were assessed using the GenomeLab Genetic Analysis System ( GeXP ) . The results showed that P01130 , P04637 , and P14780 expression levels were significantly increased in ACAT compared to NCAT samples ( p < 0 . 05 ) . Thus , P01130 , P04637 , and P14780 genes may play important roles in the development of ATH in a Malaysian study population .\",\n \"___MASK68___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .\",\n \"Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation : a novel role of the cysteinyl LT - 1 receptor . Inflammatory mediators and drugs which affect inflammation can influence the healing of injured tissues . Leukotrienes are potent inflammatory mediators , and similar to prostaglandins , are metabolites of arachidonic acid which can have positive or negative effects on bone and cartilage tissues . Here we tested the hypothesis that blocking the negative regulation of leukotrienes , would lead to enhanced endochondral bone formation during fracture repair . A closed femoral fracture was created in mice . Animals were divided into three groups for treatment with either montelukast sodium , a cysteinyl leukotriene type 1 receptor antagonist ( trade name Singulair ) , zileuton , a P09917 enzyme inhibitor ( trade name DB00744 ) , or carrier alone . The fractures were analyzed using radiographs , quantitative gene expression , histology and histomorphometry , and immunohistochemistry . Both the montelukast sodium group and the zileuton group exhibited enhanced fracture repair when compared with controls . Both treatment groups exhibited increased callous size and earlier bone formation when compared to controls as early as day 7 . Gene expression analysis of treatment groups showed increased markers of chondrocyte proliferation and differentiation , and increased early bone formation markers when compared with controls . Treatment with montelukast sodium directly targeted the cysteinyl leukotriene type 1 receptor , leading to increased chondrocyte proliferation at early time points . These novel findings suggests a potential mechanism by which the cysteinyl leukotriene type 1 receptor acts as a negative regulator of chondrocyte proliferation , with important and previously unrecognized implications for both fracture repair , and in a broader context , systemic chondrocyte growth and differentiation .\",\n \"The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .\",\n \"DB04725 inhibits interleukin - 18 - induced pro - inflammatory cytokine release and cellular proliferation in human mesangial cells . DB04725 , a novel dual anti - inflammatory drug that inhibits P09917 ( 5 - P28300 ) and cyclooxygenase ( P36551 ) , has recently been defined to have therapeutic effects in osteoarthritis . Both 5 - P28300 and P36551 play functional roles in the pathogenesis of glomerulonephritis in children as well . Q14116 is a pro - inflammatory cytokine . It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells ( HMC ) exposed to interleukin - 18 . In this study , HMC were cultured and exposed to interleukin - 18 with or without pre - treatment of licofelone . P35354 and 5 - P28300 enzyme activities in mesangial cells were determined with chromometry or high - performance liquid chromatography . DB00917 , cysteinyl leukotriene , monocyte chemotactic protein - 1 and interferon - γ concentrations in culture medium were measured using an enzyme - linked immunosorbent assay . Western blotting was employed to detect phosphorylated mitogen - activated protein kinases P27361 / 2 , p38 and P45983 / 2 in HMC . It was found that licofelone attenuated interleukin - 18 - induced P35354 enzyme activity in HMC and prostaglandin E2 release in a dose - dependent manner . Similarly , licofelone inhibited interleukin - 18 - induced 5 - P28300 enzyme activity and leukotriene release . DB04725 reduced interleukin - 18 - induced phosphorylation of p38 mitogen - activated protein kinase and suppressed monocyte chemotactic protein - 1 and interferon - γ synthesis . Moreover , licofelone inhibited Q14116 - induced proliferation of mesangial cells . We conclude that licofelone inhibits interleukin - 18 - induced pro - inflammatory cytokine release and cellular proliferation in HMC , which may represent a really interesting therapeutic approach for glomerulonephritis in children .\",\n \"Inhibition of a thrombin anion - binding exosite - 2 mutant by the glycosaminoglycan - dependent serpins protein C inhibitor and heparin cofactor II . Antithrombin ( P01008 ) , heparin cofactor II ( HCII ) and protein C inhibitor ( P05154 ; also named plasminogen activator inhibitor - 3 ) are serine protease inhibitors ( serpins ) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans . We compared the inhibition properties of P05154 and HCII to P01008 using R93A / R97A / R101A thrombin , an anion - binding exosite - 2 ( exosite - 2 ) mutant that has greatly reduced heparin - binding properties . ___MASK41___ - enhanced P05154 inhibition of R93A / R97A / R101A thrombin was only approximately 2 - fold compared to 40 - fold enhancement with wild - type recombinant thrombin . P07204 ( TM ) ( with or without the chondroitin sulfate moiety ) accelerated P05154 inhibition of both wild - type and R93A / R97A / R101A thrombins . HCII achieved the same maximum activity in the presence of heparin with both wild - type and R93A / R97A / R101A thrombins ; however , the optimum heparin concentration was 20 times greater than the reaction with wild - type thrombin , indicative of a decrease in heparin affinity . Dermatan sulfate ( DSO4 ) - catalyzed HCII thrombin inhibition was unchanged in R93A / R97A / R101A thrombin compared to wild - type recombinant thrombin . These results suggest that P05154 is similar to P01008 and depends upon ternary complex formation with heparin and these specific thrombin exosite - 2 residues to accelerate thrombin inhibition . In contrast , HCII does not require DB00125 ( 93 ) , DB00125 ( 97 ) and DB00125 ( 101 ) of thrombin exosite - 2 and further supports the hypothesis that HCII uses an allosteric process following glycosaminoglycan binding to inhibit thrombin .\",\n \"___MASK6___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .\",\n \"Leukotriene B4 amplifies NF - κB activation in mouse macrophages by reducing O15524 inhibition of MyD88 expression . Activation of NF - κB and P09917 - mediated ( P09917 - mediated ) biosynthesis of the lipid mediator leukotriene B4 ( LTB4 ) are pivotal components of host defense and inflammatory responses . However , the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and cytokines is unknown . Here we have shown that responses dependent on MyD88 ( an adaptor protein that mediates signaling through all of the known TLRs , except O15455 , as well as IL - 1β and Q14116 ) are reduced in mice lacking either P09917 or the LTB4 receptor BTL1 , and that macrophages from these mice are impaired in MyD88 - dependent activation of NF - κB . This macrophage defect was associated with lower basal and inducible expression of MyD88 and reflected impaired activation of P42224 and overexpression of the P42224 inhibitor O15524 . Expression of MyD88 and responsiveness to the O00206 ligand LPS were decreased by Stat1 siRNA silencing in WT macrophages and restored by Socs1 siRNA in P09917 - deficient macrophages . These results uncover a pivotal role in macrophages for the GPCR Q15722 in regulating activation of NF - κB through Stat1 - dependent expression of MyD88 .\",\n \"___MASK49___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK49___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .\",\n \"___MASK68___ - targeted liposomes loaded with CPT - 11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is a rare endocrine tumor that frequently metastasizes , but treatment with irinotecan ( CPT - 11 ) is limited because of side effects . P04629 is known to overexpress the somatostatin receptor subtype 2 ( P30874 ) . ___MASK68___ ( Oct ) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor - targeting ligand . We prepared Oct - targeted liposomes loaded with CPT - 11 using Oct - poly ( ethylene glycol ) ( PEG ) - lipid and evaluated Oct - mediated association and cytotoxicity of the liposomes with an P04629 cell line TT . The association of higher concentrations of modified Oct - targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct - targeted liposomes but not by free Oct . With exposure for 96 h , the cytotoxicity of Oct - targeted liposomal CPT - 11 ( IC50 : 1 . 05 ± 0 . 47 μM ) was higher than free CPT - 11 ( IC50 : 3 . 76 ± 0 . 61 μM ) or PEGylated liposomal CPT - 11 ( IC50 : 3 . 05 ± 0 . 28 μM ) . In addition , empty Oct - targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity , suggesting that Oct as a ligand showed cytotoxicity . Moreover , Oct - targeted liposomal CPT - 11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT - 11 at a one - third dose and lower administration times with free CPT - 11 . These findings indicated that Oct - targeted liposomes loaded with CPT - 11 may offer considerable potential for P04629 chemotherapy because cytotoxicity of both CPT - 11 and Oct was enhanced by effective cellular uptake via P30874 .\",\n \"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK31___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK31___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .\",\n \"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK23___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .\",\n \"___MASK1___ induces the expression of bradykinin type 2 receptors in cultured human coronary artery endothelial cells . Cardioprotective bradykinin type - 2 receptors ( BK - 2Rs ) are downregulated in the myocardial endothelium of both human and rat failing hearts . Statins are cardioprotective drugs that reduce the level of plasma cholesterol but also exert cholesterol - independent pleiotropic effects . Here we examined the effect of lovastatin on BK - 2R expression in cultured human coronary artery endothelial cells . The effect of lovastatin on the expression of BK receptors in human coronary artery endothelial cells ( HCAECs ) was examined by real - time PCR , Western blot analysis and immunocytochemistry . ___MASK1___ induced a time - and concentration - dependent increase in both BK - 2R and BK - 1R mRNA expression in the cultured HCAECs . Also , the number of functional BK - 2Rs capable of inducing BK - mediated NO production and cGMP signaling was increased in the lovastatin - treated HCAECs . Mevalonate , the direct metabolite of P04035 , reversed the effect of lovastatin . Furthermore , lovastatin inhibited Rho activation and a selective inhibitor of Rho - associated kinases , Y - 27632 , induced a similar increase in BK - 2R expression as lovastatin . In contrast , a specific inhibitor of P35354 , NS398 , significantly inhibited the lovastatin - induced expression of BK - 2Rs . Here we show for the first time that lovastatin induces the expression of BK - 2Rs in cultured human coronary artery endothelial cells through a novel cholesterol - independent pleiotropic mechanism that involves RhoA kinase inhibition and P35354 activation . Thus , reported beneficial effects of statins in cardiovascular diseases may be partly mediated by an increased expression of cardioprotective BK - 2Rs in the endothelial cells of the coronary tree . Moreover , the use of P35354 inhibitors may affect the level of endothelial BK - 2Rs in a negative fashion .\",\n \"Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .\",\n \"Interaction between P20292 and P20815 gene variants significantly increases the risk for cerebral infarctions in Chinese . In this study , we investigated associations between susceptibility genes and cerebral infarctions in a Chinese population , and whether gene - gene interactions increase the risk of cerebral infarctions . Overall , 292 patients with cerebral infarctions and 259 healthy control individuals were included . Eight variants in five candidate genes were examined for the risk of stroke , including the SG13S32 ( rs9551963 ) , SG13S42 ( rs4769060 ) , SG13S89 ( rs4769874 ) , and SG13S114 ( rs10507391 ) variants of the P09917 activating protein ( P20292 ) gene , the G860A ( rs751141 ) variant of the soluble epoxide hydrolase ( P34913 ) gene , the A1075C ( rs1057910 ) variant of the P11712 * 2 gene , the C430T ( rs1799853 ) variant of the P11712 * 3 gene , and the A6986G ( rs776746 ) variant of the P20815 gene . Gene - gene interactions were explored using generalized multifactor dimensionality reduction methods . There were no statistically significant differences in the frequencies of the genotypes of the eight candidate genes . The generalized multifactor dimensionality reduction analysis showed a significant gene - gene interaction between SG13S114 and A6986G , with scores of 10 for cross - validation consistency and 9 for the sign test ( P = 0 . 0107 ) . These gene - gene interactions predicted a significantly higher risk of cerebral infarction ( adjusted for age , hypertension , and diabetes mellitus ; odds ratio = 1 . 80495 % , confidence interval : 1 . 180 - 2 . 759 , P = 0 . 006 ) . A two - loci gene interaction confers a significantly higher risk for cerebral infarction . The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases .\",\n \"Cytokine - modulating activity of tepoxalin , a new potential antirheumatic . Tepoxalin is a new dual cyclooxygenase / P09917 anti - inflammatory compound currently under clinical investigation . It has been shown to possess anti - inflammatory activity in a variety of animal models and more recently to inhibit P60568 induced signal transduction . The current study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects . In human peripheral blood mononuclear cells ( PBMC ) stimulated with OKT3 / PMA , tepoxalin inhibited lymphocyte proliferation with an IC50 of 6 microM . Additionally , it inhibited the production of LTB4 ( IC50 = 0 . 5 microM ) and the cytokines P60568 , P05231 and P01375 alpha ( IC50 = 10 - 12 microM ) . Cytotoxicity was not demonstrated at these concentrations . Add - back experiments with either cytokines ( P60568 or P05231 ) , LTB4 or conditioned media failed to restore the proliferative response in the presence of tepoxalin . However , the concurrent addition of iron ( in the form of ferrous or ferric chloride and other iron salts ) reversed the inhibition of proliferation caused by tepoxalin . Tepoxalin also inhibits the activation of NF kappa B , a transcription factor which acts on several cytokine genes . Tepoxalin ' s effect on NF kappa B is also reversed by the addition of iron salts . These data suggest that the action of tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NF kappa B and subsequent inhibition of cytokine production .\",\n \"Enhancement of 5 - fluorouracil efficacy on high P35354 expressing HCA - 7 cells by low dose indomethacin and NS - 398 but not on low P35354 expressing HT - 29 cells . The antiproliferative effect of 5 - fluorouracil ( ___MASK73___ ) in the presence of low dose non - steroidal anti - inflammatory drugs ( NSAIDs ) on high cyclooxygenase - 2 ( P35354 ) - expressing HCA - 7 and low P35354 - expressing HT - 29 colon carcinoma cell lines was investigated . Pharmacogenetic parameters were studied to characterize the ___MASK73___ sensitivity of the two cell lines . P04818 ( TS ) and methylenetetrahydrofolate reductase ( P42898 ) polymorphisms were determined by PCR analysis . Cell proliferation was measured by P50991 assay , cell cycle distribution and apoptosis by FACS analysis . Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy . Prostaglandin E ( 2 ) ( PGE ( 2 ) ) levels were investigated with ELISA kit . The HT - 29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for P42898 677 polymorphisms predicting high ___MASK73___ sensitivity ( IC ( 50 ) : 10 microM ) . TS 3R homozygosity , TS 1496del6 and P42898 677CT heterozygosity may explain the modest ___MASK73___ sensitivity ( IC ( 50 ) : 1 . 1 mM ) of the HCA - 7 cell line . Indomethacin and NS - 398 ( 10 microM and 1 . 77 microM , respectively ) reduced the PGE ( 2 ) level in HCA - 7 cells ( > 90 % ) . Low concentrations of NSAIDs without antiproliferative potency increased the S - phase arrest and enhanced the cytotoxic action of ___MASK73___ only in HCA - 7 cells after 48 - hours treatment . The presented data suggested that the enhancement of ___MASK73___ cytotoxicity by indomethacin or NS - 398 applied in low dose is related to the potency of NSAIDs to modulate the cell - cycle distribution and the apoptosis ; however , it seems that this effect might be dependent on cell phenotype , namely on the P35354 expression .\",\n \"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK41___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .\",\n \"___MASK1___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .\",\n \"___MASK23___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .\",\n \"Suppression of cyclooxygenase - 2 overexpression by 15S - hydroxyeicosatrienoic acid in androgen - dependent prostatic adenocarcinoma cells . Emerging reports now implicate alterations of arachidonic acid ( AA ) metabolism with prostate carcinogenesis . To test this hypothesis , androgen - primed benign hyperplastic ( BHC ) and malignant tumorigenic ( P04629 ) cells derived from the Lobund - Wistar rat model of autochthonous prostate adenocarcinoma were incubated with ( 14 ) C - AA . Our data using MTCs revealed enhanced dual metabolism of ( 14 ) C - AA via P36551 to generate increased PGE ( 2 ) and via P09917 ( P28300 ) to generate increased 5S - HETE in tumorigenic cells . Western blot of MTCs revealed upregulation of P35354 expression . This paralleled the increased biosynthesis of PGE ( 2 ) . Since some polyunsaturated fatty acids have been reported to modulate AA metabolism and tumorigenesis , we primed the cells with either gamma - linolenic acid ( GLA ) or its in vivo metabolite , 15S - HETrE , prior to incubation with AA . Our data revealed suppression of P35354 expression / PGE ( 2 ) biosynthesis . In parallel , priming cells with 15S - HETrE resulted in greater suppression of P35354 expression / PGE ( 2 ) biosynthesis . These findings suggest that 15S - HETrE could function in vivo after dietary intake of GLA to suppress DB02901 - enhanced prostatic P35354 expression / PGE ( 2 ) biosynthesis and , thus , alleviate tumor growth and progression .\",\n \"Effects of selective P35354 and 5 - P28300 inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster . Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis , however , the effect on liver metastasis in pancreatic cancer is still unknown . Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N - nitrosobis - 2 - oxopropylamine ( BOP ) in Syrian hamster . Animals received selective inhibition of cyclooxygenase - 2 ( DB00482 ) and P09917 ( DB00744 ) . In week 33 , hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined . Furthermore , size and number of liver metastases per animal were determined and concentration of PGF1alpha , DB00917 and leukotrienes was measured in hepatic and pancreatic tissue . Combined therapy ( DB00482 + DB00744 ) significantly decreased incidence , number and size of liver metastases . Furthermore extra - and intrametastatic concentration of DB00917 was reduced by this treatment in hepatic tissue . Single Cox - 2 - inhibition ( DB00482 ) decreased intrametastatic hepatic PGF1alpha and DB00917 concentration while PGF1alpha concentration was reduced in non - metastatic liver ( nml ) . Moreover 5 - P28300 - inhibition ( DB00744 ) decreased intrametastatic DB00917 concentration as well as PGF1alpha and DB00917 in nml . In pancreatic carcinomas highest LT - concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour - free tissue . Hepatic LT - concentration was significantly lower in the control groups than in nml of the tumour groups . Combination of Cox - 2 - inhibition and 5 - Lox - inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma .\",\n \"Nonsteroidal anti - inflammatory drugs ( NSAID ) sparing effects of glucosamine hydrochloride through N - glycosylation inhibition ; strategy to rescue stomach from NSAID damage . Gastrointestinal or cardiovascular complications limit nonsteroidal anti - inflammatory drugs ( NSAID ) prescription . ___MASK49___ hydrochloride ( GS - HCl ) alternatively chosen , but debates still exist in its clinical efficiency . P35354 instability through inhibiting P35354 N - glycosylation of GS - HCl raised the possibility of NSAID sparing effect . Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect . IEC - 6 cells were stimulated with P01375 - α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS - HCl by Western blotting and RT - PCR . C57BL / 6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS - HCl after 3 weeks . P01375 - α increased the expression of P35354 , P35228 and inflammatory cytokines , but GS - HCl significantly attenuated P01375 - α - induced P35354 expression . Decreased P35354 after GS - HCl was caused by N - glycosylation inhibition as much as tunicamycin . Combination of reduced dose of indomethacin and GS - HCl significantly reduced the expressions of P05362 , P19320 , P10145 , IL - 1β , P08253 , P09237 , P14780 , and P24347 mRNA as well as NF - κB activation better than high dose indomethacin alone . These NSAID sparing effect of GS - HCl was further proven in collagen - induced arthritis model . Combination of GS - HCl and 2 . 5 mg / kg indomethacin showed significant protection from gastric damages as well as efficacious anti - arthritic effect . Taken together , P35354 N - glycosylation inhibition by GS - HCl led to indomethacin sparing effects , based on which combination of GS - HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID - induced gastric damage as well as excellent anti - arthritic effects .\",\n \"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .\",\n \"Unfavourable expression of pharmacologic markers in mucinous colorectal cancer . Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety . The reason for this disparity is unclear , but may result from a differential response to adjuvant chemotherapy . We examined known molecular markers for response to common chemotherapy in these two histological subtypes . In all , 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome . Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed . Quantitative expression levels of drug pathway genes were determined using TaqMan RT - PCR ( 5 - fluorouracil ( ___MASK73___ ) : P04818 , Q12882 , P19971 ; oxaliplatin : P09211 ( glutathione S - transferase pi ) , P07992 and 2 ; irinotecan : P08183 , Q9UNQ0 , P08684 , P22309 , CES2 , P11387 ) . Mucinous tumours significantly overexpressed both P04818 and P09211 relative to nonmucinous tumours and patient - matched normal mucosa . No significant differences in expression of the remaining markers were found . Mean follow - up was 20 months ; 17 patients had recurrent disease . Among patients receiving ___MASK73___ , those with mucinous tumours experienced shorter disease - free survival ( DFS ) than those with nonmucinous tumours ( median DFS 13 . 8 vs 46 . 5 months , P = 0 . 053 ) . Mucinous colorectal cancer overexpresses markers of resistance to ___MASK73___ and oxaliplatin . Likewise , DFS may be decreased in patients with mucinous tumours who receive ___MASK73___ . The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer .\",\n \"Novel combination treatments targeting chronic myeloid leukemia stem cells . Chronic myeloid leukemia ( CML ) is currently considered incurable in most patients . Stem cell transplantation , an accepted curative option for which extensive experience has been gained , is limited by high morbidity and mortality rates , particularly in older patients . Tyrosine kinase inhibitors targeting P11274 - P00519 are widely used and induce remission in a high proportion of patients , but resistance and incomplete response to these agents portends eventual relapse and disease progression . Although P11274 - P00519 inhibitors eradicate most CML cells , they are largely ineffective against the reservoir of quiescent leukemic stem cells ( LSCs ) . Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research . To date , evidence obtained from in vitro studies , animal models , and clinical CML specimens suggests that an effective approach may be to partner existing P11274 - P00519 inhibitors with compounds targeting key stem cell molecular effectors , including Wnt / β - catenin , hedgehog pathway components , histone deacetylase ( HDAC ) , transforming growth factor - β ( TGF - β ) , O60674 , promyelocytic leukemia protein , and arachidonate P09917 ( P09917 ) . Novel combinations may sensitize LSCs to P11274 - P00519 inhibitors , thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care .\",\n \"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .\",\n \"___MASK6___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK6___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK6___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK6___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .\",\n \"Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by P01375 plus cycloheximide in U937 cells . U937 human myeloid leukemia cells are induced to apoptosis by tumour necrosis factor ( P01375 ) plus cycloheximide ( CHX ) . We have analysed the effect of various inhibitors of the arachidonic acid ( AA ) metabolism on several features of this process . The formation of high molecular weight and oligonucleosomal DNA fragments as well as nuclear fragmentation were reduced by inhibitors of P09917 ( BWA4C and BWB70C ) , P09917 activating protein ( MK - 886 ) , and cytosolic P04054 ( AACOCF3 ) . None of these agents blocked the morphological changes detected by microscopy or flow cytometry , phosphatidylserine exposure on the cell surface or Caspase 3 - like activation . AA also induced nuclear fragmentation at a concentration of 1 - 20 microM . However , the mechanisms by which these inhibitors act , remain unexplained since there was no P09917 expression in the U937 cells and no AA release followed their stimulation with P01375 plus CHX .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK1___","___MASK23___","___MASK31___","___MASK38___","___MASK41___","___MASK49___","___MASK68___","___MASK6___","___MASK73___"],"string":"[\n \"___MASK1___\",\n \"___MASK23___\",\n \"___MASK31___\",\n \"___MASK38___\",\n \"___MASK41___\",\n \"___MASK49___\",\n \"___MASK68___\",\n \"___MASK6___\",\n \"___MASK73___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK38___"},"id":{"kind":"string","value":"MH_train_85"}}},{"rowIdx":86,"cells":{"query":{"kind":"string","value":"interacts_with DB00098?"},"supports":{"kind":"list like","value":["Upregulation of molecules associated with T - regulatory function by thymoglobulin pretreatment of human P01730 + cells . BACKGROUND : This study evaluated the immunologic effects of thymoglobulin in modulating human P01730 + cells . METHODS : Human P01730 + cells were purified from peripheral blood mononuclear cells by negative selection method . P01730 + cells were pretreated with thymoglobulin and incubated for 72 hr . Cells and culture supernatants were collected and studied by real - time quantitative polymerase chain reaction , fluorescence activated cell scanning , multiplex cytokine assay , and mixed lymphocyte reaction ( P08235 ) . RESULTS : DB00098 pretreated P01730 + cells demonstrated up - regulation of gene transcripts for P16410 , OX40 , forkhead box P09131 ( Foxp3 ) , CD25 , P01579 , P22301 , and P60568 as determined by real - time quantitative polymerase chain reaction . Fluorescence - activated cell scanning analysis demonstrated that P01730 + cells , pretreated with thymoglobulin , up - regulated CD25 expression on their surface , and the surface expression of P16410 and OX40 and the expression of intracellular Foxp3 were observed in these P01730 + CD25 + cells . Additionally , P08235 demonstrated that thymoglobulin - pretreated cells partially inhibited proliferation of untreated autologous P01730 + cells in response to allogeneic cells . The high levels of P01579 , P22301 , P60568 , and P05112 were detected by multiplex cytokine assay in supernatants collected from cultures of thymoglobulin - pretreated P01730 + cells . The lymphocyte proliferation of allogeneic P08235 was also partially blocked in the presence of supernatants from cultures of thymoglobulin - pretreated P01730 + cells . CONCLUSIONS : This study demonstrates that the unique effects of thymoglobulin in modulating P01730 + cells may be an important mechanism for its action in inducing immunosuppression and transplant tolerance .","Induction of bona fide regulatory T cells after liver transplantation - the potential influence of polyclonal antithymocyte globulin . T - cell - depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting . Besides prevention of alloreactivity , treatment with rabbit antithymocyte globulin ( DB00098 ) has been related to the induction of immunoregulatory T cells ( Treg ) in vitro and in vivo . To investigate Treg induced by DB00098 , we prospectively studied the effect of DB00098 induction therapy in liver - transplanted recipients in vivo ( n = 28 ) . Treg induction was further evaluated by means of Treg - specific demethylation region ( TSDR ) analysis within the Q9BZS1 locus . Whereas no induction of P01730 (+) CD25 ( high ) CD127 (-) Treg could be observed by phenotypic analysis , we could demonstrate an induction of TSDR (+) T cells within P01730 (+) T cells exclusively for DB00098 - treated patients in the long - term ( day 540 ) compared with controls ( P = NS ) . Moreover , although in vitro experiments confirm that DB00098 primarily led to a conversion of P01730 (+) CD25 (-) into P01730 (+) CD25 (+) T cells displaying immunosuppressive capacities , these cells can not be classified as bona fide Treg based on their Q9BZS1 demethylation pattern . Consequently , the generation of Treg after DB00098 co - incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined .","Sequential phases in the development of Aire - expressing medullary thymic epithelial cells involve distinct cellular input . Intrathymic deletion of immature thymocytes that express self - reactive TCR specificities is essential in the generation of self tolerance . Medullary thymic epithelial cells ( mTEC ) expressing the transcriptional regulator Aire play a key role in this process by regulating expression of tissue - restricted antigens to ensure tolerance to peripheral tissues . Here , we have analysed the cellular and molecular requirements for the initial appearance of Aire + mTEC in the embryonic thymus , in addition to their persistence in the adult thymus . Analysis of thymic ontogeny shows that the emergence of embryonic Aire + mTEC occurs prior to the appearance of mature thymocytes , and depends upon lymphoid tissue inducer cells expressing retinoic acid receptor - related orphan receptor gamma . In the adult thymus , we show that Aire + mTEC develop in the absence of thymocyte positive and negative selection and P25942 signalling , but are present at reduced frequency . Collectively these data support a model where the initial differentiation of Aire + mTEC involves receptor activator of NF - kappaB ( Q9Y6Q6 ) - O14788 interactions with lymphoid tissue inducer cells , with subsequent mTEC turnover and / or survival involving P25942 - mediated signalling following interactions with mature P01730 + thymocytes that express P29965 .","Rabbit ATG but not horse ATG promotes expansion of functional P01730 + CD25highFOXP3 + regulatory T cells in vitro . Regulatory T cells ( Treg ) play important roles in suppressing immune responses and maintaining tolerance . Rabbit antithymocyte globulin ( DB00098 ) and horse ATG ( hATG ) are widely used in the treatment of immune - mediated syndromes , but their effects on Treg are unknown . We show here that in vitro culture of normal human peripheral blood mononuclear cells ( PBMCs ) with a low - dose DB00098 resulted in marked expansion of functional Treg by converting P01730 + CD25 - T cells to P01730 + CD25 + T cells . hATG did not expand but rather decreased Treg . Immuno - blot showed increased expression of Q9BZS1 and Q13469 in P01730 + CD25 - and P01730 + CD25 + T cells exposed to DB00098 . PBMCs treated with DB00098 displayed increased interleukin - 10 in culture supernatants than those treated with hATG . Furthermore , DB00098 and hATG showed differences in their potential to stimulate P01730 + T cells as examined using different activation markers . Microarray revealed that DB00098 induced markedly different gene - expression patterns in PBMCs , compared with hATG - treated or untreated PBMCs . Our findings indicate that DB00098 expanded Treg , probably through transcriptional regulation by enhanced Q13469 expression , in turn conferring P01730 + CD25 - T cell Q9BZS1 expression and regulatory activity . The therapeutic effects of DB00098 may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function .","ATG - induced expression of Q9BZS1 in human P01730 (+) T cells in vitro is associated with T - cell activation and not the induction of Q9BZS1 (+) T regulatory cells . Several recent reports have suggested that in vitro exposure of P01730 (+) T cells to rabbit antithymocyte globulin ( DB00098 ) , which is commonly used to prevent and treat graft - versus - host disease and allograft rejection , is an effective method to induce P01730 (+) CD25 (+) Q9BZS1 (+) T regulatory cells ( Tregs ) . We and others , however , have shown that Q9BZS1 is also expressed in activated T cells . We therefore investigated whether the induction of Q9BZS1 expression by DB00098 resulted in a stable population of suppressive Tregs . We found that exposure of peripheral blood mononuclear cells ( PBMCs ) or conventional T cells to DB00098 resulted in induction of transient rather than stable expression of CD25 and Q9BZS1 . Furthermore , DB00098 - treated T effector cells acquired neither an immunosuppressive profile of cytokine production nor suppressive capacity , even at the time of maximal Q9BZS1 expression . These findings indicate that the notion that DB00098 can be used to induce Tregs in vitro for cellular therapy in vivo should be re - evaluated .","DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .","Comparative polyclonal antithymocyte globulin and antilymphocyte / antilymphoblast globulin anti - CD antigen analysis by flow cytometry . Polyclonal antithymocyte globulin ( ATG ) / antilymphocyte and antilymphoblast globulins ( ALG ) antibodies have been used successfully in transplantation , aplastic anemia and graft - versus - host disease . Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG / ALG preparations for immunosuppression . Recent reports have indicated clinical dose adjustment based on levels of patient ' s cells expressing various CD antigens . In vitro analysis of individual polyclonal ATG / ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data . Therefore , a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed . Activities found in four lots each of horse ATG ( ATGAM , Upjohn ) , rabbit and horse ATG ( thymoglobulin and lymphoglobulin , Merieux ) , horse ALG ( Minnesota ) , and DB00098 ( Fresenius ) have been compared for P06729 , CD3 , P01730 , P06127 , P09564 , CD8 , CD11a , P05107 , P10747 , P16070 , P08575 , and TCR - alpha / beta antigens . Quantitation is achieved by measuring the concentration of ATG / ALG required to give 50 % inhibition of antigen specific fluorescent - labeled monoclonal antibody relative to buffer controls . The three horse products tested have similar activity to most antigens tested . However , Fresenius DB00098 has the lowest activity for almost all antigens tested whereas the Merieux DB00098 has activities closer to the horse products . This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency .","Regulatory T cells in kidney transplant recipients : the effect of induction immunosuppression therapy . BACKGROUND : Regulatory T cells have been suggested to down - regulate the alloimmune response . The aim of this prospective open study was to evaluate the effects of different inductive agents on peripheral blood regulatory T cells in kidney transplant patients and to analyse their association with short - term graft outcome . METHODS : Regulatory and effector T cell numbers in peripheral blood were determined by flow cytometry in 71 prospectively followed kidney transplant recipients at postoperative day 0 , 7 , 14 , 21 , 28 , 60 and 90 . Patients were treated with a calcineurin inhibitor - based triple immunosuppression with polyclonal rabbit anti - thymocyte globulin ( DB00098 , n = 28 ) , basiliximab , the anti - CD25 monoclonal antibody ( n = 18 ) or without induction ( controls , n = 25 ) . Flow cytometry data were correlated to rejection incidence . RESULTS : Compared to controls , P01730 (+) CD25 (+) FoxP3 (+) regulatory T - cell expansion among P01730 (+) T cells was noticed in the DB00098 group at all post - transplant time - points by Day 14 ( P < 0 . 001 ) . A significant decrease in Treg frequency ( P < 0 . 001 ) and concurrently a transient increase of P01730 (+) CD25 ( low /-) FoxP3 (+) population were observed in basiliximab - treated patients 7 - 60 days post - transplantation . Biopsy - proven acute rejection occurred in 16 . 7 % of controls , 10 . 7 % of the DB00098 group and in 11 . 1 % of the basiliximab group . Higher P01730 (+) FoxP3 (+)/ CD8 (+) CD45RA (+) CD62L (-) ratios were observed repeatedly in those patients after basiliximab induction who were rejection free ( P < 0 . 01 ) . CONCLUSIONS : In this study , the DB00098 induction therapy was associated with an expansion of regulatory cells . Sustained high P01730 (+) FoxP3 (+)/ Teff ratios were associated with the absence of rejection after basiliximab induction .","Significance of immune cell function monitoring in renal transplantation after DB00098 induction therapy . Monitoring of immune status in transplant recipients is essential for predicting the risk of rejection or infection . In this study , we assessed the significance of immune cell function in 76 renal allograft recipients after DB00098 induction and initiation of maintenance immunosuppression . Using the Immuknow ( Cylex Inc ) assay , the amount of adenosine triphosphate ( DB00171 ) produced by P01730 + cells in response to phytohemagglutinin ( PHA ) was measured in patients whole blood . In parallel , the frequency and phenotype of P01730 + T cells were determined by flow cytometry . The Immuknow assay yielded paradoxically high DB00171 values during the first 3 months post - transplantation , despite very low P01730 + T cell counts . High DB00171 values were caused by peripheral blood myeloid cells , did not predict rejection , and occurred primarily in transplant recipients who received darbepoietin ( p = 0 . 017 ) . P01730 + T cells displayed predominantly an activated / memory phenotype and comprised a subpopulation of CD25 + Q9BZS1 + cells . Over the first 5 months post - transplantation , mean DB00171 activity gradually decreased , whereas P01730 + T cell counts slowly increased . Low DB00171 values were predictive of infection ( p = 0 . 002 ) . Thus Immuknow results need to be interpreted with caution in patients receiving DB00098 induction therapy . Although low DB00171 levels identify patients at increased risk for infection , high DB00171 values fail to correlate with rejection and do not justify increased immunosuppression .","Antithymocyte globulins suppress dendritic cell function by multiple mechanisms . BACKGROUND : The polyclonal rabbit antithymocyte and anti - T - cell immunoglobulins ( ATGs ) DB00098 ( TG ) and DB05320 ( ATG - F ) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation . Although immunosuppressive mechanisms of ATGs on T cells are well studied , less is known about their impact on dendritic cells ( DCs ) . METHODS : Effects of TG and ATG - F on immune functions and signaling pathways of human monocyte - derived DCs were determined by flow cytometry , enzyme - linked immunosorbent assay , Western blot , apoptosis assays , endocytosis assays , and T cell stimulation assays . RESULTS : TG and ATG - F bind rapidly and with high affinity to CD11c , P33681 , P42081 , P25942 , P16671 , P28907 , CD206 , and human leukocyte antigen - DR on DCs . TG and , to a lesser extent , ATG - F induce apoptosis in immature and mature DCs . Macropinocytotic and receptor - mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG - F due to their binding of the C - type lectins CD206 and Q9NNX6 . TG and ATG - F induce activation of the mitogen - activated protein kinases P27361 / 2 and p38 that contributes to the induction of apoptosis . TG and ATG - F also induce cytoplasmic - nuclear translocation of the NF - kappaB / Rel transcription factors RelB , RelA , p50 , and p52 . Production of interleukin - 12p70 in mature DCs is suppressed by TG and ATG - F . TG and ATG - F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells . CONCLUSIONS : ATGs interfere with basic DC functions , suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation .","Ex vivo expansion of human Tregs by DB00098 is dependent on intact P40763 - signaling in CD4 ⁺ T cells and requires the presence of monocytes . The addition of low , nondepleting doses of rabbit antithymocyte globulin ( ATG ) to human peripheral blood mononuclear cells has been shown to expand functional P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) in vitro . This report is the first to elucidate the exact cellular mechanisms of ATG - mediated Treg expansion . P01730 (+) T cells require monocytes , but not other antigen presenting cell subsets , to be present in coculture to expand Tregs . However , T cells do not require direct cell - cell contact with monocytes , suggesting the importance of soluble factors . Moreover , ATG initially \" reprograms \" P01730 (+) T cells , but not monocytes , and induces P40763 and P42229 signaling in P01730 (+) cells . These reprogrammed P01730 (+) T cells subsequently secrete GM - P04141 and P22301 only in case of intact P40763 signaling , which in turn promote the generation of tolerogenic P08571 (+) CD11c (+) dendritic cells characterized by enhanced P22301 and decreased IL - 12 production . Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM - P04141 and Bcl - 2 , but not TGF - β , in peripheral blood mononuclear cells . These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram P01730 (+) T cells in a P40763 - dependent but TGF - β - independent manner , leading to the generation of monocyte - derived dendritic cells with a tolerogenic cytokine profile .","Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice . Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer . Following treatment of the primary cancer , emotional and psychosocial factors within this population precipitate time to recurrence and death , however the underlying mechanism ( s ) remain unclear . Using a mouse model of bone metastasis , we provide experimental evidence that activation of the sympathetic nervous system , which is one of many pathophysiological consequences of severe stress and depression , promotes MDA - 231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma . We demonstrate that induction of O14788 expression in bone marrow osteoblasts , following β2AR stimulation , increases the migration of metastatic MDA - 231 cells in vitro , independently of P48061 - P61073 signaling . We also show that the stimulatory effect of endogenous ( chronic stress ) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β - blocker propranolol , and by knockdown of Q9Y6Q6 expression in MDA - 231 cells . These findings indicate that O14788 promotes breast cancer cell metastasis to bone via its pro - migratory effect on breast cancer cells , independently of its effect on bone turnover . The emerging clinical implication , supported by recent epidemiological studies , is that βAR - blockers and drugs interfering with O14788 signaling , such as ___MASK86___ , could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the \" vicious cycle \" of bone destruction induced by these cells .","Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation . Experimental studies have shown that rabbit antithymocyte polyclonal globulin ( ATG ) can expand human P01730 + CD25 ++ Foxp3 + cells ( Tregs ) . We investigated the major biological effects of a self - manufactured rabbit polyclonal anti - rat thymoglobulin ( DB00098 ) in vitro , as well as its effects on different peripheral T - cell subsets . Moreover , we evaluated the allogeneic suppressive capacity of DB00098 - induced Tregs in an experimental rat renal transplant model . Our results show that DB00098 has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T - cell depletion . Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets , directly proportional to the DB00098 dose used , but not of the effector memory T cells , which required significantly higher DB00098 doses . After DB00098 administration , we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats , leading to an increase in the Treg / T effector ratio . Importantly , DB00098 - induced Tregs displayed a strong donor - specific suppressive capacity when assessed in an antigen - specific allogeneic co - culture . All of these results were associated with better renal graft function in rats that received DB00098 . Our study shows that DB00098 has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post - transplant homeostatic proliferation .","Regulatory T cells increase in breast cancer and in stage IV breast cancer . Expression levels of P15692 and Her - 2 , levels of T - regulatory ( Treg ) cells , levels of CD3 + cells , and ratios of Th ( P01730 + T cells ) / Tr ( Treg ) cells were compared between stage I , II , III , and IV breast cancer patients ( n = 120 ) prior to chemotherapy and healthy women ( n = 30 ) . Cells from peripheral blood were counted by flow cytometry , Her - 2 and P15692 expression was detected by pathological examination , and Her - 2 was detected by Q5TCZ1 . Breast cancer patients had more Treg cells and a lower ratio of Th / Tr cells than the healthy women . Stage IV breast cancer patients had more Treg cells and a lower ratio of Th / Tr cells than stage I , II , or III breast cancer patients . Patients positive for P15692 had a lower ratio of Th / Tr cells compared with patients negative for P15692 , and those positive for both P15692 and Her - 2 also had a lower ratio of Th / Tr cells compared with patients not positive for both P15692 and Her - 2 . The decreased Th / Tr cells ratio indicates impaired immune function , suggesting that the stage IV breast cancer and the Her - 2 / P15692 - positive breast cancer patients have lower immune function .","In vivo characterization of rabbit anti - mouse thymocyte globulin : a surrogate for rabbit anti - human thymocyte globulin . BACKGROUND : Polyclonal rabbit anti - human thymocyte globulin ( DB00098 ) is used clinically for immunosuppression in solid organ transplantation ; however , it is difficult to fully characterize the effects of this agent in humans . METHODS : A surrogate rabbit anti - murine thymocyte globulin ( mATG ) was generated analogously to the commercial product DB00098 and in vivo activities were evaluated , including pharmacokinetics , T - cell depletion , dose response and kinetics , depletion / sparing of T - cell subsets or other leukocyte populations , and depletion in different lymphoid organs . RESULTS : Within 1 day , T cells are depleted by mATG in the blood , spleen , lymph node , and bone marrow down to doses of 1 mg / kg . Although mATG binds and depletes thymocytes in vitro , there is no thymocyte depletion in vivo at any dose level , suggesting decreased antibody accessibility to the thymus . After two doses of mATG given 3 days apart , T - cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for P01730 and CD8 T cells , respectively . There is also preferential depletion of naïve T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration . Depletion of natural killer - T cells , natural killer cells , plasma cells , and plasmablasts occurs , but is modest and more transient compared with T cells . B cells , macrophages , dendritic cells , hematopoetic stem cells , and bone marrow stromal cells seem resistant to mATG depletion . CONCLUSIONS : These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of DB00098 .","FoxP3 + , and not CD25 + , T cells increase post - transplant in islet allotransplant recipients following anti - CD25 + DB00098 immunotherapy . Anti - CD25 antibodies are used as an induction therapy in islet allotransplantation for type 1 diabetes . Although previous reports suggested that anti - CD25 treatment may lead to depletion of P01730 + CD25 + regulatory T cells ( Tregs ) and questioned its use in tolerance - promoting protocols for transplantation , the effect of anti - CD25 antibodies on the frequency and function of Tregs remains unclear . We examined the effect of anti - CD25 antibody , daclizumab , in vivo on Tregs in islet allograft recipients enrolled in a single - center study and monitored post - transplant . Our data shows that the reduction in CD25 + Treg cells observed post - transplant is due to masking of CD25 receptor by daclizumab and not due to depletion . In addition , using Treg marker , FoxP3 , we show that anti - CD25 + ATG treatment leads to an increase in FoxP3 + Tregs post - transplant . These data suggest that anti - CD25 - based therapy has beneficial effects on Tregs and combined with ATG may be a promising therapy for autoimmunity and transplantation .","Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK73___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .","Immune reconstitution following rabbit antithymocyte globulin . Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome . The effects of depleting agents on T - cell subsets and subsequent T - cell reconstitution are incompletely defined . We used flow cytometry to examine the effects of rabbit antithymocyte globulin ( DB00098 ) on the peripheral T - cell repertoire of pediatric and adult renal transplant recipients . We found that while DB00098 effectively depleted CD45RA + P26842 + naïve and CD45RO + P26842 + central memory P01730 + T cells , it had little effect on CD45RO + P26842 - P01730 + effector memory or CD45RA + CD31 - , CD45RO + P26842 + and CD45RO + P26842 - CD8 + T cell subsets . When we performed a kinetic analysis of CD31 + recent thymic emigrants and CD45RA +/ RO + T cells , we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution . We additionally examined the impact of DB00098 on peripheral P01730 + Foxp3 + T cells . We found that in adults , administration of DB00098 - induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype , while P01730 + Foxp3 + T cells of thymic origin predominated in children , providing the first evidence that DB00098 induces Treg in vivo . Collectively our data indicate that DB00098 alters the balance of regulatory to memory effector T cells posttransplant , providing an explanation for how it positively impacts transplant outcome .","Risk factors for impaired P01730 + T - cell reconstitution following rabbit antithymocyte globulin treatment in kidney transplantation . To describe long - term P01730 + T - cell reconstitution after rabbit antithymocyte globulin ( DB00098 ) treatment and identify predictive factors following kidney transplantation . A single - center retrospective study analyzed lymphocyte subsets in DB00098 - treated kidney transplant recipients ( 1986 - 2009 ) . 589 patients were analyzed ( maximum follow - up 21 years ) . A comparator group ( n = 298 ) received an anti - P60568 receptor monoclonal antibody . P01730 + T - cell lymphopenia ( < 200 / mm3 ) was present in 48 . 5 % , 9 . 2 % , 6 . 7 % , 2 . 0 % , and 0 % of patients at one , three , five , 10 , and 20 years post - transplant , respectively . P01730 + T - cell count increased during the first 10 years but remained below the pretransplant count even after 20 years . At 1 , 3 , and 6 months post - transplant , mean P01730 + T - cell count was significantly lower in patients with P01730 + T - cell lymphopenia at 12 months versus patients without lymphopenia . On multivariate analyses , significant independent predictors for long - term impaired P01730 T - cell reconstitution were recipient age , pretransplant P01730 + T - cell count , 12 - month P01730 + T - cell count , and tacrolimus or DB00688 therapy . Recipient age > 40 years was identified as a cutoff point . P01730 + T - cell reconstitution following DB00098 treatment remains impaired even after 21 years . Most risk factors for long - term impaired P01730 + T - cell reconstitution may be evaluated pretransplant or are modifiable post - transplant .","Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK68___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .","Kinetics of homeostatic proliferation and thymopoiesis after DB00098 induction therapy in kidney transplant patients . BACKGROUND : Lymphocyte - depleting therapy is associated with long - lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies . The mechanisms of T - cell repopulation and their posttransplantation kinetics are not fully understood . METHODS : We studied thymopoiesis by CD31 (+) naïve T cells ( recent thymic emigrants ) and homeostatic proliferation by Ki - 67 (+) T cells in rabbit antithymocyte globulin ( DB00098 ) - treated patients the first 6 months after transplantation . Patients receiving basiliximab or no induction therapy served as controls . RESULTS : At 6 months after transplantation , T - cell numbers were lower than before transplantation in DB00098 - treated patients , whereas T - cell numbers remained stable in both control groups . In this time period , thymopoiesis was similar between the three treatment groups ; CD8 (+) T cells showed the highest percentage of recent thymic emigrants . At month 1 , percentages of Ki - 67 (+) naïve and memory P01730 (+) and CD8 (+) T cells were the highest in DB00098 - treated patients , but these percentages declined in the months thereafter . When CD31 was used to distinguish between cytokine - and antigen - driven proliferation in naïve T cells , we found evidence for cytokine - dependent proliferation . Cytokine - dependent proliferation was also shown by in vivo increased percentages of phosphorylated P42229 and high expression levels of the interleukin - 7 receptor - α and interleukin - 15 receptor - α by T cells . CONCLUSION : These findings demonstrate that , in the first month after DB00098 therapy , cytokine - induced homeostatic proliferation is involved in T - cell repopulation of both naïve and memory T cells . At later time points , the contribution of homeostatic proliferation diminished , which explains the observed incomplete T - cell recovery .","Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion . BACKGROUND : Polyclonal antithymocyte globulins ( ATGs ) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells . However , nondepleting mechanisms may also be important mediators of graft survival . In the present study , 14 lots of thymoglobulin ( DB00098 ) were analyzed and compared for nondepletive immunomodulatory activities in vitro . METHODS : Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces P01730 + CD25 ( high ) Foxp3 + regulatory T cells , which were evaluated for consistent ability to suppress T - cell activation in mixed lymphocyte reactions . The consistency of P06729 , CD3 , CD11a , and P08575 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells . A transwell chemotaxis assay was established and used to evaluate ATG - mediated inhibition of stromal cell - derived factor ( SDF ) - 1alpha - driven Jurkat T - cell migration . RESULTS : Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities , which were consistent from batch to batch . All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T - cell surface antigens . In addition , these studies provide the first demonstration that thymoglobulin effectively inhibits P61073 / SDF - 1alpha - driven T - cell chemotaxis . CONCLUSIONS : This novel , systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival .","A double recombinant adenovirus expressing the costimulatory molecule P33681 - 1 ( murine ) and human P60568 induces complete tumor regression in a murine breast adenocarcinoma model . Tumors that express tumor - specific antigens can maintain growth in an immunocompetent organism . Current hypotheses tend toward T cell anergy as a key component for the inhibition of immunoreactivity against such tumors . Anergy is thought to occur from hyperactive stimulation of the TCR in the absence of costimulation ( costimulation leads to proliferation via P60568 production ) . Subcutaneous injection of transgenic polyoma middle T transformed breast adenocarcinoma tumor cells ( PyMT ) in the hind flank of FVB / n mice results in the formation of tumor nodules at this site . We determined the MHC class I and class II , P33681 - 1 , and P33681 - 2 expression in the tumor cells by flow cytometry and showed positive staining for only MHC class I . We show that a single E1 - deleted adenovirus constructed to express both the costimulatory molecule P33681 - 1 ( murine ) and human P60568 genes ( Ad5E1 mB7 - 1 / human P60568 ) elicits a very potent antitumor response when administered intratumorally . Ad5E1 mB7 - 1 / human P60568 induced rapid and complete regression ( 100 % ) of all tumors compared with Ad5 E1 mB7 - 1 ( 38 % ) , Ad CAIL - 2 ( 42 % ) , and Ad5E1 dl70 - 3 ( control vector ) ( 0 % ) . All mice that exhibited complete tumor regression were fully protected in tumor cell challenge experiments . The systemic immunity generated by intratumoral administration of the Ad vectors was associated with a strong anti - PyMT CTL response . These observations indicate that augmenting the immunogenicity of the tumor with coincident expression of P33681 - 1 in combination with P60568 may prove beneficial in direct tumor immunotherapy .","___MASK80___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK80___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .","Prolonged lymphocyte depletion by single - dose rabbit anti - thymocyte globulin and alemtuzumab in kidney transplantation . Although antibody induction has gained in popularity , two agents are rarely combined . We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody / combination : alemtuzumab ( C1H ) , DB00098 ( DB00098 ) , daclizumab ( Dac ) , DB00098 + C1H , and DB00098 + Dac . P01730 + T - cells were suppressed by C1H and DB00098 + C1H , as well as by DB00098 and DB00098 + Dac but to a lesser extent . The effect lasted for 3 years at around 40 % of baseline values . CD8 + T - cells showed a similar trend but had a more rapid recovery to baseline . P15391 + B - cells were effectively suppressed for 2 months by C1H and DB00098 + C1H , and abruptly returned to baseline afterwards ; suppression by DB00098 ( 7 doses ) was modest but lasted longer . A higher proportion of CD56 + CD16 + Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type . Low CD25 + T - cells by 5 - dose Dac returned to baseline around 6 months , whereas DB00098 + C1H and DB00098 + Dac showed persistent effect . P01730 + CD25hi T - cells were suppressed by both DB00098 + C1H and DB00098 + Dac , but the initial proportion of P01730 + CD25hi T - cells among P01730 + T - cells and P01730 + CD25hi / P01730 + CD25lo ratio were significantly higher in DB00098 + C1H . Overall , with extensive and persistent lymphocyte suppression by a simple administration of agents , single - dose DB00098 + C1H induction can be an alternative in renal transplantation .","Rabbit anti T - lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells , while hematopoetic stem cells are apoptosis resistant . Polyclonal anti - T - lymphocyte globulins ( ATG ) are used in allogeneic stem cell transplantation ( P09683 ) for the prophylaxis of graft versus host disease ( GVHD ) by in vivo T cell depletion . In this study we investigated the complement independent induction of apoptosis by DB00098 in peripheral blood mononuclear cell ( PBMNC ) compartments and hematopoetic stem cells ( P19526 ) . We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells . We found ATG to induce apoptosis in T - lymphocytes ( P01730 (+) , CD8 + ) , B - lymphocytes ( P11836 + ) , natural killer ( NK ) - cells ( CD56 (+) ) , and monocytes ( P08571 (+) ) . P19526 , in contrast , were apoptosis resistant and could be growth stimulated by low - dose ATG in the presence of bystander cells . The human leukemia cell lines Jurkat , Daudi , DG - 75 ( lymphoblastic ) , and K562 , HL - 60 , KG1 , and U937 ( myeloblastic ) underwent ATG - induced apoptosis , whereas the NK - cell line YT was resistant . Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia , 9 of 10 patients with chronic lymphocytic leukemia , and 4 of 8 patients with acute myeloblastic leukemia underwent ATG - induced apoptosis . We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis . ATG might support engraftment . Finally , antileukemic activity of ATG could positively influence the transplantation outcome .","Expression of cyclooxygenase - 2 ( P35354 ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase - 2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB - IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase - 2 . CD3 , P01730 , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase - 2 levels ( cyclooxygenase - 2 IDV ) of tumour vs stroma compartment ( r =- 0 . 44 , P < 0 . 0001 ) . The percentage of cases showing high tumour / stromal cyclooxygenase - 2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93 . 3 % ) with respect to patients with partial ( 60 . 5 % ) , and complete ( 43 . 7 % ) response ( P = 0 . 009 ) . Cases with a high tumour / stroma cyclooxygenase - 2 IDV ratio had a shorter overall survival rate than cases with a low tumour / stroma cyclooxygenase - 2 IDV ( P < 0 . 0001 ) . In the multivariate analysis advanced stage and the status of tumour / stroma cyclooxygenase - 2 IDV ratio retained an independent negative prognostic role . The proportion of CD3 (+) , P01730 (+) , and CD25 (+) cells was significantly lower in tumours with high tumour / stroma cyclooxygenase - 2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour / stroma cyclooxygenase - 2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase - 2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis .","___MASK86___ for joints and bones . ___MASK86___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK86___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK86___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .","___MASK37___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK37___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK37___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK37___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .","Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation : influence of Campath dose on lymphoid recovery , mixed chimerism and survival . Sixty - nine consecutive patients ( median age 54 years ) were prospectively enrolled in a single - institution protocol for allogeneic transplantation with adjusted non - myeloablative fludarabine - melfalan - based conditioning including cyclosporin A and DB00688 , and one of three modes of serotherapy . Thirty - one donors ( 45 % ) were unrelated . The first cohort of 29 had ATG ( DB00098 2 mg / kg x 3 days ) , the subsequent 26 had Campath 30 mg x 3 days subcutaneously , and the final cohort of 14 had 30 mg Campath once . The groups were similar as regards age , diagnosis and risk factors . Campath - patients had no acute toxicity , fewer days with fever and antibiotics , and required fewer transfusions than ATG - treated patients . 3 - d - Campath patients showed lower lymphocyte counts from day + 4 , and P01730 + , CD8 + , P15391 + and NK cells recovered slower than in ATG - treated patients . More Campath patients developed mixed chimerism that required DLI . 3 - d - Campath induced more serious and opportunistic infections than ATG , which resulted in a greater non - relapse mortality and an impaired overall survival despite a low tumor - related mortality . The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3 - d - Campath on immune recovery , severe infections and survival . Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity , but dose limitation to 30 mg once is recommended .","Low - dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression . Rabbit antithymocyte globulin therapy ( DB00098 ) is a potent lymphocyte - depleting agent commonly used following renal transplantation to reduce the risk of acute rejection . Standard doses ( 7 - 10 mg / kg ) of DB00098 result in profound lymphopenia and predispose patients to infection and malignancy . The effects of lower doses of DB00098 ( LoD - DB00098 , 3 - 5 mg / kg ) on peripheral blood lymphocytes ( PBL ) are as yet unknown . In this prospective clinical trial , PBL subsets were characterized by flow cytometry over 12 months following LoD - DB00098 therapy . All patients were initially treated with standard doses of tacrolimus , mycophenolic acid , and prednisone . At 3 months , patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence . LoD - DB00098 therapy resulted in prolonged suppression of P15391 + B cells , total CD3 + T cells , as well as naïve and memory P01730 + T cell and P01730 / CD25 / Foxp3 + T - regulatory subsets irrespective of chronic immunosuppressive therapy . Selective depletion was only noted in the CD4CD45RA + naïve T - cell subset resulting in an altered memory / naïve P01730 + ratio . LoD - DB00098 failed to deplete CD8 + T cells , which increased their relative contribution to the total CD3 + pool . All other lymphocyte subsets maintained near normal proportions . Thus , LoD - DB00098 therapy may lessen the adverse effects of full dose DB00098 while maintaining overall efficacy .","DB00098 - associated Cd4 + T - cell depletion and infection risk in HIV - infected renal transplant recipients . HIV - infected patients are increasingly referred for kidney transplantation , and may be at an increased risk for rejection . Treatment for rejection frequently includes thymoglobulin . We studied thymoglobulin ' s effect on P01730 + T - cell count , risk of infection and rejection reversal in 20 consecutive HIV - infected kidney recipients . All patients used antiretroviral therapy and opportunistic infection prophylaxis . Maintenance immunosuppression consisted of prednisone , mycophenolate mofetil and cyclosporine . Eleven patients received thymoglobulin ( 7 for rejection and 4 for delayed / slow graft function ) while 9 did not . These two groups were similar in age , gender , race , donor characteristics and immunosuppression . Mean P01730 + T - cell counts remained stable in patients who did not receive thymoglobulin , but became profoundly suppressed in those who did , decreasing from 475 +/- 192 to 9 +/- 10 cells / microL ( p < 0 . 001 ) . Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression . Although opportunistic infections were successfully suppressed , low P01730 + T - cell count was associated with increased risk of serious infections requiring hospitalization . Rejection reversed in 6 of 7 patients receiving thymoglobulin . We conclude that thymoglobulin reverses acute rejection in HIV - infected kidney recipients , but produces profound and long - lasting suppression of the P01730 + T - cell count associated with increased risk of infections requiring hospitalization .","Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .","A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients . PURPOSE : Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin ( DB00098 , DB00098 (®) ) to the hematopoietic cell transplant ( HCT ) conditioning regimen of IV fludarabine monophosphate ( fludarabine ) and targeted intravenous ( IV ) busulfan ( fludarabine /( T ) busulfan ) . Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients . METHODS : We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan , specifically busulfan concentration at steady state , and fludarabine , specifically F - ara - A area under the curve ( AUC ) and fludarabine triphosphate ( F - ara - DB00171 ) intracellular accumulation and concentration in separate P01730 (+) and CD8 (+) T - lymphocyte populations . RESULTS : Acute and chronic graft versus host disease ( GvHD ) occurred in 11 patients and one patient , respectively . Four patients died before day + 100 of non - relapse causes , which met the protocol stopping guidelines . The cumulative incidence of relapse was 25 % at 3 year post - HCT . Interpatient variability in the busulfan - and fludarabine - relevant pharmacologic biomarkers was 2 . 1 - to 2 . 5 - fold . F - ara - A AUC and accumulated F - ara - DB00171 in CD8 (+) cells had the highest hazard ratio for non - relapse mortality and overall survival , respectively . However , neither achieved statistical significance . CONCLUSIONS : The low rates of GvHD , particularly in its chronic form , were encouraging , and further biomarker studies are warranted to optimize the fludarabine /( T ) busulfan / DB00098 conditioning regimen .","___MASK74___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .","Suppression of IL - 12 production by soluble P29965 : evidence for involvement of the Q8TCB0 / 42 mitogen - activated protein kinase pathway . IL - 12 is a key cytokine in skewing immune responses toward Th1 - like reactions . Human monocytes / macrophages produce high amounts of bioactive IL - 12 when a priming signal ( P01579 or GM - P04141 ) precedes a second signal ( e . g . , LPS ) . We and others have previously shown that preincubation with LPS before this stimulation procedure can efficiently and selectively suppress the production of IL - 12 by human monocytes . In this study , we show that an almost complete suppression of IL - 12 production can also be observed after preincubation of monocytes with costimulatory cell surface molecules that bind to members of the TNFR superfamily ( P29965 , O14788 ( O14788 ) ) . The suppression of IL - 12 was observable on the mRNA and protein levels and was not due to endogenous production of known IL - 12 antagonists ( i . e . , P22301 , P05112 , and PGE ( 2 ) ) , to an increased number of cells undergoing apoptosis , nor to down - regulation of the P01579 or P25942 receptor . Cell surface expression of the costimulatory molecules P33681 and P42081 was not reduced by the preincubation procedure , and only a moderate reduction of P05231 production was observed . Several studies have identified signal transduction pathways that are activated by P25942 signaling , including activation of mitogen - activated protein kinases . The presence of the extracellular signal - related kinase - specific mitogen - activated protein kinase kinase 1 / 2 - specific inhibitors PD98059 and U0126 abrogated suppression induced by sCD40 ligand or other second signals . This indicates that activation of extracellular signal - regulated kinase 1 / 2 contributes to the underlying mechanism of IL - 12 suppression . This mechanism may be relevant in other inflammatory responses and may help to develop therapeutic strategies in Th1 - mediated diseases .","Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .","Rapid T cell repopulation after rabbit anti - thymocyte globulin ( DB00098 ) treatment is driven mainly by cytomegalovirus . Rabbit anti - thymocyte globulin ( DB00098 ) induces a long - lasting lymphocytopenia . P01730 (+) T cells remain depleted for up to 2 years , whereas the CD8 (+) T cell compartment is refilled rapidly by highly differentiated P26842 (-) CD45RA (+) CD57 (+) effector - type cells . Because the presence of these highly differentiated CD8 (+) T cells has been associated with cytomegalovirus ( CMV ) infection , we questioned to what extent restoration of CMV T cell immunity contributes to the re - emergence of T cells following DB00098 treatment . We compared T cell repopulation in six CMV - seropositive patients with CMV reactivation ( reactivating CMV (+) ) to that in three CMV (+) patients without reactivation ( non - reactivating CMV (+) ) , and to that in three CMV - seronegative recipients receiving a kidney from a CMV - seronegative donor ( CMV (-/-) ) . All patients received DB00098 because of acute allograft rejection . Total P01730 and CD8 counts , frequency and phenotype of virus - specific CD8 (+) T cells were determined . In reactivating CMV (+) patients , total CD8 (+) T cells reappeared rapidly , whereas in non - reactivating CMV (+) patients they lagged behind . In CMV (-/-) patients , CD8 (+) T cell counts had not yet reached pretransplant levels after 2 years . CMV reactivation was indeed followed by a progressive accumulation of CMV - specific CD8 (+) T cells . During lymphocytopenia following DB00098 treatment , serum interleukin ( IL ) - 7 levels were elevated . Although this was most prominent in the CMV - seronegative patients , it did not result in an advantage in T cell repopulation in these patients . Repopulated CD8 (+) T cells showed increased skewing in their Vβ repertoire in both CMV (-/-) and reactivating CMV - seropositive patients . We conclude that rapid T cell repopulation following DB00098 treatment is driven mainly by CMV .","___MASK20___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK20___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .","[ Renal cell carcinoma management and therapies in 2010 ] . Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy . Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies . The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against P15692 - VEGFR and P42345 . Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival . At the moment , six molecules have been approves in advanced RCC : cytokines ( P60568 and IFN ) , antiangiogenic therapies ( sunitinib , sorafenib , bevacizumab ) and P42345 inhibitors ( ___MASK37___ , everolimus ) . Nephrectomy is an important component of the multimodality treatment of mRCC . Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies . Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting .","In vitro cell death of activated lymphocytes in Omenn ' s syndrome . Omenn ' s syndrome ( OS ) is characterized by erythrodermia , hepatosplenomegaly , lymphadenopathy , hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections . Peripheral blood T cells , though usually present in normal number , show an activated phenotype ( including an increased expression of CD95 / Fas ) , a Th2 pattern of cytokine secretion and defective proliferative response to mitogens . In this report , we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms . First , a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures ( p = 0 . 009 vs . healthy controls ) . This spontaneous apoptosis is associated with reduced expression of bcl - 2 gene product ( p < 0 . 05 ) and can be prevented by addition of interleukin ( IL ) - 2 ( which also prevents down - modulation of bcl - 2 ) , while is independent from CD95 signaling . Second , lymphocytes from OS patients are highly susceptible to activation - induced cell death ( AICD ) induced with mitogens . This mechanism is largely independent from P60568 , while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody ( mAb ) . The dependence of AICD from signals transduced via CD95 was confirmed showing that cross - linking CD95 with an IgM mAb induces a higher cell death in purified P01730 + CD45R0 + cells from OS patients than in controls ( comparable for CD95 expression ) . Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS .","Rabbit anti - rat thymocyte immunoglobulin preserves renal function during ischemia / reperfusion injury in rat kidney transplantation . Ischemia / reperfusion ( I / R ) injury is an important cause of renal graft dysfunction in humans . Increases in cold and warm ischemia times lead to a higher risk of early post - transplant complications including delayed graft function and acute rejection . Moreover , prolonged cold ischemia is a predictor of long - term kidney graft loss . The protective effect of rabbit anti - rat thymocyte immunoglobulin ( DB00098 ) was evaluated in a rat model of I / R injury following syngeneic kidney transplantation . Serum creatinine concentration was evaluated at 16 h and 24 h post - transplant . Animals were sacrificed 24 h post - transplant for evaluation of histology , infiltrating leukocytes , nitrotyrosine staining , and apoptosis . DB00098 was effective in preventing renal function impairment , tissue damage and tubular apoptosis associated with I / R only when was given 2 h before transplantation but not at the time of reperfusion . Pretransplant DB00098 treatment of recipient animals effectively reduced the amount of macrophages , P01730 (+) , CD8 (+) T cells and LFA - 1 (+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme - B expression within ischemic kidney . On the other hand , granulocyte infiltration and oxidative stress were not modified by DB00098 . If these results will be translated into the clinical setting , pretransplant administration of Thymoglobuline (®) could offer the additional advantage over peri - transplant administration of limiting I / R - mediated kidney graft damage .","A cell - intrinsic inhibitor of HIV - 1 reverse transcription in P01730 (+) T cells from elite controllers . HIV - 1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication , but cell - intrinsic mechanisms that can block HIV - 1 reverse transcription in a clinically significant way are poorly defined . We find that effective HIV - 1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin - dependent kinase ( CDK ) 2 at a highly conserved DB00156 residue . P24941 - dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness . Interestingly , P38936 , a cell - intrinsic CDK inhibitor that is upregulated in P01730 (+) T cells from \" elite controllers , \" potently inhibited P24941 - dependent phosphorylation of HIV - 1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription . These data suggest that P38936 can indirectly block HIV - 1 reverse transcription by inhibiting host cofactors supporting HIV - 1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV - 1 replication .","The effect of rabbit antithymocyte globulin on human DB05914 . Mesenchymal stem cells ( MSCs ) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation . In transplantation , administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials . Therefore , it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation . We aimed to analyze the effect of rabbit antithymocyte globulin ( DB00098 ) MSCs . MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of DB00098 ( DB00098 (®) , Genzyme ; 0 . 5 - 100 μg / ml ) . Binding of DB00098 , effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested . DB00098 binds dose - dependently to MSCs . This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs . In contrast to nontreated MSCs , DB00098 preexposed MSCs were susceptible to be lysed by cytokine - activated CD8 (+) cytotoxic cells and NKT cells . The capacity of MSCs to suppress the proliferation of anti - CD3 / P10747 activated P01730 and CD8 T cells were reduced by the presence of DB00098 in the culture . DB00098 reduces the viability and antiproliferative capacity of MSCs in a dose - dependent manner and converts them into targets for CD8 T cells and NKT cell lysis .","Murine antithymocyte globulin T - cell depletion is mediated predominantly by macrophages , but the Fas / P48023 pathway selectively targets regulatory T cells . BACKGROUND : DB00098 is a T - cell - depleting polyclonal rabbit anti - human thymocyte antibody used clinically for immunosuppression in solid organ and hematopoietic stem - cell transplantation . By using a surrogate rabbit anti - mouse thymocyte globulin ( mATG ) , we previously demonstrated that murine regulatory and memory T cells are preferentially spared from mATG depletion in vivo . The current studies were designed to determine whether different effector mechanisms are involved in differential depletion of T - cell subsets by mATG . METHODS : Complement - dependent cytotoxicity , antibody - dependent cellular cytotoxicity ( ADCC ) , and apoptotic mechanisms of depletion by mATG were evaluated in vitro and in vivo . RESULTS : In vitro , there was evidence of differential susceptibility of T - cell subsets by different effector mechanisms where naïve and P01730 effector memory T cells show reduced susceptibility to apoptosis , whereas regulatory T cells are less susceptible to mATG - mediated complement - dependent cytotoxicity and ADCC . However , mATG treatment of mice depleted of ADCC effector cell types ( neutrophils , natural killer cells , or macrophages ) or deficient in complement P01031 or Fas demonstrated that mATG depletion of all T - cell subsets is mediated primarily by macrophages and that the role of neutrophils , natural killer cells , and complement is minimal in vivo . Interestingly , the Fas / P48023 pathway does play a role in regulatory T - cell depletion , which is likely a result of increased basal expression of Fas on these cells . CONCLUSIONS : These data suggest that macrophages deplete most T cells by mATG in mice , but regulatory T cells are also uniquely susceptible to mATG - mediated Fas - dependent depletion .","Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK13___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK13___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK13___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .","The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia . Anti - thymocyte globulin ( ATG ) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia . However , there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome . Therefore , in this study , we retrospectively compared the effect of two different DB00098 preparations [ DB00098 ( ATG - G ) and ATG - Fresenius ( ATG - F ) ] on immune recovery and cytomegalovirus infection after transplantation . The conditioning regimen was a combination of fludarabine , cyclophosphamide , and ATG . Low dose total body irradiation was added in alternative donor transplantation . Four patients received ATG - F at 5 mg / kg / day from day - 7 to day - 3 , whereas ATG - G was given at 2 . 5 mg / kg / day from day - 5 to day - 2 in three patients . There was no graft rejection and no grade II - IV acute graft - versus - host disease . All three patients in the ATG - G group developed positive cytomegalovirus antigenemia including two with high - grade antigenemia , whereas two of the four patients in the ATG - F group were persistently negative . Immunological evaluation on day 60 revealed that both P01730 + and CD8 + T - cell recoveries were delayed in the ATG - G group . These findings suggested that ATG - G has a stronger immunosuppressive activity than the ATG - F with a dose ratio of 1 : 2 . 5 .","Acute and chronic vascular rejection in nonhuman primate kidney transplantation . A nonhuman primate ( NHP ) study was designed to evaluate in nonlife - supporting kidney allografts the progression from acute rejection with transplant endarteritis ( TXA ) to chronic rejection ( CR ) with sclerosing vasculopathy . Group P55008 ( n = 6 ) received high cyclosporine A ( DB00091 ) immunosuppression and showed neither TXA nor CR during 90 days post - transplantation . Group G2 ( n = 6 ) received suboptimal DB00091 immunosuppression and showed severe TXA with graft loss within 46 days ( median ) . Arterial intimal changes included infiltration of macrophages and T lymphocytes ( CD3 , P01730 , CD8 ) with few myofibroblasts , abundant fibronectin / collagen IV , scant collagens I / III , high rate of cellular proliferation and no C4d accumulation along peritubular capillaries . Group P46379 ( n = 12 ) received suboptimal DB00091 and anti - rejection therapy ( DB00098 + methylprednisolone + DB00091 ) of TXA . Animals developed CR and lost grafts within 65 days ( median ) . As compared to G2 , the arterial intimal changes showed less macrophages and T lymphocytes , an increased number of myofibroblasts , abundant fibronectin / collagen IV and scar collagens I / III , C4d deposition along capillaries in 60 % of animals and transplant glomerulopathy in 80 % of animals . In conclusion , CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts , and progressive deposition of collagens in the intima . Our experimental design appears well suited to study events leading to CR .","Atypical acute rejection after hand transplantation . Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse , patchy or focal , and distributed over forearms and dorsum of the hands . This ' classical ' pattern of rejection usually spares the skin of the palm and does not affect the nails . Herein , we report the experience on four cases presenting with an ' atypical ' pattern of rejection that is novel in involving the palmar skin and the nails . All patients were young and exposed to repetitive and persistent mechanical stress of the palm . Characteristic features of rejection included a desquamative rash associated with dry skin , red papules , scaling and lichenification localized to the palm . Skin lesions were associated with nail dystrophy , degeneration , deformation or loss . Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells ( CD3 + , P01730 + and CD8 + ) , with small numbers of B cells ( P11836 + and CD79a + ) and a low number of Forkhead transcription factor 3 ( Q9BZS1 ) - positive cells in one patient . The lesions persisted over weeks to months , responded poorly to steroid treatment and were managed with antithymocyte globulin ( ATG ; DB00098 , Genzyme , Cambridge , MA ) , alemtuzumab and / or intensified maintenance immunosuppression .","Selective serotonin reuptake inhibitors attenuate the antigen presentation from dendritic cells to effector T lymphocytes . ___MASK20___ , one of the selective serotonin reuptake inhibitors ( SSRIs ) , has been found to possess immune modulation effects , in addition to its antidepressant effects . However , it remains unclear whether SSRIs can suppress the antigen - presenting function of dendritic cells ( DCs ) . Therefore , ___MASK20___ was applied to a co - culture of Aggregatibacter actinomycetemcomitans ( Aa ) - reactive T cells ( × Aa - T ) isolated from Aa - immunized mice and DCs . This resulted in the suppressed proliferation of × Aa - T stimulated with Aa - antigen presentation by DCs . Specifically , ___MASK20___ increased the extracellular 5 - hydroxytryptamine ( 5 - HT ) in the × Aa - T / DC co - culture , whereas exogenously applied 5 - HT promoted T - cell proliferation in the × Aa - T / DC co - culture , indicating that ___MASK20___ - mediated suppression of × Aa - T / DC responses can not be attributed to extracellular 5 - HT . Instead , ___MASK20___ remarkably suppressed the expression of costimulatory molecule Q9Y6W8 - L on DCs . ___MASK20___ also promoted a greater proportion of P42081 ( Low ) immature DCs than P42081 ( High ) mature DCs , while maintaining the expression levels of P33681 , MHC - class - II and Q9NZQ7 . These results suggested that ___MASK20___ suppressed the ability of DCs to present bacterial antigens to T cells , and the resulting T - cell proliferation , in a P31645 / 5 - HT - independent manner and that diminished expression of Q9Y6W8 - L on DCs and increase of P42081 ( Low ) immature DCs caused by ___MASK20___ might be partially associated with ___MASK20___ - mediated suppression of DC / T - cell responses .","Human P01730 (+) CD25 (+) Cells in Combination with P28906 (+) Cells and DB00098 to Prevent Anti - hematopoietic Stem Cell T Cell Alloreactivity . Cotransplantation of human P28906 (+) hematopoietic stem cells ( P19526 ) and P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) could prevent anti - P19526 alloreactivity and reduce the risk of rejection in HLA mismatched transplants . To pursue this hypothesis we cocultured P28906 (+) cells and P01730 (+) CD25 (+) cells immunomagnetically isolated ( Milteny ) from human peripheral blood ( unmanipulated or granulocyte - colony stimulating factor [ DB00099 ] mobilized ) or cord blood . Enriched Tregs obtained from the same source ( autologous ) of P28906 (+) cells showed greater inhibitory effect on T cell alloreactivity than third - party ( allogeneic ) Tregs . The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic P28906 (+) cells and Tregs did not modify the clonogenic activity of P28906 (+) cells in vitro . Cotransplantation of Tregs with P28906 (+) cells at 1 : 1 or 2 : 1 ratios in nonobese diabetic / severe combined immunodeficiency ( NOD / SCID ) mice resulted in normal hematopoietic stem cell engraftment . Incubation with physiologic doses of rabbit antithymocyte globulin ( DB00098 , thymoglobulin ) did not affect the number of Tregs in 6 - day culture . Upon exposure to thymoglobulin Tregs maintained their suppressive activity , increased expression of P32248 , and released multiple cytokines , primarily interleukin ( IL ) 10 . Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with P28906 (+) cells after preparative regimens including thymoglobulin .","___MASK13___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .","Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .","Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .","Naive P01730 t cell proliferation is controlled by mammalian target of rapamycin regulation of Q8TEB7 expression . In this study , we demonstrate that the E3 ubiquitin ligase gene related to anergy in lymphocytes ( Q8TEB7 ) is expressed in quiescent naive mouse and human P01730 T cells and has a functional role in inhibiting naive T cell proliferation . Following TCR engagement , P10747 costimulation results in the expression of P60568 whose signaling through its receptor activates the Akt - mammalian target of rapamycin ( P42345 ) pathway . Activation of P42345 allows selective mRNA translation , including the epistatic regulator of Q8TEB7 , Q96FW1 ( Otub1 ) , whose expression results in the degradation of Q8TEB7 and allows T cell proliferation . The activation of P42345 appears to be the critical component of IL - 2R signaling regulating Q8TEB7 expression . P16410 - Ig treatment blocks P10747 costimulation and resultant P60568 expression , whereas rapamycin and anti - P60568 treatment block P42345 activation downstream of IL - 2R signaling . Thus , all three of these biotherapeutics inhibit P42345 - dependent translation of mRNA transcripts , resulting in blockade of Otub1 expression , maintenance of Q8TEB7 , and inhibition of P01730 T cell proliferation . These observations provide a mechanistic pathway sequentially linking P10747 costimulation , IL - 2R signaling , and P42345 activation as important requirements for naive P01730 T cell proliferation through the regulation of Otub1 and Q8TEB7 expression . Our findings also extend the role of Q8TEB7 beyond anergy induction and maintenance , suggesting that endogenous Q8TEB7 regulates general cell cycle and proliferation of primary naive P01730 T cells .","SV40 infection associated with rituximab treatment after kidney transplantation in nonhuman primates . BACKGROUND : A regimen consisting of polyclonal anti - T - cell antibody , sirolimus ( Q86TD4 ) , and donor bone marrow ( DBM ) infusion induces robust transplantation tolerance to skin allografts in mice . We investigated the effect of a similar regimen in a nonhuman primate ( NHP ) model . METHODS : Cynomolgus macaques ( Macaca fascicularis ) were transplanted with mismatched kidney allografts . Recipients were treated with 7 doses of antithymocyte globulin ( DB00098 , day 1 to 9 ) , sirolimus , and DBM infusion ( day 14 ) . Anti - P11836 antibody , rituximab , was given on days 0 and 5 . RESULTS : A regimen of DB00098 , 30 days of Q86TD4 , and DBM infusion induced significantly greater prolongation of graft survival with a mean survival time of 88 days compared with the control regimen ( no DBM ) with an mean survival time of 53 days ( P = 0 . 022 ) . Unlike the murine skin allograft model , all grafts were rejected within 111 days . A combination of DB00098 , continuous Q86TD4 , and rituximab caused graft and systemic SV40 infection and failed to achieve further extension of graft survival . C4d deposition was observed in 50 % of recipients as early as 18 days , suggesting antidonor antibody production . A transient , low - to - moderate degrees of multilineage chimerism was observed after DBM infusion . Treatment with DB00098 resulted in profound depletion of P01730 + and CD8 + T cells , whereas addition of rituximab achieved prolonged ( up to 3 months ) depletion of P11836 + B cells . CONCLUSION : The DB00098 , Q86TD4 , and DBM protocol is simple and produces long - term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long - term tolerance .","ATG induction in renal transplant recipients : Long - term hazard of severe infection is associated with long - term functional T cell impairment but not the ATG - induced P01730 cell decline . BACKGROUND AND METHODS : We showed previously that DB00098 induction induces a strong decrease of P01730 + T cells together with impaired in vitro P60568 secretion up to 1 year post - transplant . To further characterize long - term immunological effects of ATG induction 2 and 5 years post - transplant , we used sensitive intracellular cytokine analysis in the same prospective study of 84 renal transplant recipients ( ATG , n = 44 ) . RESULTS : A significantly increased frequency of severe infectious disease ( HR = 2 . 0 , p = 0 . 027 ) as well as suppressed T cell functions were found within 2 years after ATG induction but not beyond ( logistic regression ( logreg ) : P01730 cell P22301 responses , p = 0 . 064 ; T cell proliferation , p = 0 . 038 ) . Impaired T cell proliferation at 2 years was associated with occurrence of severe infection ( p = 0 . 017 ) . Importantly , a strong and persistent decrease of P01730 cell counts ( p < 0 . 0005 at 5 years ) was independently associated with ATG induction ( logreg p = 0 . 002 ) but not related to functional P01730 cell impairment ( helper activity / cytokine production ) or an increased risk of infection . CONCLUSIONS : Severe infection up to 2 years after ATG induction was associated with impaired T cell proliferative capacity but not with the profound decline in P01730 cell counts that occurred after ATG induction and persisted up to 5 years .","Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK30___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .","Preferential increase in memory and regulatory subsets during T - lymphocyte immune reconstitution after DB00098 induction therapy with maintenance sirolimus vs cyclosporine . BACKGROUND : DB00877 maintenance therapy with DB00098 induction is a promising regimen that may preserve renal function . Data are lacking , however , about the immunologic effects of combined DB00098 - sirolimus . METHODS : In a 12 - month , prospective , randomised , open - label , single - centre pilot study , de novo deceased - donor kidney transplant patients were randomised to receive cyclosporine or sirolimus , with DB00098 induction , mycophenolate mofetil and corticosteroids . Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution . RESULTS : Nineteen patients were recruited ( sirolimus 9 , cyclosporine 10 ) . Reconstitution of the P01730 (+) T - lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1 , but CD8 (+) reconstitution did not differ significantly between groups . The proportion of naïve P01730 (+) T - lymphocytes showed an initial decrease with sirolimus versus cyclosporine . Naïve CD8 (+) T - lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3 , but remained unchanged with sirolimus . Memory P01730 (+) T - lymphocytes occurred more frequently in sirolimus - versus cyclosporine - treated patients during year 1 . The proportion of memory CD8 (+) T - lymphocytes decreased at months 1 and 3 compared to baseline in the DB00091 arm , but did not change in the sirolimus cohort . By month 12 , the proportion of both naïve and memory P01730 (+) and CD8 (+) T - lymphocytes had become similar with sirolimus or cyclosporine . There were fewer naïve B - lymphocytes in the sirolimus cohort and more P15391 (-) IgD (+/-) P26842 (+) memory B - lymphocytes . CONCLUSIONS : In this small population , homeostatic reconstitution after DB00098 induction showed disproportionately high recovery of memory T - lymphocyte subsets during sirolimus therapy , which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation .","Effect of different induction strategies on effector , regulatory and memory lymphocyte sub - populations in clinical islet transplantation . This prospective study assessed lymphocyte subsets in the peripheral blood of 42 islet allograft recipients using flow cytometry from 2 weeks and up to 2 years post - transplantation . Subjects received daclizumab ( n = 16 ) , DB00098 ( n = 12 ) or alemtuzumab ( n = 14 ) . DB00087 was associated with an early ( within 1 month ) and transient ( up to 6 months ) increase in the frequency of CD3 (+) P01730 (+) Foxp3 (+) T cells , while daclizumab induced a near complete loss of these cells ( P < or = 0 . 001 ) . The frequency of memory P01730 (+) T cells was increased following depleting immunosuppression induction with either DB00098 or alemtuzumab ( P < or = 0 . 05 ) , but remained unchanged while using daclizumab . DB00087 induction resulted in a significant loss of memory B lymphocytes when compared with the other induction groups ( P < or = 0 . 001 ) . While the clinical significance of these findings remains to be fully determined , the observed altered balance between effector , regulatory and memory cells suggests that the immune status of patients will be affected according to the induction strategy chosen .","Effect of thymoglobulin induction on HIV - infected renal transplant recipients : differences between HIV - positive and HIV - negative patients . The best immunosuppressive regimen in HIV - infected renal transplant recipients has not been established . DB00098 has been associated with an increased risk of serious bacterial infections in HIV - negative patients and , for this reason , there is some concern over its use in the HIV - infected population . We describe three consecutive HIV - infected renal transplant recipients who received thymoglobulin as induction therapy , and we compared their progress with a cohort of 23 HIV - negative recipients . Median follow - up was 24 and 11 months , respectively . Nadir lymphocytopenia was observed at 1 week in both groups , and their absolute lymphocyte count recovery was similar . An early and deep ( < 30 cells / mm ( 3 ) ) P01730 (+) T cell lymphocytopenia was seen in two of the three HIV - infected patients . No opportunistic infections were diagnosed in HIV - positive patients . One HIV - positive patient had a bacterial infection and five HIV - negative patients had one or more bacterial infections . DB00098 was safe in our three HIV - infected renal transplant recipients . Until those data are confirmed in larger studies , close monitoring is recommended during the thymoglobulin - induced P01730 (+) T cell lymphocytopenia period .","Acute cellular rejection . The incidence of acute rejection of the kidney allograft in the world has been around 15 % during the period between 2001 and 2003 . It is clinically defined as an elevation in the level of serum creatinine by more than 0 . 3 mg / dL and is diagnosed by kidney biopsy . On pathologic examination , the interstitium of the allograft is diffusely edematous and infiltrated by P01730 and CD8 lymphocytes . Tubulitis occurs when the lymphocytes and monocytes extend into the walls and lumina of the tubules . Presence of leukocytes determines infection or antibody - mediated rejection . Typically C4d staining is negative . Other causes of acute allograft dysfunction included prerenal factors , interstitial nephritis , infection , acute tubular necrosis , toxicity by drugs , and obstruction in the urinary tract . The primary diagnostic assessments include history , especially adherence to immunosuppressive therapy , physical examination , blood and urine laboratory tests , measurement of the serum levels of the drugs , and ultrasonography . Diagnosis of acute cellular rejection depends on biopsy , P11836 staining for refractory cases , negative C4d staining , presence of markers of activating lymphocyte , and proteomic study . Treatment of acute cellular rejection in kidney transplant recipients include pulse steroid for the first rejection episode . It can be repeated for recurrent or resistant rejection . DB00098 and OKT3 are used as the second line of treatment if graft function is deteriorating . Changing the protocol from cyclosporine to tacrolimus or adding mycophenolate mofetil or sirolimus might be effective . Prognosis depends on number of rejection episodes , the use of potent drugs , time of rejection from transplantation , and response to treatment .","Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK80___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .","Oocyte - expressed interleukin 7 suppresses granulosa cell apoptosis and promotes oocyte maturation in rats . Development of ovarian follicles is regulated by pituitary - derived gonadotropins together with local ovarian paracrine factors . Based on DNA microarray data , we performed RT - PCR and immunostaining to demonstrate the expression of interleukin 7 transcripts in oocytes of preantral , antral , and preovulatory follicles in rats . We also found the expression of interleukin 7 receptor and the coreceptor interleukin 2 receptor gamma in granulosa cells , cumulus cells , and preovulatory oocytes . In cultured rat granulosa cells obtained from early antral and preovulatory follicles , treatment with interleukin 7 stimulated the phosphorylation of AKT , glycogen synthase kinase ( P49841 ) , and P42229 proteins in a time - and dose - dependent manner . Furthermore , measurement of mitochondrial reductase activity indicated that treatment with interleukin 7 , similar to gonadotropins , increased the number of viable granulosa cells during a 24 - h culture period . Furthermore , monitoring of the activities of apoptotic enzymes ( caspase 3 / 7 ) indicated that treatment with interleukin 7 suppressed apoptosis of cultured granulosa cells from both antral and preovulatory follicles following serum withdrawal . The apoptosis - suppressing actions of interleukin 7 were blocked by an inhibitor of the phosphoinositol - 3 - kinase ( PIK3 ) / AKT pathway . Furthermore , treatment of cultured preovulatory follicles with interleukin 7 , like treatment with human chorionic gonadotropin , induced germinal vesicle breakdown of oocytes . The stimulatory effect of interleukin 7 was also blocked by inhibitors of the PIK3 / AKT pathway . The present findings suggest that oocyte - derived interleukin 7 could act on neighboring granulosa cells as a survival factor and promote the nuclear maturation of preovulatory oocytes through activation of the PIK3 / AKT pathway ."],"string":"[\n \"Upregulation of molecules associated with T - regulatory function by thymoglobulin pretreatment of human P01730 + cells . BACKGROUND : This study evaluated the immunologic effects of thymoglobulin in modulating human P01730 + cells . METHODS : Human P01730 + cells were purified from peripheral blood mononuclear cells by negative selection method . P01730 + cells were pretreated with thymoglobulin and incubated for 72 hr . Cells and culture supernatants were collected and studied by real - time quantitative polymerase chain reaction , fluorescence activated cell scanning , multiplex cytokine assay , and mixed lymphocyte reaction ( P08235 ) . RESULTS : DB00098 pretreated P01730 + cells demonstrated up - regulation of gene transcripts for P16410 , OX40 , forkhead box P09131 ( Foxp3 ) , CD25 , P01579 , P22301 , and P60568 as determined by real - time quantitative polymerase chain reaction . Fluorescence - activated cell scanning analysis demonstrated that P01730 + cells , pretreated with thymoglobulin , up - regulated CD25 expression on their surface , and the surface expression of P16410 and OX40 and the expression of intracellular Foxp3 were observed in these P01730 + CD25 + cells . Additionally , P08235 demonstrated that thymoglobulin - pretreated cells partially inhibited proliferation of untreated autologous P01730 + cells in response to allogeneic cells . The high levels of P01579 , P22301 , P60568 , and P05112 were detected by multiplex cytokine assay in supernatants collected from cultures of thymoglobulin - pretreated P01730 + cells . The lymphocyte proliferation of allogeneic P08235 was also partially blocked in the presence of supernatants from cultures of thymoglobulin - pretreated P01730 + cells . CONCLUSIONS : This study demonstrates that the unique effects of thymoglobulin in modulating P01730 + cells may be an important mechanism for its action in inducing immunosuppression and transplant tolerance .\",\n \"Induction of bona fide regulatory T cells after liver transplantation - the potential influence of polyclonal antithymocyte globulin . T - cell - depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting . Besides prevention of alloreactivity , treatment with rabbit antithymocyte globulin ( DB00098 ) has been related to the induction of immunoregulatory T cells ( Treg ) in vitro and in vivo . To investigate Treg induced by DB00098 , we prospectively studied the effect of DB00098 induction therapy in liver - transplanted recipients in vivo ( n = 28 ) . Treg induction was further evaluated by means of Treg - specific demethylation region ( TSDR ) analysis within the Q9BZS1 locus . Whereas no induction of P01730 (+) CD25 ( high ) CD127 (-) Treg could be observed by phenotypic analysis , we could demonstrate an induction of TSDR (+) T cells within P01730 (+) T cells exclusively for DB00098 - treated patients in the long - term ( day 540 ) compared with controls ( P = NS ) . Moreover , although in vitro experiments confirm that DB00098 primarily led to a conversion of P01730 (+) CD25 (-) into P01730 (+) CD25 (+) T cells displaying immunosuppressive capacities , these cells can not be classified as bona fide Treg based on their Q9BZS1 demethylation pattern . Consequently , the generation of Treg after DB00098 co - incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined .\",\n \"Sequential phases in the development of Aire - expressing medullary thymic epithelial cells involve distinct cellular input . Intrathymic deletion of immature thymocytes that express self - reactive TCR specificities is essential in the generation of self tolerance . Medullary thymic epithelial cells ( mTEC ) expressing the transcriptional regulator Aire play a key role in this process by regulating expression of tissue - restricted antigens to ensure tolerance to peripheral tissues . Here , we have analysed the cellular and molecular requirements for the initial appearance of Aire + mTEC in the embryonic thymus , in addition to their persistence in the adult thymus . Analysis of thymic ontogeny shows that the emergence of embryonic Aire + mTEC occurs prior to the appearance of mature thymocytes , and depends upon lymphoid tissue inducer cells expressing retinoic acid receptor - related orphan receptor gamma . In the adult thymus , we show that Aire + mTEC develop in the absence of thymocyte positive and negative selection and P25942 signalling , but are present at reduced frequency . Collectively these data support a model where the initial differentiation of Aire + mTEC involves receptor activator of NF - kappaB ( Q9Y6Q6 ) - O14788 interactions with lymphoid tissue inducer cells , with subsequent mTEC turnover and / or survival involving P25942 - mediated signalling following interactions with mature P01730 + thymocytes that express P29965 .\",\n \"Rabbit ATG but not horse ATG promotes expansion of functional P01730 + CD25highFOXP3 + regulatory T cells in vitro . Regulatory T cells ( Treg ) play important roles in suppressing immune responses and maintaining tolerance . Rabbit antithymocyte globulin ( DB00098 ) and horse ATG ( hATG ) are widely used in the treatment of immune - mediated syndromes , but their effects on Treg are unknown . We show here that in vitro culture of normal human peripheral blood mononuclear cells ( PBMCs ) with a low - dose DB00098 resulted in marked expansion of functional Treg by converting P01730 + CD25 - T cells to P01730 + CD25 + T cells . hATG did not expand but rather decreased Treg . Immuno - blot showed increased expression of Q9BZS1 and Q13469 in P01730 + CD25 - and P01730 + CD25 + T cells exposed to DB00098 . PBMCs treated with DB00098 displayed increased interleukin - 10 in culture supernatants than those treated with hATG . Furthermore , DB00098 and hATG showed differences in their potential to stimulate P01730 + T cells as examined using different activation markers . Microarray revealed that DB00098 induced markedly different gene - expression patterns in PBMCs , compared with hATG - treated or untreated PBMCs . Our findings indicate that DB00098 expanded Treg , probably through transcriptional regulation by enhanced Q13469 expression , in turn conferring P01730 + CD25 - T cell Q9BZS1 expression and regulatory activity . The therapeutic effects of DB00098 may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function .\",\n \"ATG - induced expression of Q9BZS1 in human P01730 (+) T cells in vitro is associated with T - cell activation and not the induction of Q9BZS1 (+) T regulatory cells . Several recent reports have suggested that in vitro exposure of P01730 (+) T cells to rabbit antithymocyte globulin ( DB00098 ) , which is commonly used to prevent and treat graft - versus - host disease and allograft rejection , is an effective method to induce P01730 (+) CD25 (+) Q9BZS1 (+) T regulatory cells ( Tregs ) . We and others , however , have shown that Q9BZS1 is also expressed in activated T cells . We therefore investigated whether the induction of Q9BZS1 expression by DB00098 resulted in a stable population of suppressive Tregs . We found that exposure of peripheral blood mononuclear cells ( PBMCs ) or conventional T cells to DB00098 resulted in induction of transient rather than stable expression of CD25 and Q9BZS1 . Furthermore , DB00098 - treated T effector cells acquired neither an immunosuppressive profile of cytokine production nor suppressive capacity , even at the time of maximal Q9BZS1 expression . These findings indicate that the notion that DB00098 can be used to induce Tregs in vitro for cellular therapy in vivo should be re - evaluated .\",\n \"DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .\",\n \"Comparative polyclonal antithymocyte globulin and antilymphocyte / antilymphoblast globulin anti - CD antigen analysis by flow cytometry . Polyclonal antithymocyte globulin ( ATG ) / antilymphocyte and antilymphoblast globulins ( ALG ) antibodies have been used successfully in transplantation , aplastic anemia and graft - versus - host disease . Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG / ALG preparations for immunosuppression . Recent reports have indicated clinical dose adjustment based on levels of patient ' s cells expressing various CD antigens . In vitro analysis of individual polyclonal ATG / ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data . Therefore , a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed . Activities found in four lots each of horse ATG ( ATGAM , Upjohn ) , rabbit and horse ATG ( thymoglobulin and lymphoglobulin , Merieux ) , horse ALG ( Minnesota ) , and DB00098 ( Fresenius ) have been compared for P06729 , CD3 , P01730 , P06127 , P09564 , CD8 , CD11a , P05107 , P10747 , P16070 , P08575 , and TCR - alpha / beta antigens . Quantitation is achieved by measuring the concentration of ATG / ALG required to give 50 % inhibition of antigen specific fluorescent - labeled monoclonal antibody relative to buffer controls . The three horse products tested have similar activity to most antigens tested . However , Fresenius DB00098 has the lowest activity for almost all antigens tested whereas the Merieux DB00098 has activities closer to the horse products . This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency .\",\n \"Regulatory T cells in kidney transplant recipients : the effect of induction immunosuppression therapy . BACKGROUND : Regulatory T cells have been suggested to down - regulate the alloimmune response . The aim of this prospective open study was to evaluate the effects of different inductive agents on peripheral blood regulatory T cells in kidney transplant patients and to analyse their association with short - term graft outcome . METHODS : Regulatory and effector T cell numbers in peripheral blood were determined by flow cytometry in 71 prospectively followed kidney transplant recipients at postoperative day 0 , 7 , 14 , 21 , 28 , 60 and 90 . Patients were treated with a calcineurin inhibitor - based triple immunosuppression with polyclonal rabbit anti - thymocyte globulin ( DB00098 , n = 28 ) , basiliximab , the anti - CD25 monoclonal antibody ( n = 18 ) or without induction ( controls , n = 25 ) . Flow cytometry data were correlated to rejection incidence . RESULTS : Compared to controls , P01730 (+) CD25 (+) FoxP3 (+) regulatory T - cell expansion among P01730 (+) T cells was noticed in the DB00098 group at all post - transplant time - points by Day 14 ( P < 0 . 001 ) . A significant decrease in Treg frequency ( P < 0 . 001 ) and concurrently a transient increase of P01730 (+) CD25 ( low /-) FoxP3 (+) population were observed in basiliximab - treated patients 7 - 60 days post - transplantation . Biopsy - proven acute rejection occurred in 16 . 7 % of controls , 10 . 7 % of the DB00098 group and in 11 . 1 % of the basiliximab group . Higher P01730 (+) FoxP3 (+)/ CD8 (+) CD45RA (+) CD62L (-) ratios were observed repeatedly in those patients after basiliximab induction who were rejection free ( P < 0 . 01 ) . CONCLUSIONS : In this study , the DB00098 induction therapy was associated with an expansion of regulatory cells . Sustained high P01730 (+) FoxP3 (+)/ Teff ratios were associated with the absence of rejection after basiliximab induction .\",\n \"Significance of immune cell function monitoring in renal transplantation after DB00098 induction therapy . Monitoring of immune status in transplant recipients is essential for predicting the risk of rejection or infection . In this study , we assessed the significance of immune cell function in 76 renal allograft recipients after DB00098 induction and initiation of maintenance immunosuppression . Using the Immuknow ( Cylex Inc ) assay , the amount of adenosine triphosphate ( DB00171 ) produced by P01730 + cells in response to phytohemagglutinin ( PHA ) was measured in patients whole blood . In parallel , the frequency and phenotype of P01730 + T cells were determined by flow cytometry . The Immuknow assay yielded paradoxically high DB00171 values during the first 3 months post - transplantation , despite very low P01730 + T cell counts . High DB00171 values were caused by peripheral blood myeloid cells , did not predict rejection , and occurred primarily in transplant recipients who received darbepoietin ( p = 0 . 017 ) . P01730 + T cells displayed predominantly an activated / memory phenotype and comprised a subpopulation of CD25 + Q9BZS1 + cells . Over the first 5 months post - transplantation , mean DB00171 activity gradually decreased , whereas P01730 + T cell counts slowly increased . Low DB00171 values were predictive of infection ( p = 0 . 002 ) . Thus Immuknow results need to be interpreted with caution in patients receiving DB00098 induction therapy . Although low DB00171 levels identify patients at increased risk for infection , high DB00171 values fail to correlate with rejection and do not justify increased immunosuppression .\",\n \"Antithymocyte globulins suppress dendritic cell function by multiple mechanisms . BACKGROUND : The polyclonal rabbit antithymocyte and anti - T - cell immunoglobulins ( ATGs ) DB00098 ( TG ) and DB05320 ( ATG - F ) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation . Although immunosuppressive mechanisms of ATGs on T cells are well studied , less is known about their impact on dendritic cells ( DCs ) . METHODS : Effects of TG and ATG - F on immune functions and signaling pathways of human monocyte - derived DCs were determined by flow cytometry , enzyme - linked immunosorbent assay , Western blot , apoptosis assays , endocytosis assays , and T cell stimulation assays . RESULTS : TG and ATG - F bind rapidly and with high affinity to CD11c , P33681 , P42081 , P25942 , P16671 , P28907 , CD206 , and human leukocyte antigen - DR on DCs . TG and , to a lesser extent , ATG - F induce apoptosis in immature and mature DCs . Macropinocytotic and receptor - mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG - F due to their binding of the C - type lectins CD206 and Q9NNX6 . TG and ATG - F induce activation of the mitogen - activated protein kinases P27361 / 2 and p38 that contributes to the induction of apoptosis . TG and ATG - F also induce cytoplasmic - nuclear translocation of the NF - kappaB / Rel transcription factors RelB , RelA , p50 , and p52 . Production of interleukin - 12p70 in mature DCs is suppressed by TG and ATG - F . TG and ATG - F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells . CONCLUSIONS : ATGs interfere with basic DC functions , suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation .\",\n \"Ex vivo expansion of human Tregs by DB00098 is dependent on intact P40763 - signaling in CD4 ⁺ T cells and requires the presence of monocytes . The addition of low , nondepleting doses of rabbit antithymocyte globulin ( ATG ) to human peripheral blood mononuclear cells has been shown to expand functional P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) in vitro . This report is the first to elucidate the exact cellular mechanisms of ATG - mediated Treg expansion . P01730 (+) T cells require monocytes , but not other antigen presenting cell subsets , to be present in coculture to expand Tregs . However , T cells do not require direct cell - cell contact with monocytes , suggesting the importance of soluble factors . Moreover , ATG initially \\\" reprograms \\\" P01730 (+) T cells , but not monocytes , and induces P40763 and P42229 signaling in P01730 (+) cells . These reprogrammed P01730 (+) T cells subsequently secrete GM - P04141 and P22301 only in case of intact P40763 signaling , which in turn promote the generation of tolerogenic P08571 (+) CD11c (+) dendritic cells characterized by enhanced P22301 and decreased IL - 12 production . Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM - P04141 and Bcl - 2 , but not TGF - β , in peripheral blood mononuclear cells . These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram P01730 (+) T cells in a P40763 - dependent but TGF - β - independent manner , leading to the generation of monocyte - derived dendritic cells with a tolerogenic cytokine profile .\",\n \"Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice . Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer . Following treatment of the primary cancer , emotional and psychosocial factors within this population precipitate time to recurrence and death , however the underlying mechanism ( s ) remain unclear . Using a mouse model of bone metastasis , we provide experimental evidence that activation of the sympathetic nervous system , which is one of many pathophysiological consequences of severe stress and depression , promotes MDA - 231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma . We demonstrate that induction of O14788 expression in bone marrow osteoblasts , following β2AR stimulation , increases the migration of metastatic MDA - 231 cells in vitro , independently of P48061 - P61073 signaling . We also show that the stimulatory effect of endogenous ( chronic stress ) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β - blocker propranolol , and by knockdown of Q9Y6Q6 expression in MDA - 231 cells . These findings indicate that O14788 promotes breast cancer cell metastasis to bone via its pro - migratory effect on breast cancer cells , independently of its effect on bone turnover . The emerging clinical implication , supported by recent epidemiological studies , is that βAR - blockers and drugs interfering with O14788 signaling , such as ___MASK86___ , could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the \\\" vicious cycle \\\" of bone destruction induced by these cells .\",\n \"Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation . Experimental studies have shown that rabbit antithymocyte polyclonal globulin ( ATG ) can expand human P01730 + CD25 ++ Foxp3 + cells ( Tregs ) . We investigated the major biological effects of a self - manufactured rabbit polyclonal anti - rat thymoglobulin ( DB00098 ) in vitro , as well as its effects on different peripheral T - cell subsets . Moreover , we evaluated the allogeneic suppressive capacity of DB00098 - induced Tregs in an experimental rat renal transplant model . Our results show that DB00098 has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T - cell depletion . Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets , directly proportional to the DB00098 dose used , but not of the effector memory T cells , which required significantly higher DB00098 doses . After DB00098 administration , we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats , leading to an increase in the Treg / T effector ratio . Importantly , DB00098 - induced Tregs displayed a strong donor - specific suppressive capacity when assessed in an antigen - specific allogeneic co - culture . All of these results were associated with better renal graft function in rats that received DB00098 . Our study shows that DB00098 has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post - transplant homeostatic proliferation .\",\n \"Regulatory T cells increase in breast cancer and in stage IV breast cancer . Expression levels of P15692 and Her - 2 , levels of T - regulatory ( Treg ) cells , levels of CD3 + cells , and ratios of Th ( P01730 + T cells ) / Tr ( Treg ) cells were compared between stage I , II , III , and IV breast cancer patients ( n = 120 ) prior to chemotherapy and healthy women ( n = 30 ) . Cells from peripheral blood were counted by flow cytometry , Her - 2 and P15692 expression was detected by pathological examination , and Her - 2 was detected by Q5TCZ1 . Breast cancer patients had more Treg cells and a lower ratio of Th / Tr cells than the healthy women . Stage IV breast cancer patients had more Treg cells and a lower ratio of Th / Tr cells than stage I , II , or III breast cancer patients . Patients positive for P15692 had a lower ratio of Th / Tr cells compared with patients negative for P15692 , and those positive for both P15692 and Her - 2 also had a lower ratio of Th / Tr cells compared with patients not positive for both P15692 and Her - 2 . The decreased Th / Tr cells ratio indicates impaired immune function , suggesting that the stage IV breast cancer and the Her - 2 / P15692 - positive breast cancer patients have lower immune function .\",\n \"In vivo characterization of rabbit anti - mouse thymocyte globulin : a surrogate for rabbit anti - human thymocyte globulin . BACKGROUND : Polyclonal rabbit anti - human thymocyte globulin ( DB00098 ) is used clinically for immunosuppression in solid organ transplantation ; however , it is difficult to fully characterize the effects of this agent in humans . METHODS : A surrogate rabbit anti - murine thymocyte globulin ( mATG ) was generated analogously to the commercial product DB00098 and in vivo activities were evaluated , including pharmacokinetics , T - cell depletion , dose response and kinetics , depletion / sparing of T - cell subsets or other leukocyte populations , and depletion in different lymphoid organs . RESULTS : Within 1 day , T cells are depleted by mATG in the blood , spleen , lymph node , and bone marrow down to doses of 1 mg / kg . Although mATG binds and depletes thymocytes in vitro , there is no thymocyte depletion in vivo at any dose level , suggesting decreased antibody accessibility to the thymus . After two doses of mATG given 3 days apart , T - cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for P01730 and CD8 T cells , respectively . There is also preferential depletion of naïve T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration . Depletion of natural killer - T cells , natural killer cells , plasma cells , and plasmablasts occurs , but is modest and more transient compared with T cells . B cells , macrophages , dendritic cells , hematopoetic stem cells , and bone marrow stromal cells seem resistant to mATG depletion . CONCLUSIONS : These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of DB00098 .\",\n \"FoxP3 + , and not CD25 + , T cells increase post - transplant in islet allotransplant recipients following anti - CD25 + DB00098 immunotherapy . Anti - CD25 antibodies are used as an induction therapy in islet allotransplantation for type 1 diabetes . Although previous reports suggested that anti - CD25 treatment may lead to depletion of P01730 + CD25 + regulatory T cells ( Tregs ) and questioned its use in tolerance - promoting protocols for transplantation , the effect of anti - CD25 antibodies on the frequency and function of Tregs remains unclear . We examined the effect of anti - CD25 antibody , daclizumab , in vivo on Tregs in islet allograft recipients enrolled in a single - center study and monitored post - transplant . Our data shows that the reduction in CD25 + Treg cells observed post - transplant is due to masking of CD25 receptor by daclizumab and not due to depletion . In addition , using Treg marker , FoxP3 , we show that anti - CD25 + ATG treatment leads to an increase in FoxP3 + Tregs post - transplant . These data suggest that anti - CD25 - based therapy has beneficial effects on Tregs and combined with ATG may be a promising therapy for autoimmunity and transplantation .\",\n \"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK73___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .\",\n \"Immune reconstitution following rabbit antithymocyte globulin . Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome . The effects of depleting agents on T - cell subsets and subsequent T - cell reconstitution are incompletely defined . We used flow cytometry to examine the effects of rabbit antithymocyte globulin ( DB00098 ) on the peripheral T - cell repertoire of pediatric and adult renal transplant recipients . We found that while DB00098 effectively depleted CD45RA + P26842 + naïve and CD45RO + P26842 + central memory P01730 + T cells , it had little effect on CD45RO + P26842 - P01730 + effector memory or CD45RA + CD31 - , CD45RO + P26842 + and CD45RO + P26842 - CD8 + T cell subsets . When we performed a kinetic analysis of CD31 + recent thymic emigrants and CD45RA +/ RO + T cells , we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution . We additionally examined the impact of DB00098 on peripheral P01730 + Foxp3 + T cells . We found that in adults , administration of DB00098 - induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype , while P01730 + Foxp3 + T cells of thymic origin predominated in children , providing the first evidence that DB00098 induces Treg in vivo . Collectively our data indicate that DB00098 alters the balance of regulatory to memory effector T cells posttransplant , providing an explanation for how it positively impacts transplant outcome .\",\n \"Risk factors for impaired P01730 + T - cell reconstitution following rabbit antithymocyte globulin treatment in kidney transplantation . To describe long - term P01730 + T - cell reconstitution after rabbit antithymocyte globulin ( DB00098 ) treatment and identify predictive factors following kidney transplantation . A single - center retrospective study analyzed lymphocyte subsets in DB00098 - treated kidney transplant recipients ( 1986 - 2009 ) . 589 patients were analyzed ( maximum follow - up 21 years ) . A comparator group ( n = 298 ) received an anti - P60568 receptor monoclonal antibody . P01730 + T - cell lymphopenia ( < 200 / mm3 ) was present in 48 . 5 % , 9 . 2 % , 6 . 7 % , 2 . 0 % , and 0 % of patients at one , three , five , 10 , and 20 years post - transplant , respectively . P01730 + T - cell count increased during the first 10 years but remained below the pretransplant count even after 20 years . At 1 , 3 , and 6 months post - transplant , mean P01730 + T - cell count was significantly lower in patients with P01730 + T - cell lymphopenia at 12 months versus patients without lymphopenia . On multivariate analyses , significant independent predictors for long - term impaired P01730 T - cell reconstitution were recipient age , pretransplant P01730 + T - cell count , 12 - month P01730 + T - cell count , and tacrolimus or DB00688 therapy . Recipient age > 40 years was identified as a cutoff point . P01730 + T - cell reconstitution following DB00098 treatment remains impaired even after 21 years . Most risk factors for long - term impaired P01730 + T - cell reconstitution may be evaluated pretransplant or are modifiable post - transplant .\",\n \"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK68___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .\",\n \"Kinetics of homeostatic proliferation and thymopoiesis after DB00098 induction therapy in kidney transplant patients . BACKGROUND : Lymphocyte - depleting therapy is associated with long - lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies . The mechanisms of T - cell repopulation and their posttransplantation kinetics are not fully understood . METHODS : We studied thymopoiesis by CD31 (+) naïve T cells ( recent thymic emigrants ) and homeostatic proliferation by Ki - 67 (+) T cells in rabbit antithymocyte globulin ( DB00098 ) - treated patients the first 6 months after transplantation . Patients receiving basiliximab or no induction therapy served as controls . RESULTS : At 6 months after transplantation , T - cell numbers were lower than before transplantation in DB00098 - treated patients , whereas T - cell numbers remained stable in both control groups . In this time period , thymopoiesis was similar between the three treatment groups ; CD8 (+) T cells showed the highest percentage of recent thymic emigrants . At month 1 , percentages of Ki - 67 (+) naïve and memory P01730 (+) and CD8 (+) T cells were the highest in DB00098 - treated patients , but these percentages declined in the months thereafter . When CD31 was used to distinguish between cytokine - and antigen - driven proliferation in naïve T cells , we found evidence for cytokine - dependent proliferation . Cytokine - dependent proliferation was also shown by in vivo increased percentages of phosphorylated P42229 and high expression levels of the interleukin - 7 receptor - α and interleukin - 15 receptor - α by T cells . CONCLUSION : These findings demonstrate that , in the first month after DB00098 therapy , cytokine - induced homeostatic proliferation is involved in T - cell repopulation of both naïve and memory T cells . At later time points , the contribution of homeostatic proliferation diminished , which explains the observed incomplete T - cell recovery .\",\n \"Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion . BACKGROUND : Polyclonal antithymocyte globulins ( ATGs ) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells . However , nondepleting mechanisms may also be important mediators of graft survival . In the present study , 14 lots of thymoglobulin ( DB00098 ) were analyzed and compared for nondepletive immunomodulatory activities in vitro . METHODS : Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces P01730 + CD25 ( high ) Foxp3 + regulatory T cells , which were evaluated for consistent ability to suppress T - cell activation in mixed lymphocyte reactions . The consistency of P06729 , CD3 , CD11a , and P08575 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells . A transwell chemotaxis assay was established and used to evaluate ATG - mediated inhibition of stromal cell - derived factor ( SDF ) - 1alpha - driven Jurkat T - cell migration . RESULTS : Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities , which were consistent from batch to batch . All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T - cell surface antigens . In addition , these studies provide the first demonstration that thymoglobulin effectively inhibits P61073 / SDF - 1alpha - driven T - cell chemotaxis . CONCLUSIONS : This novel , systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival .\",\n \"A double recombinant adenovirus expressing the costimulatory molecule P33681 - 1 ( murine ) and human P60568 induces complete tumor regression in a murine breast adenocarcinoma model . Tumors that express tumor - specific antigens can maintain growth in an immunocompetent organism . Current hypotheses tend toward T cell anergy as a key component for the inhibition of immunoreactivity against such tumors . Anergy is thought to occur from hyperactive stimulation of the TCR in the absence of costimulation ( costimulation leads to proliferation via P60568 production ) . Subcutaneous injection of transgenic polyoma middle T transformed breast adenocarcinoma tumor cells ( PyMT ) in the hind flank of FVB / n mice results in the formation of tumor nodules at this site . We determined the MHC class I and class II , P33681 - 1 , and P33681 - 2 expression in the tumor cells by flow cytometry and showed positive staining for only MHC class I . We show that a single E1 - deleted adenovirus constructed to express both the costimulatory molecule P33681 - 1 ( murine ) and human P60568 genes ( Ad5E1 mB7 - 1 / human P60568 ) elicits a very potent antitumor response when administered intratumorally . Ad5E1 mB7 - 1 / human P60568 induced rapid and complete regression ( 100 % ) of all tumors compared with Ad5 E1 mB7 - 1 ( 38 % ) , Ad CAIL - 2 ( 42 % ) , and Ad5E1 dl70 - 3 ( control vector ) ( 0 % ) . All mice that exhibited complete tumor regression were fully protected in tumor cell challenge experiments . The systemic immunity generated by intratumoral administration of the Ad vectors was associated with a strong anti - PyMT CTL response . These observations indicate that augmenting the immunogenicity of the tumor with coincident expression of P33681 - 1 in combination with P60568 may prove beneficial in direct tumor immunotherapy .\",\n \"___MASK80___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK80___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .\",\n \"Prolonged lymphocyte depletion by single - dose rabbit anti - thymocyte globulin and alemtuzumab in kidney transplantation . Although antibody induction has gained in popularity , two agents are rarely combined . We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody / combination : alemtuzumab ( C1H ) , DB00098 ( DB00098 ) , daclizumab ( Dac ) , DB00098 + C1H , and DB00098 + Dac . P01730 + T - cells were suppressed by C1H and DB00098 + C1H , as well as by DB00098 and DB00098 + Dac but to a lesser extent . The effect lasted for 3 years at around 40 % of baseline values . CD8 + T - cells showed a similar trend but had a more rapid recovery to baseline . P15391 + B - cells were effectively suppressed for 2 months by C1H and DB00098 + C1H , and abruptly returned to baseline afterwards ; suppression by DB00098 ( 7 doses ) was modest but lasted longer . A higher proportion of CD56 + CD16 + Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type . Low CD25 + T - cells by 5 - dose Dac returned to baseline around 6 months , whereas DB00098 + C1H and DB00098 + Dac showed persistent effect . P01730 + CD25hi T - cells were suppressed by both DB00098 + C1H and DB00098 + Dac , but the initial proportion of P01730 + CD25hi T - cells among P01730 + T - cells and P01730 + CD25hi / P01730 + CD25lo ratio were significantly higher in DB00098 + C1H . Overall , with extensive and persistent lymphocyte suppression by a simple administration of agents , single - dose DB00098 + C1H induction can be an alternative in renal transplantation .\",\n \"Rabbit anti T - lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells , while hematopoetic stem cells are apoptosis resistant . Polyclonal anti - T - lymphocyte globulins ( ATG ) are used in allogeneic stem cell transplantation ( P09683 ) for the prophylaxis of graft versus host disease ( GVHD ) by in vivo T cell depletion . In this study we investigated the complement independent induction of apoptosis by DB00098 in peripheral blood mononuclear cell ( PBMNC ) compartments and hematopoetic stem cells ( P19526 ) . We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells . We found ATG to induce apoptosis in T - lymphocytes ( P01730 (+) , CD8 + ) , B - lymphocytes ( P11836 + ) , natural killer ( NK ) - cells ( CD56 (+) ) , and monocytes ( P08571 (+) ) . P19526 , in contrast , were apoptosis resistant and could be growth stimulated by low - dose ATG in the presence of bystander cells . The human leukemia cell lines Jurkat , Daudi , DG - 75 ( lymphoblastic ) , and K562 , HL - 60 , KG1 , and U937 ( myeloblastic ) underwent ATG - induced apoptosis , whereas the NK - cell line YT was resistant . Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia , 9 of 10 patients with chronic lymphocytic leukemia , and 4 of 8 patients with acute myeloblastic leukemia underwent ATG - induced apoptosis . We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis . ATG might support engraftment . Finally , antileukemic activity of ATG could positively influence the transplantation outcome .\",\n \"Expression of cyclooxygenase - 2 ( P35354 ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase - 2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB - IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase - 2 . CD3 , P01730 , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase - 2 levels ( cyclooxygenase - 2 IDV ) of tumour vs stroma compartment ( r =- 0 . 44 , P < 0 . 0001 ) . The percentage of cases showing high tumour / stromal cyclooxygenase - 2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93 . 3 % ) with respect to patients with partial ( 60 . 5 % ) , and complete ( 43 . 7 % ) response ( P = 0 . 009 ) . Cases with a high tumour / stroma cyclooxygenase - 2 IDV ratio had a shorter overall survival rate than cases with a low tumour / stroma cyclooxygenase - 2 IDV ( P < 0 . 0001 ) . In the multivariate analysis advanced stage and the status of tumour / stroma cyclooxygenase - 2 IDV ratio retained an independent negative prognostic role . The proportion of CD3 (+) , P01730 (+) , and CD25 (+) cells was significantly lower in tumours with high tumour / stroma cyclooxygenase - 2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour / stroma cyclooxygenase - 2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase - 2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis .\",\n \"___MASK86___ for joints and bones . ___MASK86___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK86___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK86___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .\",\n \"___MASK37___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK37___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK37___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK37___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .\",\n \"Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation : influence of Campath dose on lymphoid recovery , mixed chimerism and survival . Sixty - nine consecutive patients ( median age 54 years ) were prospectively enrolled in a single - institution protocol for allogeneic transplantation with adjusted non - myeloablative fludarabine - melfalan - based conditioning including cyclosporin A and DB00688 , and one of three modes of serotherapy . Thirty - one donors ( 45 % ) were unrelated . The first cohort of 29 had ATG ( DB00098 2 mg / kg x 3 days ) , the subsequent 26 had Campath 30 mg x 3 days subcutaneously , and the final cohort of 14 had 30 mg Campath once . The groups were similar as regards age , diagnosis and risk factors . Campath - patients had no acute toxicity , fewer days with fever and antibiotics , and required fewer transfusions than ATG - treated patients . 3 - d - Campath patients showed lower lymphocyte counts from day + 4 , and P01730 + , CD8 + , P15391 + and NK cells recovered slower than in ATG - treated patients . More Campath patients developed mixed chimerism that required DLI . 3 - d - Campath induced more serious and opportunistic infections than ATG , which resulted in a greater non - relapse mortality and an impaired overall survival despite a low tumor - related mortality . The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3 - d - Campath on immune recovery , severe infections and survival . Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity , but dose limitation to 30 mg once is recommended .\",\n \"Low - dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression . Rabbit antithymocyte globulin therapy ( DB00098 ) is a potent lymphocyte - depleting agent commonly used following renal transplantation to reduce the risk of acute rejection . Standard doses ( 7 - 10 mg / kg ) of DB00098 result in profound lymphopenia and predispose patients to infection and malignancy . The effects of lower doses of DB00098 ( LoD - DB00098 , 3 - 5 mg / kg ) on peripheral blood lymphocytes ( PBL ) are as yet unknown . In this prospective clinical trial , PBL subsets were characterized by flow cytometry over 12 months following LoD - DB00098 therapy . All patients were initially treated with standard doses of tacrolimus , mycophenolic acid , and prednisone . At 3 months , patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence . LoD - DB00098 therapy resulted in prolonged suppression of P15391 + B cells , total CD3 + T cells , as well as naïve and memory P01730 + T cell and P01730 / CD25 / Foxp3 + T - regulatory subsets irrespective of chronic immunosuppressive therapy . Selective depletion was only noted in the CD4CD45RA + naïve T - cell subset resulting in an altered memory / naïve P01730 + ratio . LoD - DB00098 failed to deplete CD8 + T cells , which increased their relative contribution to the total CD3 + pool . All other lymphocyte subsets maintained near normal proportions . Thus , LoD - DB00098 therapy may lessen the adverse effects of full dose DB00098 while maintaining overall efficacy .\",\n \"DB00098 - associated Cd4 + T - cell depletion and infection risk in HIV - infected renal transplant recipients . HIV - infected patients are increasingly referred for kidney transplantation , and may be at an increased risk for rejection . Treatment for rejection frequently includes thymoglobulin . We studied thymoglobulin ' s effect on P01730 + T - cell count , risk of infection and rejection reversal in 20 consecutive HIV - infected kidney recipients . All patients used antiretroviral therapy and opportunistic infection prophylaxis . Maintenance immunosuppression consisted of prednisone , mycophenolate mofetil and cyclosporine . Eleven patients received thymoglobulin ( 7 for rejection and 4 for delayed / slow graft function ) while 9 did not . These two groups were similar in age , gender , race , donor characteristics and immunosuppression . Mean P01730 + T - cell counts remained stable in patients who did not receive thymoglobulin , but became profoundly suppressed in those who did , decreasing from 475 +/- 192 to 9 +/- 10 cells / microL ( p < 0 . 001 ) . Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression . Although opportunistic infections were successfully suppressed , low P01730 + T - cell count was associated with increased risk of serious infections requiring hospitalization . Rejection reversed in 6 of 7 patients receiving thymoglobulin . We conclude that thymoglobulin reverses acute rejection in HIV - infected kidney recipients , but produces profound and long - lasting suppression of the P01730 + T - cell count associated with increased risk of infections requiring hospitalization .\",\n \"Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .\",\n \"A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients . PURPOSE : Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin ( DB00098 , DB00098 (®) ) to the hematopoietic cell transplant ( HCT ) conditioning regimen of IV fludarabine monophosphate ( fludarabine ) and targeted intravenous ( IV ) busulfan ( fludarabine /( T ) busulfan ) . Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients . METHODS : We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan , specifically busulfan concentration at steady state , and fludarabine , specifically F - ara - A area under the curve ( AUC ) and fludarabine triphosphate ( F - ara - DB00171 ) intracellular accumulation and concentration in separate P01730 (+) and CD8 (+) T - lymphocyte populations . RESULTS : Acute and chronic graft versus host disease ( GvHD ) occurred in 11 patients and one patient , respectively . Four patients died before day + 100 of non - relapse causes , which met the protocol stopping guidelines . The cumulative incidence of relapse was 25 % at 3 year post - HCT . Interpatient variability in the busulfan - and fludarabine - relevant pharmacologic biomarkers was 2 . 1 - to 2 . 5 - fold . F - ara - A AUC and accumulated F - ara - DB00171 in CD8 (+) cells had the highest hazard ratio for non - relapse mortality and overall survival , respectively . However , neither achieved statistical significance . CONCLUSIONS : The low rates of GvHD , particularly in its chronic form , were encouraging , and further biomarker studies are warranted to optimize the fludarabine /( T ) busulfan / DB00098 conditioning regimen .\",\n \"___MASK74___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .\",\n \"Suppression of IL - 12 production by soluble P29965 : evidence for involvement of the Q8TCB0 / 42 mitogen - activated protein kinase pathway . IL - 12 is a key cytokine in skewing immune responses toward Th1 - like reactions . Human monocytes / macrophages produce high amounts of bioactive IL - 12 when a priming signal ( P01579 or GM - P04141 ) precedes a second signal ( e . g . , LPS ) . We and others have previously shown that preincubation with LPS before this stimulation procedure can efficiently and selectively suppress the production of IL - 12 by human monocytes . In this study , we show that an almost complete suppression of IL - 12 production can also be observed after preincubation of monocytes with costimulatory cell surface molecules that bind to members of the TNFR superfamily ( P29965 , O14788 ( O14788 ) ) . The suppression of IL - 12 was observable on the mRNA and protein levels and was not due to endogenous production of known IL - 12 antagonists ( i . e . , P22301 , P05112 , and PGE ( 2 ) ) , to an increased number of cells undergoing apoptosis , nor to down - regulation of the P01579 or P25942 receptor . Cell surface expression of the costimulatory molecules P33681 and P42081 was not reduced by the preincubation procedure , and only a moderate reduction of P05231 production was observed . Several studies have identified signal transduction pathways that are activated by P25942 signaling , including activation of mitogen - activated protein kinases . The presence of the extracellular signal - related kinase - specific mitogen - activated protein kinase kinase 1 / 2 - specific inhibitors PD98059 and U0126 abrogated suppression induced by sCD40 ligand or other second signals . This indicates that activation of extracellular signal - regulated kinase 1 / 2 contributes to the underlying mechanism of IL - 12 suppression . This mechanism may be relevant in other inflammatory responses and may help to develop therapeutic strategies in Th1 - mediated diseases .\",\n \"Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .\",\n \"Rapid T cell repopulation after rabbit anti - thymocyte globulin ( DB00098 ) treatment is driven mainly by cytomegalovirus . Rabbit anti - thymocyte globulin ( DB00098 ) induces a long - lasting lymphocytopenia . P01730 (+) T cells remain depleted for up to 2 years , whereas the CD8 (+) T cell compartment is refilled rapidly by highly differentiated P26842 (-) CD45RA (+) CD57 (+) effector - type cells . Because the presence of these highly differentiated CD8 (+) T cells has been associated with cytomegalovirus ( CMV ) infection , we questioned to what extent restoration of CMV T cell immunity contributes to the re - emergence of T cells following DB00098 treatment . We compared T cell repopulation in six CMV - seropositive patients with CMV reactivation ( reactivating CMV (+) ) to that in three CMV (+) patients without reactivation ( non - reactivating CMV (+) ) , and to that in three CMV - seronegative recipients receiving a kidney from a CMV - seronegative donor ( CMV (-/-) ) . All patients received DB00098 because of acute allograft rejection . Total P01730 and CD8 counts , frequency and phenotype of virus - specific CD8 (+) T cells were determined . In reactivating CMV (+) patients , total CD8 (+) T cells reappeared rapidly , whereas in non - reactivating CMV (+) patients they lagged behind . In CMV (-/-) patients , CD8 (+) T cell counts had not yet reached pretransplant levels after 2 years . CMV reactivation was indeed followed by a progressive accumulation of CMV - specific CD8 (+) T cells . During lymphocytopenia following DB00098 treatment , serum interleukin ( IL ) - 7 levels were elevated . Although this was most prominent in the CMV - seronegative patients , it did not result in an advantage in T cell repopulation in these patients . Repopulated CD8 (+) T cells showed increased skewing in their Vβ repertoire in both CMV (-/-) and reactivating CMV - seropositive patients . We conclude that rapid T cell repopulation following DB00098 treatment is driven mainly by CMV .\",\n \"___MASK20___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK20___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .\",\n \"[ Renal cell carcinoma management and therapies in 2010 ] . Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy . Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies . The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against P15692 - VEGFR and P42345 . Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival . At the moment , six molecules have been approves in advanced RCC : cytokines ( P60568 and IFN ) , antiangiogenic therapies ( sunitinib , sorafenib , bevacizumab ) and P42345 inhibitors ( ___MASK37___ , everolimus ) . Nephrectomy is an important component of the multimodality treatment of mRCC . Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies . Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting .\",\n \"In vitro cell death of activated lymphocytes in Omenn ' s syndrome . Omenn ' s syndrome ( OS ) is characterized by erythrodermia , hepatosplenomegaly , lymphadenopathy , hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections . Peripheral blood T cells , though usually present in normal number , show an activated phenotype ( including an increased expression of CD95 / Fas ) , a Th2 pattern of cytokine secretion and defective proliferative response to mitogens . In this report , we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms . First , a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures ( p = 0 . 009 vs . healthy controls ) . This spontaneous apoptosis is associated with reduced expression of bcl - 2 gene product ( p < 0 . 05 ) and can be prevented by addition of interleukin ( IL ) - 2 ( which also prevents down - modulation of bcl - 2 ) , while is independent from CD95 signaling . Second , lymphocytes from OS patients are highly susceptible to activation - induced cell death ( AICD ) induced with mitogens . This mechanism is largely independent from P60568 , while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody ( mAb ) . The dependence of AICD from signals transduced via CD95 was confirmed showing that cross - linking CD95 with an IgM mAb induces a higher cell death in purified P01730 + CD45R0 + cells from OS patients than in controls ( comparable for CD95 expression ) . Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS .\",\n \"Rabbit anti - rat thymocyte immunoglobulin preserves renal function during ischemia / reperfusion injury in rat kidney transplantation . Ischemia / reperfusion ( I / R ) injury is an important cause of renal graft dysfunction in humans . Increases in cold and warm ischemia times lead to a higher risk of early post - transplant complications including delayed graft function and acute rejection . Moreover , prolonged cold ischemia is a predictor of long - term kidney graft loss . The protective effect of rabbit anti - rat thymocyte immunoglobulin ( DB00098 ) was evaluated in a rat model of I / R injury following syngeneic kidney transplantation . Serum creatinine concentration was evaluated at 16 h and 24 h post - transplant . Animals were sacrificed 24 h post - transplant for evaluation of histology , infiltrating leukocytes , nitrotyrosine staining , and apoptosis . DB00098 was effective in preventing renal function impairment , tissue damage and tubular apoptosis associated with I / R only when was given 2 h before transplantation but not at the time of reperfusion . Pretransplant DB00098 treatment of recipient animals effectively reduced the amount of macrophages , P01730 (+) , CD8 (+) T cells and LFA - 1 (+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme - B expression within ischemic kidney . On the other hand , granulocyte infiltration and oxidative stress were not modified by DB00098 . If these results will be translated into the clinical setting , pretransplant administration of Thymoglobuline (®) could offer the additional advantage over peri - transplant administration of limiting I / R - mediated kidney graft damage .\",\n \"A cell - intrinsic inhibitor of HIV - 1 reverse transcription in P01730 (+) T cells from elite controllers . HIV - 1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication , but cell - intrinsic mechanisms that can block HIV - 1 reverse transcription in a clinically significant way are poorly defined . We find that effective HIV - 1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin - dependent kinase ( CDK ) 2 at a highly conserved DB00156 residue . P24941 - dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness . Interestingly , P38936 , a cell - intrinsic CDK inhibitor that is upregulated in P01730 (+) T cells from \\\" elite controllers , \\\" potently inhibited P24941 - dependent phosphorylation of HIV - 1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription . These data suggest that P38936 can indirectly block HIV - 1 reverse transcription by inhibiting host cofactors supporting HIV - 1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV - 1 replication .\",\n \"The effect of rabbit antithymocyte globulin on human DB05914 . Mesenchymal stem cells ( MSCs ) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation . In transplantation , administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials . Therefore , it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation . We aimed to analyze the effect of rabbit antithymocyte globulin ( DB00098 ) MSCs . MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of DB00098 ( DB00098 (®) , Genzyme ; 0 . 5 - 100 μg / ml ) . Binding of DB00098 , effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested . DB00098 binds dose - dependently to MSCs . This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs . In contrast to nontreated MSCs , DB00098 preexposed MSCs were susceptible to be lysed by cytokine - activated CD8 (+) cytotoxic cells and NKT cells . The capacity of MSCs to suppress the proliferation of anti - CD3 / P10747 activated P01730 and CD8 T cells were reduced by the presence of DB00098 in the culture . DB00098 reduces the viability and antiproliferative capacity of MSCs in a dose - dependent manner and converts them into targets for CD8 T cells and NKT cell lysis .\",\n \"Murine antithymocyte globulin T - cell depletion is mediated predominantly by macrophages , but the Fas / P48023 pathway selectively targets regulatory T cells . BACKGROUND : DB00098 is a T - cell - depleting polyclonal rabbit anti - human thymocyte antibody used clinically for immunosuppression in solid organ and hematopoietic stem - cell transplantation . By using a surrogate rabbit anti - mouse thymocyte globulin ( mATG ) , we previously demonstrated that murine regulatory and memory T cells are preferentially spared from mATG depletion in vivo . The current studies were designed to determine whether different effector mechanisms are involved in differential depletion of T - cell subsets by mATG . METHODS : Complement - dependent cytotoxicity , antibody - dependent cellular cytotoxicity ( ADCC ) , and apoptotic mechanisms of depletion by mATG were evaluated in vitro and in vivo . RESULTS : In vitro , there was evidence of differential susceptibility of T - cell subsets by different effector mechanisms where naïve and P01730 effector memory T cells show reduced susceptibility to apoptosis , whereas regulatory T cells are less susceptible to mATG - mediated complement - dependent cytotoxicity and ADCC . However , mATG treatment of mice depleted of ADCC effector cell types ( neutrophils , natural killer cells , or macrophages ) or deficient in complement P01031 or Fas demonstrated that mATG depletion of all T - cell subsets is mediated primarily by macrophages and that the role of neutrophils , natural killer cells , and complement is minimal in vivo . Interestingly , the Fas / P48023 pathway does play a role in regulatory T - cell depletion , which is likely a result of increased basal expression of Fas on these cells . CONCLUSIONS : These data suggest that macrophages deplete most T cells by mATG in mice , but regulatory T cells are also uniquely susceptible to mATG - mediated Fas - dependent depletion .\",\n \"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK13___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK13___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK13___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .\",\n \"The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia . Anti - thymocyte globulin ( ATG ) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia . However , there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome . Therefore , in this study , we retrospectively compared the effect of two different DB00098 preparations [ DB00098 ( ATG - G ) and ATG - Fresenius ( ATG - F ) ] on immune recovery and cytomegalovirus infection after transplantation . The conditioning regimen was a combination of fludarabine , cyclophosphamide , and ATG . Low dose total body irradiation was added in alternative donor transplantation . Four patients received ATG - F at 5 mg / kg / day from day - 7 to day - 3 , whereas ATG - G was given at 2 . 5 mg / kg / day from day - 5 to day - 2 in three patients . There was no graft rejection and no grade II - IV acute graft - versus - host disease . All three patients in the ATG - G group developed positive cytomegalovirus antigenemia including two with high - grade antigenemia , whereas two of the four patients in the ATG - F group were persistently negative . Immunological evaluation on day 60 revealed that both P01730 + and CD8 + T - cell recoveries were delayed in the ATG - G group . These findings suggested that ATG - G has a stronger immunosuppressive activity than the ATG - F with a dose ratio of 1 : 2 . 5 .\",\n \"Acute and chronic vascular rejection in nonhuman primate kidney transplantation . A nonhuman primate ( NHP ) study was designed to evaluate in nonlife - supporting kidney allografts the progression from acute rejection with transplant endarteritis ( TXA ) to chronic rejection ( CR ) with sclerosing vasculopathy . Group P55008 ( n = 6 ) received high cyclosporine A ( DB00091 ) immunosuppression and showed neither TXA nor CR during 90 days post - transplantation . Group G2 ( n = 6 ) received suboptimal DB00091 immunosuppression and showed severe TXA with graft loss within 46 days ( median ) . Arterial intimal changes included infiltration of macrophages and T lymphocytes ( CD3 , P01730 , CD8 ) with few myofibroblasts , abundant fibronectin / collagen IV , scant collagens I / III , high rate of cellular proliferation and no C4d accumulation along peritubular capillaries . Group P46379 ( n = 12 ) received suboptimal DB00091 and anti - rejection therapy ( DB00098 + methylprednisolone + DB00091 ) of TXA . Animals developed CR and lost grafts within 65 days ( median ) . As compared to G2 , the arterial intimal changes showed less macrophages and T lymphocytes , an increased number of myofibroblasts , abundant fibronectin / collagen IV and scar collagens I / III , C4d deposition along capillaries in 60 % of animals and transplant glomerulopathy in 80 % of animals . In conclusion , CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts , and progressive deposition of collagens in the intima . Our experimental design appears well suited to study events leading to CR .\",\n \"Atypical acute rejection after hand transplantation . Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse , patchy or focal , and distributed over forearms and dorsum of the hands . This ' classical ' pattern of rejection usually spares the skin of the palm and does not affect the nails . Herein , we report the experience on four cases presenting with an ' atypical ' pattern of rejection that is novel in involving the palmar skin and the nails . All patients were young and exposed to repetitive and persistent mechanical stress of the palm . Characteristic features of rejection included a desquamative rash associated with dry skin , red papules , scaling and lichenification localized to the palm . Skin lesions were associated with nail dystrophy , degeneration , deformation or loss . Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells ( CD3 + , P01730 + and CD8 + ) , with small numbers of B cells ( P11836 + and CD79a + ) and a low number of Forkhead transcription factor 3 ( Q9BZS1 ) - positive cells in one patient . The lesions persisted over weeks to months , responded poorly to steroid treatment and were managed with antithymocyte globulin ( ATG ; DB00098 , Genzyme , Cambridge , MA ) , alemtuzumab and / or intensified maintenance immunosuppression .\",\n \"Selective serotonin reuptake inhibitors attenuate the antigen presentation from dendritic cells to effector T lymphocytes . ___MASK20___ , one of the selective serotonin reuptake inhibitors ( SSRIs ) , has been found to possess immune modulation effects , in addition to its antidepressant effects . However , it remains unclear whether SSRIs can suppress the antigen - presenting function of dendritic cells ( DCs ) . Therefore , ___MASK20___ was applied to a co - culture of Aggregatibacter actinomycetemcomitans ( Aa ) - reactive T cells ( × Aa - T ) isolated from Aa - immunized mice and DCs . This resulted in the suppressed proliferation of × Aa - T stimulated with Aa - antigen presentation by DCs . Specifically , ___MASK20___ increased the extracellular 5 - hydroxytryptamine ( 5 - HT ) in the × Aa - T / DC co - culture , whereas exogenously applied 5 - HT promoted T - cell proliferation in the × Aa - T / DC co - culture , indicating that ___MASK20___ - mediated suppression of × Aa - T / DC responses can not be attributed to extracellular 5 - HT . Instead , ___MASK20___ remarkably suppressed the expression of costimulatory molecule Q9Y6W8 - L on DCs . ___MASK20___ also promoted a greater proportion of P42081 ( Low ) immature DCs than P42081 ( High ) mature DCs , while maintaining the expression levels of P33681 , MHC - class - II and Q9NZQ7 . These results suggested that ___MASK20___ suppressed the ability of DCs to present bacterial antigens to T cells , and the resulting T - cell proliferation , in a P31645 / 5 - HT - independent manner and that diminished expression of Q9Y6W8 - L on DCs and increase of P42081 ( Low ) immature DCs caused by ___MASK20___ might be partially associated with ___MASK20___ - mediated suppression of DC / T - cell responses .\",\n \"Human P01730 (+) CD25 (+) Cells in Combination with P28906 (+) Cells and DB00098 to Prevent Anti - hematopoietic Stem Cell T Cell Alloreactivity . Cotransplantation of human P28906 (+) hematopoietic stem cells ( P19526 ) and P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) could prevent anti - P19526 alloreactivity and reduce the risk of rejection in HLA mismatched transplants . To pursue this hypothesis we cocultured P28906 (+) cells and P01730 (+) CD25 (+) cells immunomagnetically isolated ( Milteny ) from human peripheral blood ( unmanipulated or granulocyte - colony stimulating factor [ DB00099 ] mobilized ) or cord blood . Enriched Tregs obtained from the same source ( autologous ) of P28906 (+) cells showed greater inhibitory effect on T cell alloreactivity than third - party ( allogeneic ) Tregs . The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic P28906 (+) cells and Tregs did not modify the clonogenic activity of P28906 (+) cells in vitro . Cotransplantation of Tregs with P28906 (+) cells at 1 : 1 or 2 : 1 ratios in nonobese diabetic / severe combined immunodeficiency ( NOD / SCID ) mice resulted in normal hematopoietic stem cell engraftment . Incubation with physiologic doses of rabbit antithymocyte globulin ( DB00098 , thymoglobulin ) did not affect the number of Tregs in 6 - day culture . Upon exposure to thymoglobulin Tregs maintained their suppressive activity , increased expression of P32248 , and released multiple cytokines , primarily interleukin ( IL ) 10 . Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with P28906 (+) cells after preparative regimens including thymoglobulin .\",\n \"___MASK13___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .\",\n \"Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .\",\n \"Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .\",\n \"Naive P01730 t cell proliferation is controlled by mammalian target of rapamycin regulation of Q8TEB7 expression . In this study , we demonstrate that the E3 ubiquitin ligase gene related to anergy in lymphocytes ( Q8TEB7 ) is expressed in quiescent naive mouse and human P01730 T cells and has a functional role in inhibiting naive T cell proliferation . Following TCR engagement , P10747 costimulation results in the expression of P60568 whose signaling through its receptor activates the Akt - mammalian target of rapamycin ( P42345 ) pathway . Activation of P42345 allows selective mRNA translation , including the epistatic regulator of Q8TEB7 , Q96FW1 ( Otub1 ) , whose expression results in the degradation of Q8TEB7 and allows T cell proliferation . The activation of P42345 appears to be the critical component of IL - 2R signaling regulating Q8TEB7 expression . P16410 - Ig treatment blocks P10747 costimulation and resultant P60568 expression , whereas rapamycin and anti - P60568 treatment block P42345 activation downstream of IL - 2R signaling . Thus , all three of these biotherapeutics inhibit P42345 - dependent translation of mRNA transcripts , resulting in blockade of Otub1 expression , maintenance of Q8TEB7 , and inhibition of P01730 T cell proliferation . These observations provide a mechanistic pathway sequentially linking P10747 costimulation , IL - 2R signaling , and P42345 activation as important requirements for naive P01730 T cell proliferation through the regulation of Otub1 and Q8TEB7 expression . Our findings also extend the role of Q8TEB7 beyond anergy induction and maintenance , suggesting that endogenous Q8TEB7 regulates general cell cycle and proliferation of primary naive P01730 T cells .\",\n \"SV40 infection associated with rituximab treatment after kidney transplantation in nonhuman primates . BACKGROUND : A regimen consisting of polyclonal anti - T - cell antibody , sirolimus ( Q86TD4 ) , and donor bone marrow ( DBM ) infusion induces robust transplantation tolerance to skin allografts in mice . We investigated the effect of a similar regimen in a nonhuman primate ( NHP ) model . METHODS : Cynomolgus macaques ( Macaca fascicularis ) were transplanted with mismatched kidney allografts . Recipients were treated with 7 doses of antithymocyte globulin ( DB00098 , day 1 to 9 ) , sirolimus , and DBM infusion ( day 14 ) . Anti - P11836 antibody , rituximab , was given on days 0 and 5 . RESULTS : A regimen of DB00098 , 30 days of Q86TD4 , and DBM infusion induced significantly greater prolongation of graft survival with a mean survival time of 88 days compared with the control regimen ( no DBM ) with an mean survival time of 53 days ( P = 0 . 022 ) . Unlike the murine skin allograft model , all grafts were rejected within 111 days . A combination of DB00098 , continuous Q86TD4 , and rituximab caused graft and systemic SV40 infection and failed to achieve further extension of graft survival . C4d deposition was observed in 50 % of recipients as early as 18 days , suggesting antidonor antibody production . A transient , low - to - moderate degrees of multilineage chimerism was observed after DBM infusion . Treatment with DB00098 resulted in profound depletion of P01730 + and CD8 + T cells , whereas addition of rituximab achieved prolonged ( up to 3 months ) depletion of P11836 + B cells . CONCLUSION : The DB00098 , Q86TD4 , and DBM protocol is simple and produces long - term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long - term tolerance .\",\n \"ATG induction in renal transplant recipients : Long - term hazard of severe infection is associated with long - term functional T cell impairment but not the ATG - induced P01730 cell decline . BACKGROUND AND METHODS : We showed previously that DB00098 induction induces a strong decrease of P01730 + T cells together with impaired in vitro P60568 secretion up to 1 year post - transplant . To further characterize long - term immunological effects of ATG induction 2 and 5 years post - transplant , we used sensitive intracellular cytokine analysis in the same prospective study of 84 renal transplant recipients ( ATG , n = 44 ) . RESULTS : A significantly increased frequency of severe infectious disease ( HR = 2 . 0 , p = 0 . 027 ) as well as suppressed T cell functions were found within 2 years after ATG induction but not beyond ( logistic regression ( logreg ) : P01730 cell P22301 responses , p = 0 . 064 ; T cell proliferation , p = 0 . 038 ) . Impaired T cell proliferation at 2 years was associated with occurrence of severe infection ( p = 0 . 017 ) . Importantly , a strong and persistent decrease of P01730 cell counts ( p < 0 . 0005 at 5 years ) was independently associated with ATG induction ( logreg p = 0 . 002 ) but not related to functional P01730 cell impairment ( helper activity / cytokine production ) or an increased risk of infection . CONCLUSIONS : Severe infection up to 2 years after ATG induction was associated with impaired T cell proliferative capacity but not with the profound decline in P01730 cell counts that occurred after ATG induction and persisted up to 5 years .\",\n \"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK30___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .\",\n \"Preferential increase in memory and regulatory subsets during T - lymphocyte immune reconstitution after DB00098 induction therapy with maintenance sirolimus vs cyclosporine . BACKGROUND : DB00877 maintenance therapy with DB00098 induction is a promising regimen that may preserve renal function . Data are lacking , however , about the immunologic effects of combined DB00098 - sirolimus . METHODS : In a 12 - month , prospective , randomised , open - label , single - centre pilot study , de novo deceased - donor kidney transplant patients were randomised to receive cyclosporine or sirolimus , with DB00098 induction , mycophenolate mofetil and corticosteroids . Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution . RESULTS : Nineteen patients were recruited ( sirolimus 9 , cyclosporine 10 ) . Reconstitution of the P01730 (+) T - lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1 , but CD8 (+) reconstitution did not differ significantly between groups . The proportion of naïve P01730 (+) T - lymphocytes showed an initial decrease with sirolimus versus cyclosporine . Naïve CD8 (+) T - lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3 , but remained unchanged with sirolimus . Memory P01730 (+) T - lymphocytes occurred more frequently in sirolimus - versus cyclosporine - treated patients during year 1 . The proportion of memory CD8 (+) T - lymphocytes decreased at months 1 and 3 compared to baseline in the DB00091 arm , but did not change in the sirolimus cohort . By month 12 , the proportion of both naïve and memory P01730 (+) and CD8 (+) T - lymphocytes had become similar with sirolimus or cyclosporine . There were fewer naïve B - lymphocytes in the sirolimus cohort and more P15391 (-) IgD (+/-) P26842 (+) memory B - lymphocytes . CONCLUSIONS : In this small population , homeostatic reconstitution after DB00098 induction showed disproportionately high recovery of memory T - lymphocyte subsets during sirolimus therapy , which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation .\",\n \"Effect of different induction strategies on effector , regulatory and memory lymphocyte sub - populations in clinical islet transplantation . This prospective study assessed lymphocyte subsets in the peripheral blood of 42 islet allograft recipients using flow cytometry from 2 weeks and up to 2 years post - transplantation . Subjects received daclizumab ( n = 16 ) , DB00098 ( n = 12 ) or alemtuzumab ( n = 14 ) . DB00087 was associated with an early ( within 1 month ) and transient ( up to 6 months ) increase in the frequency of CD3 (+) P01730 (+) Foxp3 (+) T cells , while daclizumab induced a near complete loss of these cells ( P < or = 0 . 001 ) . The frequency of memory P01730 (+) T cells was increased following depleting immunosuppression induction with either DB00098 or alemtuzumab ( P < or = 0 . 05 ) , but remained unchanged while using daclizumab . DB00087 induction resulted in a significant loss of memory B lymphocytes when compared with the other induction groups ( P < or = 0 . 001 ) . While the clinical significance of these findings remains to be fully determined , the observed altered balance between effector , regulatory and memory cells suggests that the immune status of patients will be affected according to the induction strategy chosen .\",\n \"Effect of thymoglobulin induction on HIV - infected renal transplant recipients : differences between HIV - positive and HIV - negative patients . The best immunosuppressive regimen in HIV - infected renal transplant recipients has not been established . DB00098 has been associated with an increased risk of serious bacterial infections in HIV - negative patients and , for this reason , there is some concern over its use in the HIV - infected population . We describe three consecutive HIV - infected renal transplant recipients who received thymoglobulin as induction therapy , and we compared their progress with a cohort of 23 HIV - negative recipients . Median follow - up was 24 and 11 months , respectively . Nadir lymphocytopenia was observed at 1 week in both groups , and their absolute lymphocyte count recovery was similar . An early and deep ( < 30 cells / mm ( 3 ) ) P01730 (+) T cell lymphocytopenia was seen in two of the three HIV - infected patients . No opportunistic infections were diagnosed in HIV - positive patients . One HIV - positive patient had a bacterial infection and five HIV - negative patients had one or more bacterial infections . DB00098 was safe in our three HIV - infected renal transplant recipients . Until those data are confirmed in larger studies , close monitoring is recommended during the thymoglobulin - induced P01730 (+) T cell lymphocytopenia period .\",\n \"Acute cellular rejection . The incidence of acute rejection of the kidney allograft in the world has been around 15 % during the period between 2001 and 2003 . It is clinically defined as an elevation in the level of serum creatinine by more than 0 . 3 mg / dL and is diagnosed by kidney biopsy . On pathologic examination , the interstitium of the allograft is diffusely edematous and infiltrated by P01730 and CD8 lymphocytes . Tubulitis occurs when the lymphocytes and monocytes extend into the walls and lumina of the tubules . Presence of leukocytes determines infection or antibody - mediated rejection . Typically C4d staining is negative . Other causes of acute allograft dysfunction included prerenal factors , interstitial nephritis , infection , acute tubular necrosis , toxicity by drugs , and obstruction in the urinary tract . The primary diagnostic assessments include history , especially adherence to immunosuppressive therapy , physical examination , blood and urine laboratory tests , measurement of the serum levels of the drugs , and ultrasonography . Diagnosis of acute cellular rejection depends on biopsy , P11836 staining for refractory cases , negative C4d staining , presence of markers of activating lymphocyte , and proteomic study . Treatment of acute cellular rejection in kidney transplant recipients include pulse steroid for the first rejection episode . It can be repeated for recurrent or resistant rejection . DB00098 and OKT3 are used as the second line of treatment if graft function is deteriorating . Changing the protocol from cyclosporine to tacrolimus or adding mycophenolate mofetil or sirolimus might be effective . Prognosis depends on number of rejection episodes , the use of potent drugs , time of rejection from transplantation , and response to treatment .\",\n \"Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK80___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .\",\n \"Oocyte - expressed interleukin 7 suppresses granulosa cell apoptosis and promotes oocyte maturation in rats . Development of ovarian follicles is regulated by pituitary - derived gonadotropins together with local ovarian paracrine factors . Based on DNA microarray data , we performed RT - PCR and immunostaining to demonstrate the expression of interleukin 7 transcripts in oocytes of preantral , antral , and preovulatory follicles in rats . We also found the expression of interleukin 7 receptor and the coreceptor interleukin 2 receptor gamma in granulosa cells , cumulus cells , and preovulatory oocytes . In cultured rat granulosa cells obtained from early antral and preovulatory follicles , treatment with interleukin 7 stimulated the phosphorylation of AKT , glycogen synthase kinase ( P49841 ) , and P42229 proteins in a time - and dose - dependent manner . Furthermore , measurement of mitochondrial reductase activity indicated that treatment with interleukin 7 , similar to gonadotropins , increased the number of viable granulosa cells during a 24 - h culture period . Furthermore , monitoring of the activities of apoptotic enzymes ( caspase 3 / 7 ) indicated that treatment with interleukin 7 suppressed apoptosis of cultured granulosa cells from both antral and preovulatory follicles following serum withdrawal . The apoptosis - suppressing actions of interleukin 7 were blocked by an inhibitor of the phosphoinositol - 3 - kinase ( PIK3 ) / AKT pathway . Furthermore , treatment of cultured preovulatory follicles with interleukin 7 , like treatment with human chorionic gonadotropin , induced germinal vesicle breakdown of oocytes . The stimulatory effect of interleukin 7 was also blocked by inhibitors of the PIK3 / AKT pathway . The present findings suggest that oocyte - derived interleukin 7 could act on neighboring granulosa cells as a survival factor and promote the nuclear maturation of preovulatory oocytes through activation of the PIK3 / AKT pathway .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK13___","___MASK20___","___MASK30___","___MASK37___","___MASK68___","___MASK73___","___MASK74___","___MASK80___","___MASK86___"],"string":"[\n \"___MASK13___\",\n \"___MASK20___\",\n \"___MASK30___\",\n \"___MASK37___\",\n \"___MASK68___\",\n \"___MASK73___\",\n \"___MASK74___\",\n \"___MASK80___\",\n \"___MASK86___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK86___"},"id":{"kind":"string","value":"MH_train_86"}}},{"rowIdx":87,"cells":{"query":{"kind":"string","value":"interacts_with DB06674?"},"supports":{"kind":"list like","value":["___MASK88___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","Effectiveness of infliximab , adalimumab and DB06674 for non - infectious refractory uveitis in adults . AIM : To discuss the available data regarding the off - label uses of anti - P01375 agents in non - infectious uveitis . DATA SOURCE : A literature search was performed in Medline through PubMed from January 2001 to January 2014 . STUDY SELECTION AND DATA EXTRACTION : English - language articles about uveitis treatment with anti - P01375 drugs in adult patients were reviewed . DATA SYNTHESIS : The use of anti - P01375 - Î ± drugs for treatment of several refractory manifestations of refractory uveitis in adult patients is increasing . However , due to the lack of evidence from randomized controlled trials , the use of anti - P01375 in uveitis remains â off - labelâ in most countries . There is no trial - based evidence to support it except for the experience provided by cases and case series . This experience , which is continuously increasing , has yielded encouraging results . Anti - P01375 - Î ± drugs , such as infliximab , adalimumab , and DB06674 , are reasonably effective for controlling ocular inflammation and sparing patients corticosteroid treatment in non - infectious refractory uveitis . Approximately 80 % of patients on infliximab , adalimumab , or DB06674 were able to achieve sustained control of inflammation by 6 months . CONCLUSION : Anti - P01375 - Î ± therapy is effective in inducing clinical remission for refractory uveitis , with a relatively low rate of treatment - ending adverse events . However , randomized and controlled trials are required to adequately assess the maintained clinical efficacy and safety profile in the long term of anti - P01375 agents for non - infectious refractory uveitis .","Tuberculosis risk in patients treated with non - anti - tumor necrosis factor - α ( P01375 - α ) targeted biologics and recently licensed P01375 - α inhibitors : data from clinical trials and national registries . This review aimed to evaluate the risk of active tuberculosis ( TB ) occurrence in patients with rheumatic disorders receiving non - anti - tumor necrosis factor ( P01375 ) targeted biologics anakinra ( ANK ) , tocilizumab ( TCZ ) , rituximab ( RTX ) , abatacept ( ABA ) , and recently approved anti - P01375 DB06674 ( GOL ) , and certolizumab pegol ( P53007 ) . In recent findings , no cases of active TB were recorded in patients with rheumatoid arthritis ( RA ) and other rheumatic conditions treated with anti - P11836 + RTX and anti - P10747 ABA . No patient receiving anti - interleukin 1 ( IL - 1 ) ANK developed active TB , and an increased risk was excluded in a Canadian database . In contrast , 8 active TB cases were observed in 21 trials of patients with RA receiving anti - P05231 TCZ , while no increased TB risk resulted from Japanese postmarketing surveillance . Among GOL - treated and P53007 - treated patients , 8 and 10 active TB cases occurred , respectively , while no data are available from registries . However , all but 1 TB case recorded in patients treated with TCZ , GOL , and P53007 occurred in TB - endemic countries . No TB risk resulted for ANK , RTX , and ABA , suggesting pretreatment screening procedures for latent TB infection detection are unnecessary . Because all TB cases occurred in countries at high risk for TB , where TB exposure could have occurred during treatment , no definitive conclusions can be drawn for TCZ , GOL , and P53007 .","Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .","Elevation of P15941 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis : a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs . OBJECTIVE : The associations between elevated levels of serum P15941 ( P15941 ) and treatment of rheumatoid arthritis ( RA ) with tumor necrosis factor ( P01375 ) inhibitors were investigated in five Japanese clinical trials . METHODS : Percentages and incidence rates were calculated for elevated serum P15941 levels . Adverse events associated with elevated levels of serum P15941 were investigated . RESULTS : In RISING , a clinical trial for infliximab , 15 . 6 % of the enrolled patients met criterion B ( P15941 ≥ 500 U / ml and > 1 . 5 - fold increase over the baseline value ) by week 54 . In HIKARI , 7 . 8 % of the certolizumab pegol ( CZP ) group and 0 % of the placebo group met criterion B during the double - blind ( DB ) period ( p = 0 . 003 ) . In J - RAPID , 8 . 4 % of the methotrexate ( MTX ) + CZP and 3 . 9 % of the MTX + placebo groups met criterion B during the DB period . In GO - MONO , 1 . 8 % of the DB06674 ( GLM ) and 1 . 3 % of the placebo groups met criterion B during the DB period . In GO - FORTH , 7 . 1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period ( p = 0 . 017 ) . No adverse events accompanied the elevation of serum P15941 levels in 95 . 7 % of these patients . CONCLUSION : Serum P15941 levels may increase during anti - P01375 therapy without significant clinical events . In these patients , continuing treatment with P01375 inhibitors under careful observation is a reasonable option .","[ New biologic and non biologic disease modifying anti - rheumatic drugs for rheumatoid arthritis ] . P01375 inhibitors , infliximab , etanercept and adalimumab , and tocilizumab are available in Japan and have been successful at improving the signs and symptoms of RA and , thereby , have set a new standard for disease control of RA and have the potential to protect joints from structural damage or to improve quality of life and mortality . However , the rate of successful induction of remission was about 30 % and the treatment strategies for the patients who do not respond to these biologics should be established . Randomized clinical trials targeting T or B lymphocytes have been conducted in addition to the new anti - P01375 blockers like DB06674 or certolizumab pegol . Anti - P11836 antibodies such as rituximab ( chimeric ) , ocrelizumab ( humanized ) , ofatuzumab ( full human ) demonstrated effectiveness to the patients who do not respond to P01375 blockers . P16410 Ig , which can transduce negative signal into T lymphocytes in the co - stimulatory pathway , has also showed a good response to refractory RA . Furthermore , low molecular agents such as Jak ( Janus kinase ) 3 or syk ( spleen tyrosine kinase ) inhibitors demonstrated rapid and strong suppression of synovitis and are thought to be new candidates for the drugs to overcome refractory RA .","Biologic agents for rheumatoid arthritis : 2008 and beyond . Rheumatoid arthritis ( RA ) is a chronic disease with a complex underlying pathology and varied presentation in patients . Several novel biologic disease - modifying antirheumatic drugs have become available for the treatment of RA . Agents in late - stage clinical trials include DB06674 and certolizumab , which are anti - tumor necrosis factor ( P01375 ) - alpha agents ; ocrelizumab , an anti - P11836 agent ; and tocilizumab , an inhibitor of interleukin - 6 . As treatment options for RA expand , nursing care will play an increasingly important role in empowering patients through interventions such as patient education and adverse effect management .","Treatment of psoriasis and psoriatic arthritis . Skin and joint manifestations associated with psoriasis and psoriatic arthritis ( PsA ) can significantly impact a patient ' s quality of life . Successful treatment is imperative in order to improve signs and symptoms of the disease , and to alleviate physical or psychological distress . For patients with mild psoriasis with or without PsA , topical agents and targeted phototherapy are appropriate treatments for psoriasis . Systemic therapies , such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis , but their long - term use is hindered by safety concerns . Advancements in understanding the pathogenesis of psoriasis , including the role of T cells and cytokines , have been crucial to the development of biological therapies . These target the immune system and are suitable options for patients with extensive disease . Biological therapies for the treatment of psoriasis include targeted therapies ( alefacept ) and anti - cytokine therapies ( anti - tumour necrosis factor [ P01375 ] therapies [ adalimumab , etanercept , infliximab ] and a monoclonal antibody against interleukin [ IL ] - 12 and IL - 23 [ ustekinumab ] ) . Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage . Non - steroidal anti - inflammatory drugs or local intra - articular injections of corticosteroids can be used successfully in patients with mild PsA ; however , neither treatment prevents the development of structural joint damage . For patients with moderate to severely active PsA , disease - modifying antirheumatic drugs ( such as methotrexate ) , P01375 inhibitor treatments ( adalimumab , etanercept , infliximab and DB06674 ) or their combination are considered first - line treatment . This review provides a brief overview of treatment options for psoriasis and PsA , with an emphasis on the efficacy and safety of anti - P01375 therapies .","Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .","Golimumab and malignancies : true or false association ? Malignancy is one of the comorbidities linked to DB06674 , a biological P01375 - α blocker . In this systematic review and meta - analysis , we searched different databases and analyzed original publications to elucidate the remaining open question about the real association of malignancies with DB06674 therapy . The most frequent cancer in patients treated with DB06674 , in association or not with methotrexate , is the lung adenocarcinoma . However , lymphoma is not very commonly represented in these patients . We show that there is no major and evident risk of malignancies associated with DB06674 in current scientific literature . An increased risk of malignancies may be associated with DB06674 , but this warrants further clinical confirmation . Also , this risk mentioned in different studies must be taken with caution because of number of limits and biases .","Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK70___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .","Tumor necrosis factors blocking agents : analogies and differences . Five anti - P01375 agents , infliximab , adalimumab , etanercept , DB06674 and certolizumab pegol are approved worldwide for the treatment of RA . Anti - P01375 agents , bind to and neutralize soluble P01375 , but exert different effects on transmembrane P01375 - expressing cells ( P01375 - producing cells ) . Differences on affinity and avidity for soluble and transmembrane P01375 were showed . Different activity on cells apoptosis , complement - dependent cytotoxicity ( CDC ) antibody dependent cell - mediated cytotoxicity ( Q15848 ) were described . Some dramatic changes in gene expression were seen with all the anti - TNFs . Reviewing the biology of transmembrane P01375 and its interaction with anti - P01375 agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities .","Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .","P01375 inhibitors in asthma and P48444 : we must not throw the baby out with the bath water . P01375 ( P01375 ) - alpha , a pleiotropic cytokine that exerts a variety of effects , such as growth promotion , growth inhibition , angiogenesis , cytotoxicity , inflammation , and immunomodulation , has been implicated in several inflammatory conditions . It plays a significant role in many inflammatory diseases of lungs . Given that there is significant literature supporting the pathobiologic role of P01375 in asthma , mainly in severe refractory asthma , and P48444 , P01375 inhibitors ( infliximab , DB06674 and etanercept ) are now regarded as the potential new medications in asthma and P48444 management . The studies reported in literature indicate that P01375 inhibitors are effective in a relatively small subgroup of patients with severe asthma , possibly defined by an increased P01375 axis , but they seem to be ineffective in P48444 , although an observational study demonstrated that P01375 inhibitors were associated with a reduction in the rate of P48444 hospitalisation among patients with P48444 receiving these agents to treat their rheumatoid arthritis . These findings require a smart approach because there is still good reason to target P01375 , perhaps in a more carefully selected patient group . P01375 treatment should , therefore , not be thrown out , or abandoned . Indeed , since severe asthma and P48444 are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them , it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from P01375 inhibitors .","Q9UKU7 : Golimumab in ulcerative colitis : a ' ménage à trois ' of drugs . Golimumab , a human anti - P01375 antibody , is effective in patients with ulcerative colitis , according to new findings from an international phase III double - blind trial . The addition of this drug makes a ménage à trois of available drugs -- comprising infliximab , adalimumab and DB06674 -- for the treatment of ulcerative colitis .","Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .","Efficacy and safety of P01375 - α inhibitors in refractory primary complex aphthosis : a patient series and overview of the literature . BACKGROUND : Otherwise healthy patients with severe recurrent mucocutaneous aphthous ulcerations ( complex aphthosis ) may require systemic immunomodulatory therapy . However , a subset of patients remain resistant or intolerant to recommended therapeutic agents . Recently , case reports have described that tumor necrosis factor - α ( P01375 - α ) inhibitors may induce remission in these patients . METHODS : Data on efficacy and safety of various P01375 - α inhibitors used as monotherapy in a case series of 18 patients with refractory primary complex aphthosis are presented . RESULTS : A total of 16 patients ( 89 % ) obtained complete or almost clearance of orogenital aphthous ulcerations rapidly after onset of therapy either with etanercept , adalimumab , infliximab or DB06674 . Duration of treatment ranged between 3 and 77 months . Nine patients ( 50 % ) received more than one P01375 - α inhibitor during the course of treatment . Five ( 28 % ) patients experienced side effects that could be related to treatment with P01375 - α inhibitors . CONCLUSION : P01375 - α inhibitors are an effective and safe treatment option for patients with severe complex aphthosis who do not respond sufficiently to standard therapy as recommended by existing guidelines . However , the final position of P01375 - α inhibitors in the therapeutic armamentarium awaits randomized controlled trials .","Off - label uses of anti - P01375 therapy in three frequent disorders : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system . Thus , its blockade with the so - called anti - P01375 agents ( infliximab , etanercept , adalimumab , certolizumab pegol , and DB06674 ) has turned into the most important tool in the management of a variety of disorders , such as rheumatoid arthritis , spondyloarthropatties , inflammatory bowel disease , and psoriasis . Nonetheless , theoretically , some other autoimmune disorders may benefit from these agents . Our aim is to review these off - label uses of anti - P01375 blockers in three common conditions : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders , this review is mainly based on case reports and case series .","Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .","P01375 inhibitors in psoriasis : an update . Three inhibitors of tumor necrosis factor ( P01375 ) currently are approved for the treatment of psoriasis : etanercept , infliximab , and adalimumab . The other two P01375 inhibitors , DB06674 and certolizumab pegol , have shown efficacy against plaque psoriasis in clinical trials of psoriatic arthritis ( PsA ) . This article reviews the most recent evidence on the efficacy and safety of the P01375 inhibitors in psoriasis , with special attention to preventing and managing immunogenicity .","Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .","Current , new and future biological agents on the horizon for the treatment of inflammatory bowel diseases . Biological agents for inflammatory bowel diseases ( Q9UKU7 ) targeting tumor necrosis factor ( P01375 ) have changed the way to treat Q9UKU7 refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission . A better understanding of the components of the pathological processes that are a hallmark of Q9UKU7 has led to the development of a new family of biological agents in Crohn ' s disease and ulcerative colitis . Biosimilars , which are copy versions of currently licensed biological agents , will be soon available . The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions , while a new anti - P01375 agent , namely DB06674 , has been recently approved for refractory ulcerative colitis . Beyond P01375 blockers , anti - adhesion molecules appear to be a potent drug class for Q9UKU7 . DB09033 was recently approved for both Crohn ' s disease and ulcerative colitis . Numerous other compounds are in the pipeline . Ustekinumab looks very promising for Crohn ' s disease . O15105 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials . Herein , we review the efficacy and safety of new and emerging biological agents that are currently investigated in Q9UKU7 clinical trials .","Biologic therapies in the treatment of psoriasis : a comprehensive evidence - based basic science and clinical review and a practical guide to tuberculosis monitoring . The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab , etanercept , adalimumab , efalizumab , DB06674 , certolizumab , alefacept , secukinumab , abatacept , and ustekinumab . These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications . Herein , we present a comprehensive , unbiased comparison of these medications focusing on their differences . For example , P01375 antagonists can differ in the way they are dissolved and administered , the effector molecules they can bind , serum peak and trough levels , the types of intracellular signals they can induce , the in vivo complexes that they can form , their protein structure , and their incidence and timing of rare adverse events , among other things . A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head - to - head comparison trials . The safety of biologics in terms of their long - term adverse events is discussed , as is their use in different types of psoriasis and in different patient populations . Finally , all anti - P01375 agents have been associated with a variety of serious and \" routine \" opportunistic infections , particularly tuberculosis . For this reason , anti - tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent . The uses and limitations of both the tuberculin skin test ( Q16762 ) and QuantiFeron ®- TB Gold ( QFT ) are discussed , as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy . Recommendations for tuberculosis monitoring are provided .","Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK56___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .","Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .","Safety of anti - P01375 therapy in inflammatory bowel disease during pregnancy . INTRODUCTION : The highest incidence of inflammatory bowel disease ( Q9UKU7 ) is seen between the second and fourth decades of life , which is the most fertile age for women . Increased disease activity has been shown to effect female fertility and pregnancy outcomes , stressing the need for drugs that can safely induce and maintain clinical remission without harming either the mother or fetus . AREAS COVERED : Anti - P01375 - α agents have been shown to be effective in both inducing and maintaining remission among Q9UKU7 patients . This review highlights the results of previous studies conducted on pregnant women who were exposed to anti - P01375 - α agents during the course of their pregnancy . The drugs reviewed include infliximab ( IFX ) , adalimumab ( P00813 ) , certolizumab pegol ( CZP ) and DB06674 ( GMB ) . Of > 200 articles reviewed , 105 were included in the manuscript based on relevance . The keywords used were anti - P01375 , infliximab , adalimumab , certolizumab , DB06674 , biologics , pregnancy and inflammatory bowel disease . EXPERT OPINION : Anti - P01375 agents have been studied extensively during pregnancy from the early case reports to the more recent prospective Pregnancy in Q9UKU7 and Neonatal Outcomes study . A comprehensive review of the literature has shown that biologics can be safely used during pregnancy . In view of this safety data , it is recommended to maintain therapy during pregnancy .","Synergism between bosutinib ( ___MASK92___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .","Safety and clinical efficacy of DB06674 in the treatment of arthritides . Golimumab is a human anti - tumor necrosis factor ( P01375 ) - alpha monoclonal antibody that was recently approved for the treatment of patients with rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . This review covers the published clinical trial data on the use of DB06674 for the approved indications mentioned above with respect to efficacy and safety . The various ongoing trials for DB06674 have yielded promising results in terms of efficacy and safety in methotrexate - naive and - resistant patients with rheumatoid arthritis , as well as in patients who were previously treated with other anti - P01375 agents . In addition , the efficacy of DB06674 in psoriatic arthritis and ankylosing spondylitis has also been demonstrated . The real safety information will be available only once the drug has been used in many more patients , who frequently have comorbid conditions .","New therapies in the management of rheumatoid arthritis . PURPOSE OF REVIEW : The therapeutic landscape in the management of rheumatoid arthritis ( RA ) has witnessed significant changes over the past decade . The ambition to improve outcomes further , minimize safety concerns and provide more convenient means of administration are all factors that continue to drive continued drug development . This review summarizes novel therapies that have been most recently under investigation . RECENT FINDINGS : More refined drug technology has seen the development of subcutaneous forms of existing therapies ( abatacept , tocilizumab ) , as well as newer - generation monoclonal antibodies ( e . g . B - cell - depleting agents , ocrelizumab and ofatumumab and the P01375 - inhibitors certolizumab and DB06674 ) . Alternative methods of targeting critical pathways , for example Blys inhibition ( atacicept ) and P05231 as opposed to P05231 receptor antagonism , have also been evaluated . Finally , small molecules are receiving increasing attention , with some of the protein kinases inhibitors particularly promising . SUMMARY : The new emerging therapies for the management of RA illustrate much diversity , in terms of both drug technology as well as the immunological target . Although not all may succeed in reaching the market , important insights can still be gained . Challenging and exciting times lie ahead as these new technologies are embraced and efforts are made to determine how best to implement in practice .","Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 .","Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK2___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .","Dermatologic adverse events : DB06674 , friend or foe ? Golimumab is a fully human anti - P01375 blocker that has demonstrated its efficacy in the treatment of numerous kinds of diseases . Although it is generally safe and well tolerated , various adverse events have been reported . The present aim is to improve the understanding of dermatologic adverse events associated with DB06674 following a search of various scientific databases . This systematic review and meta - analysis shows that DB06674 is associated neither with severe injection - site reactions nor with injection - site erythema . We found no significant lupus - like syndromes , and no significant skin squamous cell carcinoma . We further suggest systematic dermatologic monitoring in clinical practice during DB06674 therapy . Subsequent research should employ a larger cohort of patients to ensure clear and significant future conclusions .","___MASK22___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK22___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .","Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .","Miscellaneous adverse events with biologic agents ( excludes infection and malignancy ) . Anti - tumor necrosis factor - α ( anti - P01375 ) agents are frequently used in the treatment of inflammatory bowel disease ( Q9UKU7 ) . Currently , there are 4 anti - P01375 therapies that are Food and Drug Administration - approved for moderate to severe Q9UKU7 : infliximab , adalimumab , DB06674 , and certolizumab pegol . For most noninfectious , nonmalignant adverse events , cessation of anti - P01375 therapy typically leads to improvement or resolution of drug - induced complications . In this article , the current knowledge regarding the noninfectious and nonmalignant toxicities associated with anti - P01375 agents is summarized .","Psoriatic arthritis : treatment strategies using biologic agents . The traditional management of psoriatic arthritis ( PsA ) includes NSAIDs , corticosteroids and DMARDs . Advancement in the knowledge of the immunopathogenesis of PsA has been associated with the development of biologic agents which have revolutionized the management of the disease . Among biologics drugs , there are the 4 currently available anti - TNFα blocking agents ( etanercept , infliximab , adalimumab and DB06674 ) which are more effective than traditional DMARDs on symptoms / signs of inflammation , quality of life , function , and in inhibiting the progression of the structural joint damage . Despite of the high cost , P01375 inhibitors are cost - effective on both the musculoskeletal and skin manifestations of psoriatic disease .","Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .","P01375 - alpha antagonists : differential clinical effects by different biotechnological molecules . Inhibitors of tumor necrosis factor - alpha have deeply changed the therapy of several inflammatory human diseases . For instance , clinical management of rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools , such as antagonist of P01375 molecule . These drugs include etanercept , a soluble P01375 receptor antagonist , three anti - P01375 antibodies , adalimumab , infliximab , DB06674 and certolizumab a humanized Fab fragment combined with polyethylene glycol . These compounds efficiently inhibit several P01375 biological - mediated effects , however , they have also shown differential clinical efficacy in several trials from different autoimmune diseases . It is of clinical relevance that non - responders to one of these drugs often positively responded to another . Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects . However , partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses . Therefore , these apparently homogeneous agents can not be considered equivalent in their clinically efficacy . Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual P01375 inhibitors .","Treatment of ankylosing spondylitis with P01375 blockers : a meta - analysis . Biological agents directed against tumor necrosis factor ( P01375 ) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non - steroidal anti - inflammatory drugs . To evaluate the efficacy and safety of the anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , and certolizumab for the treatment of ankylosing spondylitis , we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE , MEDLINE , Cochrane Controlled Trials Register and LILACS databases ( September / 2012 ) , manual literature search , and the gray literature . Study selections and data collection were performed by two independent reviewers , with disagreements solved by a third reviewer . The following outcomes were evaluated : ASAS 20 response , disease activity , physical function , vertebral mobility , adverse events , and withdraws . The meta - analysis was performed using the Review Manager (®) 5 . 1 software by applying the random effects model . Eighteen studies were included in this review . No study of certolizumab was included . Patients treated with anti - P01375 agents were more likely to display an ASAS 20 response after 12 / 14 weeks ( RR 2 . 21 ; 95 % CI 1 . 91 ; 2 . 56 ) and 24 weeks ( RR 2 . 68 ; 95 % CI 2 . 06 ; 3 . 48 ) compared with controls , which was also true for several other efficacy outcomes . Meta - analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks . DB00051 , infliximab , etanercept , and DB06674 can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis . Safety outcomes deserve further study , especially with respect to long - term follow - ups .","Selective P01375 - α inhibitor - induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 - α is a pro - inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune - mediated or inflammatory diseases . P01375 - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long - term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .","Golimumab in uveitis previously treated with other anti - P01375 drugs : a retrospective study of three cases from a single centre and literature review . OBJECTIVES : The aim of this paper is to assess the clinical response to DB06674 ( GLM ) in patients with non - infectious uveitis from a single centre that had previously been treated with other anti - P01375 - α drugs . METHODS : A retrospective chart review was carried out of patients with immune - mediated uveitis refractory to standard synthetic immunosuppressive drugs who were treated with GLM at Hospital Universitario Marqués de Valdecilla , Santander ( Spain ) . Patients were included in this study if they had previously been treated with other anti - P01375 - α drugs . A literature review of patients with immune - mediated uveitis undergoing GLM therapy was conducted . RESULTS : Three patients ( 2 men and 1 woman ) were included in this study . Two of them were refractory to other anti - P01375 - α drugs . The median age of patients was 26 years ( range 20 - 42 ) . Uveitis was bilateral in two patients . The underlying diseases were uveitis associated with HLA - Q8TCY5 and psoriasis in one case and sarcoidosis in the other two cases . Improvement of the main ocular parameters following GLM therapy was achieved in all cases . After a median follow - up of 3 ( range 1 - 9 ) months using GLM therapy , none of the patients had experienced new relapses of uveitis . None of them had side effects during treatment with this drug . A literature review disclosed that our observations were in keeping with other reports that showed good response to GLM in 13 of 16 patients with immune - mediated uveitis refractory to other biologic agents . CONCLUSIONS : Although the follow - up was too short in our series , GLM could be an effective and safe therapy for the management of patients with uveitis previously treated with other anti - P01375 - α drugs .","NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .","The use of biologic therapies in the treatment of rheumatoid arthritis . The use of biologic agents has revolutionized the management of rheumatoid arthritis ( RA ) in the past two decades . These biologic agents directly target molecules and cells involved in the pathogenesis of RA . Biologic agents indeed lead to a better prognosis and clinical remission in patients with RA , especially in patients who are not well - controlled with traditional disease - modifying anti - rheumatic drugs ( DMARDs ) . Currently , five P01375 inhibitors ( infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol ) , an P05231 receptor antagonist ( tocilizumab ) , an IL - 1 receptor antagonist ( anakinra ) , a B cell depleting agent ( rituximab ) and a T cell co - stimulation inhibitor ( abatacept ) have been approved for the treatment of RA . With the increased understanding of the pathogenic mechanisms of RA and advantages in manufacturing biotechnology of pharmaceutical companies , a series of novel biologic therapeutic approaches are being developed . In the present paper , we will summarize the biologic agents currently available to treat RA , and the prospective biologic therapies that might be used in the management of RA in future .","Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK23___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK23___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK23___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK23___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .","The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD ) 80 / anti - P42081 fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non - neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .","___MASK22___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .","Apoptosis and the FLIP and NF - kappa B proteins as pharmacodynamic criteria for biosimilar P01375 antagonists . Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale . The imminent expiration of the patents on reference biological products which block the cytokine P01375 - α ( tumor necrosis factor - α ) raises the possibility of bringing so - called biosimilars to the market ( similar to the biologicals of reference products ) . This occurrence is inevitable , but criteria to adequately evaluate these medications are now needed . Even among controversy , there is a demand from publications correlating the pro - apoptotic mechanism of the original P01375 - α antagonists ( etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) in the treatment of rheumatoid arthritis and other diseases . In this article , the authors discuss the possibility of utilizing the pro - apoptotic effect correlated with the regulation of the anti - apoptotic proteins FLIP and NF - κB as new criteria for analyzing the pharmacodynamics of possible biosimilar P01375 - α antagonists which should be submitted to regulatory agencies for evaluation .","Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .","One target , different effects : a comparison of distinct therapeutic antibodies against the same targets . To date , more than 30 antibodies have been approved worldwide for therapeutic use . While the monoclonal antibody market is rapidly growing , the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders . Moreover , antibodies against only five targets ( P01375 - α , P04626 , P11836 , P00533 , and P15692 ) account for more than 80 percent of the worldwide market of therapeutic antibodies . The shortage of novel , clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets , based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another . For example , four antibodies against P01375 - α have been approved by the FDA -- infliximab , adalimumab , DB06674 , and certolizumab pegol -- with many more in clinical and preclinical development . The situation is similar for P04626 , P11836 , P00533 , and P15692 , each having one or more approved antibodies and many more under development . This review discusses the different binding characteristics , mechanisms of action , and biological and clinical activities of multiple monoclonal antibodies against P01375 - α , HER - 2 , P11836 , and P00533 and provides insights into the development of therapeutic antibodies .","DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .","Can we reduce the dosage of biologics in spondyloarthritis ? P01375 blockers have revolutionized the management of spondyloarthritis ( SpA ) . To date , four anti - TNFα agents ( etanercept , infliximab , adalimumab , DB06674 ) have been approved for the management of ankylosing spondylitis ( AS ) and psoriatic arthritis ( PsA ) . The first objective in the management of AS and PsA with P01375 inhibitors is to reduce disease activity to clinical remission or low disease activity . After remission has been achieved , this state should be maintained as long as possible . However , the financial burden associated with the cost of anti - P01375 agents as well as concerns about their long - term safety suggest reducing the dosage of the drug or discontinuing the therapy in the hopes of drug - free remission . The aim of this review is to examine what has , till now , been published on this topic in axial SpA , which includes AS and non - radiographic axial SpA ( nr - axSpA ) , peripheral SpA and PsA . Discontinuation of therapy in axial SpA is not possible in the majority of patients , while on the contrary , reducing the dosage often is . In some patients with peripheral SpA and PsA it is also possible to discontinue therapy and to achieve drug - free remission .","Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .","P01375 inhibitors - state of knowledge . P01375 ( P01375 ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 inhibitors in modern therapy . The main safety aspects of P01375 inhibitor administration are described in particular , with special consideration of the available meta - analyses . Finally , perspectives on the next - generation P01375 inhibitors and their use in the clinic are given .","___MASK22___ antagonizes P01375 induction of P19320 on endothelial cells by inhibiting mTORC2 . Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells ( ECs ) . Here we report that rapamycin pretreatment reduced the ability of P01375 - treated ECs to capture T cells under conditions of venular flow . This functional change was caused by inhibition of P01375 - induced expression of vascular cell adhesion molecule - 1 ( P19320 ) and could be mimicked by knockdown of mammalian target of rapamycin ( P42345 ) or rictor , but not raptor , implicating mTORC2 as the target of rapamycin for this effect . Mechanistically , mTORC2 acts through Akt to repress Raf1 - Q02750 / 2 - P27361 / 2 signaling , and inhibition of mTORC2 consequently results in hyperactivation of P27361 / 2 . Increased P27361 / 2 activity antagonizes P19320 expression by repressing P01375 induction of the transcription factor P10914 . Preventing activation of P27361 / 2 reduced the ability of rapamycin to inhibit P01375 - induced P19320 expression . In vivo , rapamycin inhibited mTORC2 activity and potentiated activation of P27361 / 2 . These changes correlated with reduced endothelial expression of P01375 - induced P19320 , which was restored via pharmacological inhibition of P27361 / 2 . Functionally , rapamycin reduced infiltration of leukocytes into renal glomeruli , an effect which was partially reversed by inhibition of P27361 / 2 . These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target .","Pharmacology of P01375 blockade in rheumatoid arthritis and other chronic inflammatory diseases . P01375 - alpha ( P01375 ) has been unequivocally validated as a therapeutic target in a number of immune - mediated inflammatory disorders ( IMIDs ) . There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF . But approaches to P01375 inhibition differ and currently include mAbs ( infliximab , adalimumab , and DB06674 ) , either chimeric or human in sequence , a PEGylated Fab ' fragment ( certolizumab ) , and an IgG1 - P20333 fusion protein ( etanercept ) . It is emerging that the pharmacological properties of these three anti - P01375 subtypes differ with respect to Fc function , binding of tmTNF and the possible consequences of this , as well as the ability to form complexes . The mode of administration of each agent , clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety .","___MASK30___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK30___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .","Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .","Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK35___ and Tissue P00747 Activator in Occluded Arteries .","Effect of interferon - gamma and P01375 on P15941 mucin expression in ovarian carcinoma cell lines . In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment , a study was designed to investigate whether the biological response modifiers interferon - gamma ( P01579 ) and tumour necrosis factor - alpha ( P01375 ) could effect the expression of an epitope on the tumour associated P15941 epithelial mucin . Four ovarian carcinoma cell lines showing high ( OAW42 and GG ) and low ( JAM and PE01 ) basal expression of P15941 were treated with 10 - 1000 U / mL of P01579 or P01375 for one or five days . Changes in P15941 expression in cells exposed to P01579 or P01375 were monitored using an ELISA technique with the monoclonal antibody O43633 which reacts with a core protein epitope on the P15941 mucin , and then corrected for the number of viable cells present . P01375 had little effect on P15941 expression , but one or five days exposure to P01579 significantly increased P15941 expression ( p < 0 . 01 ) in all cell lines including the two cell lines that initially showed little or no expression .","Spondyloarthritides . The most important clinical features of the spondyloarthritides ( SpA ) are not only inflammatory back pain ( Q9H4E7 ) but also peripheral ( enthesitis ) and extra - articular symptoms . For clinical purposes , two forms related to the predominant clinical manifestation - axial and peripheral SpA - and five subgroups - ankylosing spondylitis ( AS ) , SpA associated with psoriasis and inflammatory bowel disease ( Q9UKU7 ) , reactive arthritis and undifferentiated SpA - are differentiated . Axial SpA including AS is the most frequent subtype of SpA , followed by psoriatic arthritis and undifferentiated SpA , while reactive arthritis and Q9UKU7 - related SpA are less frequent . The prevalence of SpA has been shown to be similar to rheumatoid arthritis . The outcome of the disease is influenced by the degree of disease activity over time , which is mainly related not only to inflammation but also on the structural damage ( new bone formation ) that occurs over time . Treatment options for patients with SpA have been limited for decades . Non - steroidal anti - inflammatory agents are currently considered first choice , since they have shown good amelioration of symptoms in SpA patients especially when suffering by the typical symptom of Q9H4E7 . Furthermore , there is a clear role for regular physiotherapy in AS to prevent loss of spinal mobility . For patients who have insufficiently responded to conventional therapies , four anti - tumour necrosis factor ( P01375 ) agents are available and are approved for the treatment of patients with active AS : infliximab , etanercept , adalimumab and DB06674 . As far as it stands now , P01375 blockers seem to have no influence on new bone formation in AS .","New treatments for inflammatory rheumatic disease . As our understanding of the pathogenesis of autoimmune diseases is growing , new therapies are being developed to target disease - specific pathways . Since the introduction of etanercept in 1998 , several biotechnological agents have been developed , most of them indicated in the treatment of rheumatoid arthritis , but also psoriatic arthritis . Most currently available molecules target P01375 - alfa with different strategies ( i . e . , etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) , P05231 ( tocilizumab ) , P16410 ( abatacept ) , and B cells ( rituximab , belimumab ) as they are key mediators in the cascade of inflammation . Further , small molecules have been recently developed to target intracellular signaling , such as Janus Kinases for tofacitinib , the first FDA - approved small molecule for rheumatoid arthritis . Most novel treatments are being developed for arthritis with specific differences between rheumatoid and psoriatic arthritis , as well as for systemic lupus erythematosus , following the approval of belimumab . Finally , biologic therapies are effective also in gout , mainly targeting interleukin - 1 to block the inflammasome . This review article describes the new and upcoming treatment options for rheumatoid arthritis , psoriatic arthritis , systemic lupus erythematosus , and gout to dissect what we should be aware of when discussing these new and promising molecules .","Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK70___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK70___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .","Biologics in the management of ulcerative colitis - comparative safety and efficacy of P01375 - α antagonists . Ulcerative colitis can cause debilitating symptoms and complications such as colonic strictures , colonic dysplasia , colorectal cancer , and toxic megacolon or perforation . Goals of treatment in ulcerative colitis include resolution of gastrointestinal symptoms , healing of colonic mucosa , and prevention of disease complications . Our treatment armamentarium has expanded dramatically over the past 10 years , and we now have multiple biologic agents approved for the treatment of moderate - severe disease , in addition to conventional therapies such as 5 - aminosalicylates , thiopurines , and corticosteroids . In this review , we will provide a detailed discussion of the three tumor necrosis factor - alpha ( P01375 - α ) inhibitors currently approved for treatment of ulcerative colitis : infliximab , adalimumab , and DB06674 . All three agents are effective for inducing and maintaining clinical response and remission in patients with ulcerative colitis , and they have comparable safety profiles . There are no head - to - head trials comparing their efficacy , and the choice of agent is most often based on insurance coverage , route of administration , and patient preference . Combination therapy with an immunomodulator is proven to be more effective than anti - P01375 monotherapy , and patients who lose response to an anti - P01375 agent should undergo dose intensification in order to regain clinical response . Despite therapeutic optimization , a significant percentage of patients will not achieve clinical remission with anti - P01375 agents , and so newer therapies are on the horizon ."],"string":"[\n \"___MASK88___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"Effectiveness of infliximab , adalimumab and DB06674 for non - infectious refractory uveitis in adults . AIM : To discuss the available data regarding the off - label uses of anti - P01375 agents in non - infectious uveitis . DATA SOURCE : A literature search was performed in Medline through PubMed from January 2001 to January 2014 . STUDY SELECTION AND DATA EXTRACTION : English - language articles about uveitis treatment with anti - P01375 drugs in adult patients were reviewed . DATA SYNTHESIS : The use of anti - P01375 - Î ± drugs for treatment of several refractory manifestations of refractory uveitis in adult patients is increasing . However , due to the lack of evidence from randomized controlled trials , the use of anti - P01375 in uveitis remains â off - labelâ in most countries . There is no trial - based evidence to support it except for the experience provided by cases and case series . This experience , which is continuously increasing , has yielded encouraging results . Anti - P01375 - Î ± drugs , such as infliximab , adalimumab , and DB06674 , are reasonably effective for controlling ocular inflammation and sparing patients corticosteroid treatment in non - infectious refractory uveitis . Approximately 80 % of patients on infliximab , adalimumab , or DB06674 were able to achieve sustained control of inflammation by 6 months . CONCLUSION : Anti - P01375 - Î ± therapy is effective in inducing clinical remission for refractory uveitis , with a relatively low rate of treatment - ending adverse events . However , randomized and controlled trials are required to adequately assess the maintained clinical efficacy and safety profile in the long term of anti - P01375 agents for non - infectious refractory uveitis .\",\n \"Tuberculosis risk in patients treated with non - anti - tumor necrosis factor - α ( P01375 - α ) targeted biologics and recently licensed P01375 - α inhibitors : data from clinical trials and national registries . This review aimed to evaluate the risk of active tuberculosis ( TB ) occurrence in patients with rheumatic disorders receiving non - anti - tumor necrosis factor ( P01375 ) targeted biologics anakinra ( ANK ) , tocilizumab ( TCZ ) , rituximab ( RTX ) , abatacept ( ABA ) , and recently approved anti - P01375 DB06674 ( GOL ) , and certolizumab pegol ( P53007 ) . In recent findings , no cases of active TB were recorded in patients with rheumatoid arthritis ( RA ) and other rheumatic conditions treated with anti - P11836 + RTX and anti - P10747 ABA . No patient receiving anti - interleukin 1 ( IL - 1 ) ANK developed active TB , and an increased risk was excluded in a Canadian database . In contrast , 8 active TB cases were observed in 21 trials of patients with RA receiving anti - P05231 TCZ , while no increased TB risk resulted from Japanese postmarketing surveillance . Among GOL - treated and P53007 - treated patients , 8 and 10 active TB cases occurred , respectively , while no data are available from registries . However , all but 1 TB case recorded in patients treated with TCZ , GOL , and P53007 occurred in TB - endemic countries . No TB risk resulted for ANK , RTX , and ABA , suggesting pretreatment screening procedures for latent TB infection detection are unnecessary . Because all TB cases occurred in countries at high risk for TB , where TB exposure could have occurred during treatment , no definitive conclusions can be drawn for TCZ , GOL , and P53007 .\",\n \"Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .\",\n \"Elevation of P15941 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis : a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs . OBJECTIVE : The associations between elevated levels of serum P15941 ( P15941 ) and treatment of rheumatoid arthritis ( RA ) with tumor necrosis factor ( P01375 ) inhibitors were investigated in five Japanese clinical trials . METHODS : Percentages and incidence rates were calculated for elevated serum P15941 levels . Adverse events associated with elevated levels of serum P15941 were investigated . RESULTS : In RISING , a clinical trial for infliximab , 15 . 6 % of the enrolled patients met criterion B ( P15941 ≥ 500 U / ml and > 1 . 5 - fold increase over the baseline value ) by week 54 . In HIKARI , 7 . 8 % of the certolizumab pegol ( CZP ) group and 0 % of the placebo group met criterion B during the double - blind ( DB ) period ( p = 0 . 003 ) . In J - RAPID , 8 . 4 % of the methotrexate ( MTX ) + CZP and 3 . 9 % of the MTX + placebo groups met criterion B during the DB period . In GO - MONO , 1 . 8 % of the DB06674 ( GLM ) and 1 . 3 % of the placebo groups met criterion B during the DB period . In GO - FORTH , 7 . 1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period ( p = 0 . 017 ) . No adverse events accompanied the elevation of serum P15941 levels in 95 . 7 % of these patients . CONCLUSION : Serum P15941 levels may increase during anti - P01375 therapy without significant clinical events . In these patients , continuing treatment with P01375 inhibitors under careful observation is a reasonable option .\",\n \"[ New biologic and non biologic disease modifying anti - rheumatic drugs for rheumatoid arthritis ] . P01375 inhibitors , infliximab , etanercept and adalimumab , and tocilizumab are available in Japan and have been successful at improving the signs and symptoms of RA and , thereby , have set a new standard for disease control of RA and have the potential to protect joints from structural damage or to improve quality of life and mortality . However , the rate of successful induction of remission was about 30 % and the treatment strategies for the patients who do not respond to these biologics should be established . Randomized clinical trials targeting T or B lymphocytes have been conducted in addition to the new anti - P01375 blockers like DB06674 or certolizumab pegol . Anti - P11836 antibodies such as rituximab ( chimeric ) , ocrelizumab ( humanized ) , ofatuzumab ( full human ) demonstrated effectiveness to the patients who do not respond to P01375 blockers . P16410 Ig , which can transduce negative signal into T lymphocytes in the co - stimulatory pathway , has also showed a good response to refractory RA . Furthermore , low molecular agents such as Jak ( Janus kinase ) 3 or syk ( spleen tyrosine kinase ) inhibitors demonstrated rapid and strong suppression of synovitis and are thought to be new candidates for the drugs to overcome refractory RA .\",\n \"Biologic agents for rheumatoid arthritis : 2008 and beyond . Rheumatoid arthritis ( RA ) is a chronic disease with a complex underlying pathology and varied presentation in patients . Several novel biologic disease - modifying antirheumatic drugs have become available for the treatment of RA . Agents in late - stage clinical trials include DB06674 and certolizumab , which are anti - tumor necrosis factor ( P01375 ) - alpha agents ; ocrelizumab , an anti - P11836 agent ; and tocilizumab , an inhibitor of interleukin - 6 . As treatment options for RA expand , nursing care will play an increasingly important role in empowering patients through interventions such as patient education and adverse effect management .\",\n \"Treatment of psoriasis and psoriatic arthritis . Skin and joint manifestations associated with psoriasis and psoriatic arthritis ( PsA ) can significantly impact a patient ' s quality of life . Successful treatment is imperative in order to improve signs and symptoms of the disease , and to alleviate physical or psychological distress . For patients with mild psoriasis with or without PsA , topical agents and targeted phototherapy are appropriate treatments for psoriasis . Systemic therapies , such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis , but their long - term use is hindered by safety concerns . Advancements in understanding the pathogenesis of psoriasis , including the role of T cells and cytokines , have been crucial to the development of biological therapies . These target the immune system and are suitable options for patients with extensive disease . Biological therapies for the treatment of psoriasis include targeted therapies ( alefacept ) and anti - cytokine therapies ( anti - tumour necrosis factor [ P01375 ] therapies [ adalimumab , etanercept , infliximab ] and a monoclonal antibody against interleukin [ IL ] - 12 and IL - 23 [ ustekinumab ] ) . Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage . Non - steroidal anti - inflammatory drugs or local intra - articular injections of corticosteroids can be used successfully in patients with mild PsA ; however , neither treatment prevents the development of structural joint damage . For patients with moderate to severely active PsA , disease - modifying antirheumatic drugs ( such as methotrexate ) , P01375 inhibitor treatments ( adalimumab , etanercept , infliximab and DB06674 ) or their combination are considered first - line treatment . This review provides a brief overview of treatment options for psoriasis and PsA , with an emphasis on the efficacy and safety of anti - P01375 therapies .\",\n \"Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .\",\n \"Golimumab and malignancies : true or false association ? Malignancy is one of the comorbidities linked to DB06674 , a biological P01375 - α blocker . In this systematic review and meta - analysis , we searched different databases and analyzed original publications to elucidate the remaining open question about the real association of malignancies with DB06674 therapy . The most frequent cancer in patients treated with DB06674 , in association or not with methotrexate , is the lung adenocarcinoma . However , lymphoma is not very commonly represented in these patients . We show that there is no major and evident risk of malignancies associated with DB06674 in current scientific literature . An increased risk of malignancies may be associated with DB06674 , but this warrants further clinical confirmation . Also , this risk mentioned in different studies must be taken with caution because of number of limits and biases .\",\n \"Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK70___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .\",\n \"Tumor necrosis factors blocking agents : analogies and differences . Five anti - P01375 agents , infliximab , adalimumab , etanercept , DB06674 and certolizumab pegol are approved worldwide for the treatment of RA . Anti - P01375 agents , bind to and neutralize soluble P01375 , but exert different effects on transmembrane P01375 - expressing cells ( P01375 - producing cells ) . Differences on affinity and avidity for soluble and transmembrane P01375 were showed . Different activity on cells apoptosis , complement - dependent cytotoxicity ( CDC ) antibody dependent cell - mediated cytotoxicity ( Q15848 ) were described . Some dramatic changes in gene expression were seen with all the anti - TNFs . Reviewing the biology of transmembrane P01375 and its interaction with anti - P01375 agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities .\",\n \"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .\",\n \"P01375 inhibitors in asthma and P48444 : we must not throw the baby out with the bath water . P01375 ( P01375 ) - alpha , a pleiotropic cytokine that exerts a variety of effects , such as growth promotion , growth inhibition , angiogenesis , cytotoxicity , inflammation , and immunomodulation , has been implicated in several inflammatory conditions . It plays a significant role in many inflammatory diseases of lungs . Given that there is significant literature supporting the pathobiologic role of P01375 in asthma , mainly in severe refractory asthma , and P48444 , P01375 inhibitors ( infliximab , DB06674 and etanercept ) are now regarded as the potential new medications in asthma and P48444 management . The studies reported in literature indicate that P01375 inhibitors are effective in a relatively small subgroup of patients with severe asthma , possibly defined by an increased P01375 axis , but they seem to be ineffective in P48444 , although an observational study demonstrated that P01375 inhibitors were associated with a reduction in the rate of P48444 hospitalisation among patients with P48444 receiving these agents to treat their rheumatoid arthritis . These findings require a smart approach because there is still good reason to target P01375 , perhaps in a more carefully selected patient group . P01375 treatment should , therefore , not be thrown out , or abandoned . Indeed , since severe asthma and P48444 are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them , it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from P01375 inhibitors .\",\n \"Q9UKU7 : Golimumab in ulcerative colitis : a ' ménage à trois ' of drugs . Golimumab , a human anti - P01375 antibody , is effective in patients with ulcerative colitis , according to new findings from an international phase III double - blind trial . The addition of this drug makes a ménage à trois of available drugs -- comprising infliximab , adalimumab and DB06674 -- for the treatment of ulcerative colitis .\",\n \"Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .\",\n \"Efficacy and safety of P01375 - α inhibitors in refractory primary complex aphthosis : a patient series and overview of the literature . BACKGROUND : Otherwise healthy patients with severe recurrent mucocutaneous aphthous ulcerations ( complex aphthosis ) may require systemic immunomodulatory therapy . However , a subset of patients remain resistant or intolerant to recommended therapeutic agents . Recently , case reports have described that tumor necrosis factor - α ( P01375 - α ) inhibitors may induce remission in these patients . METHODS : Data on efficacy and safety of various P01375 - α inhibitors used as monotherapy in a case series of 18 patients with refractory primary complex aphthosis are presented . RESULTS : A total of 16 patients ( 89 % ) obtained complete or almost clearance of orogenital aphthous ulcerations rapidly after onset of therapy either with etanercept , adalimumab , infliximab or DB06674 . Duration of treatment ranged between 3 and 77 months . Nine patients ( 50 % ) received more than one P01375 - α inhibitor during the course of treatment . Five ( 28 % ) patients experienced side effects that could be related to treatment with P01375 - α inhibitors . CONCLUSION : P01375 - α inhibitors are an effective and safe treatment option for patients with severe complex aphthosis who do not respond sufficiently to standard therapy as recommended by existing guidelines . However , the final position of P01375 - α inhibitors in the therapeutic armamentarium awaits randomized controlled trials .\",\n \"Off - label uses of anti - P01375 therapy in three frequent disorders : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system . Thus , its blockade with the so - called anti - P01375 agents ( infliximab , etanercept , adalimumab , certolizumab pegol , and DB06674 ) has turned into the most important tool in the management of a variety of disorders , such as rheumatoid arthritis , spondyloarthropatties , inflammatory bowel disease , and psoriasis . Nonetheless , theoretically , some other autoimmune disorders may benefit from these agents . Our aim is to review these off - label uses of anti - P01375 blockers in three common conditions : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders , this review is mainly based on case reports and case series .\",\n \"Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \\\" nongenomic \\\" pathway which , is clearly discernable from the classical , \\\" genomic \\\" action pathway of the P35869 by not requiring the participation of P27540 .\",\n \"P01375 inhibitors in psoriasis : an update . Three inhibitors of tumor necrosis factor ( P01375 ) currently are approved for the treatment of psoriasis : etanercept , infliximab , and adalimumab . The other two P01375 inhibitors , DB06674 and certolizumab pegol , have shown efficacy against plaque psoriasis in clinical trials of psoriatic arthritis ( PsA ) . This article reviews the most recent evidence on the efficacy and safety of the P01375 inhibitors in psoriasis , with special attention to preventing and managing immunogenicity .\",\n \"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .\",\n \"Current , new and future biological agents on the horizon for the treatment of inflammatory bowel diseases . Biological agents for inflammatory bowel diseases ( Q9UKU7 ) targeting tumor necrosis factor ( P01375 ) have changed the way to treat Q9UKU7 refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission . A better understanding of the components of the pathological processes that are a hallmark of Q9UKU7 has led to the development of a new family of biological agents in Crohn ' s disease and ulcerative colitis . Biosimilars , which are copy versions of currently licensed biological agents , will be soon available . The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions , while a new anti - P01375 agent , namely DB06674 , has been recently approved for refractory ulcerative colitis . Beyond P01375 blockers , anti - adhesion molecules appear to be a potent drug class for Q9UKU7 . DB09033 was recently approved for both Crohn ' s disease and ulcerative colitis . Numerous other compounds are in the pipeline . Ustekinumab looks very promising for Crohn ' s disease . O15105 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials . Herein , we review the efficacy and safety of new and emerging biological agents that are currently investigated in Q9UKU7 clinical trials .\",\n \"Biologic therapies in the treatment of psoriasis : a comprehensive evidence - based basic science and clinical review and a practical guide to tuberculosis monitoring . The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab , etanercept , adalimumab , efalizumab , DB06674 , certolizumab , alefacept , secukinumab , abatacept , and ustekinumab . These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications . Herein , we present a comprehensive , unbiased comparison of these medications focusing on their differences . For example , P01375 antagonists can differ in the way they are dissolved and administered , the effector molecules they can bind , serum peak and trough levels , the types of intracellular signals they can induce , the in vivo complexes that they can form , their protein structure , and their incidence and timing of rare adverse events , among other things . A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head - to - head comparison trials . The safety of biologics in terms of their long - term adverse events is discussed , as is their use in different types of psoriasis and in different patient populations . Finally , all anti - P01375 agents have been associated with a variety of serious and \\\" routine \\\" opportunistic infections , particularly tuberculosis . For this reason , anti - tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent . The uses and limitations of both the tuberculin skin test ( Q16762 ) and QuantiFeron ®- TB Gold ( QFT ) are discussed , as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy . Recommendations for tuberculosis monitoring are provided .\",\n \"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK56___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .\",\n \"Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .\",\n \"Safety of anti - P01375 therapy in inflammatory bowel disease during pregnancy . INTRODUCTION : The highest incidence of inflammatory bowel disease ( Q9UKU7 ) is seen between the second and fourth decades of life , which is the most fertile age for women . Increased disease activity has been shown to effect female fertility and pregnancy outcomes , stressing the need for drugs that can safely induce and maintain clinical remission without harming either the mother or fetus . AREAS COVERED : Anti - P01375 - α agents have been shown to be effective in both inducing and maintaining remission among Q9UKU7 patients . This review highlights the results of previous studies conducted on pregnant women who were exposed to anti - P01375 - α agents during the course of their pregnancy . The drugs reviewed include infliximab ( IFX ) , adalimumab ( P00813 ) , certolizumab pegol ( CZP ) and DB06674 ( GMB ) . Of > 200 articles reviewed , 105 were included in the manuscript based on relevance . The keywords used were anti - P01375 , infliximab , adalimumab , certolizumab , DB06674 , biologics , pregnancy and inflammatory bowel disease . EXPERT OPINION : Anti - P01375 agents have been studied extensively during pregnancy from the early case reports to the more recent prospective Pregnancy in Q9UKU7 and Neonatal Outcomes study . A comprehensive review of the literature has shown that biologics can be safely used during pregnancy . In view of this safety data , it is recommended to maintain therapy during pregnancy .\",\n \"Synergism between bosutinib ( ___MASK92___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .\",\n \"Safety and clinical efficacy of DB06674 in the treatment of arthritides . Golimumab is a human anti - tumor necrosis factor ( P01375 ) - alpha monoclonal antibody that was recently approved for the treatment of patients with rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . This review covers the published clinical trial data on the use of DB06674 for the approved indications mentioned above with respect to efficacy and safety . The various ongoing trials for DB06674 have yielded promising results in terms of efficacy and safety in methotrexate - naive and - resistant patients with rheumatoid arthritis , as well as in patients who were previously treated with other anti - P01375 agents . In addition , the efficacy of DB06674 in psoriatic arthritis and ankylosing spondylitis has also been demonstrated . The real safety information will be available only once the drug has been used in many more patients , who frequently have comorbid conditions .\",\n \"New therapies in the management of rheumatoid arthritis . PURPOSE OF REVIEW : The therapeutic landscape in the management of rheumatoid arthritis ( RA ) has witnessed significant changes over the past decade . The ambition to improve outcomes further , minimize safety concerns and provide more convenient means of administration are all factors that continue to drive continued drug development . This review summarizes novel therapies that have been most recently under investigation . RECENT FINDINGS : More refined drug technology has seen the development of subcutaneous forms of existing therapies ( abatacept , tocilizumab ) , as well as newer - generation monoclonal antibodies ( e . g . B - cell - depleting agents , ocrelizumab and ofatumumab and the P01375 - inhibitors certolizumab and DB06674 ) . Alternative methods of targeting critical pathways , for example Blys inhibition ( atacicept ) and P05231 as opposed to P05231 receptor antagonism , have also been evaluated . Finally , small molecules are receiving increasing attention , with some of the protein kinases inhibitors particularly promising . SUMMARY : The new emerging therapies for the management of RA illustrate much diversity , in terms of both drug technology as well as the immunological target . Although not all may succeed in reaching the market , important insights can still be gained . Challenging and exciting times lie ahead as these new technologies are embraced and efforts are made to determine how best to implement in practice .\",\n \"Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 .\",\n \"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK2___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .\",\n \"Dermatologic adverse events : DB06674 , friend or foe ? Golimumab is a fully human anti - P01375 blocker that has demonstrated its efficacy in the treatment of numerous kinds of diseases . Although it is generally safe and well tolerated , various adverse events have been reported . The present aim is to improve the understanding of dermatologic adverse events associated with DB06674 following a search of various scientific databases . This systematic review and meta - analysis shows that DB06674 is associated neither with severe injection - site reactions nor with injection - site erythema . We found no significant lupus - like syndromes , and no significant skin squamous cell carcinoma . We further suggest systematic dermatologic monitoring in clinical practice during DB06674 therapy . Subsequent research should employ a larger cohort of patients to ensure clear and significant future conclusions .\",\n \"___MASK22___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK22___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .\",\n \"Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .\",\n \"Miscellaneous adverse events with biologic agents ( excludes infection and malignancy ) . Anti - tumor necrosis factor - α ( anti - P01375 ) agents are frequently used in the treatment of inflammatory bowel disease ( Q9UKU7 ) . Currently , there are 4 anti - P01375 therapies that are Food and Drug Administration - approved for moderate to severe Q9UKU7 : infliximab , adalimumab , DB06674 , and certolizumab pegol . For most noninfectious , nonmalignant adverse events , cessation of anti - P01375 therapy typically leads to improvement or resolution of drug - induced complications . In this article , the current knowledge regarding the noninfectious and nonmalignant toxicities associated with anti - P01375 agents is summarized .\",\n \"Psoriatic arthritis : treatment strategies using biologic agents . The traditional management of psoriatic arthritis ( PsA ) includes NSAIDs , corticosteroids and DMARDs . Advancement in the knowledge of the immunopathogenesis of PsA has been associated with the development of biologic agents which have revolutionized the management of the disease . Among biologics drugs , there are the 4 currently available anti - TNFα blocking agents ( etanercept , infliximab , adalimumab and DB06674 ) which are more effective than traditional DMARDs on symptoms / signs of inflammation , quality of life , function , and in inhibiting the progression of the structural joint damage . Despite of the high cost , P01375 inhibitors are cost - effective on both the musculoskeletal and skin manifestations of psoriatic disease .\",\n \"Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .\",\n \"P01375 - alpha antagonists : differential clinical effects by different biotechnological molecules . Inhibitors of tumor necrosis factor - alpha have deeply changed the therapy of several inflammatory human diseases . For instance , clinical management of rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools , such as antagonist of P01375 molecule . These drugs include etanercept , a soluble P01375 receptor antagonist , three anti - P01375 antibodies , adalimumab , infliximab , DB06674 and certolizumab a humanized Fab fragment combined with polyethylene glycol . These compounds efficiently inhibit several P01375 biological - mediated effects , however , they have also shown differential clinical efficacy in several trials from different autoimmune diseases . It is of clinical relevance that non - responders to one of these drugs often positively responded to another . Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects . However , partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses . Therefore , these apparently homogeneous agents can not be considered equivalent in their clinically efficacy . Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual P01375 inhibitors .\",\n \"Treatment of ankylosing spondylitis with P01375 blockers : a meta - analysis . Biological agents directed against tumor necrosis factor ( P01375 ) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non - steroidal anti - inflammatory drugs . To evaluate the efficacy and safety of the anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , and certolizumab for the treatment of ankylosing spondylitis , we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE , MEDLINE , Cochrane Controlled Trials Register and LILACS databases ( September / 2012 ) , manual literature search , and the gray literature . Study selections and data collection were performed by two independent reviewers , with disagreements solved by a third reviewer . The following outcomes were evaluated : ASAS 20 response , disease activity , physical function , vertebral mobility , adverse events , and withdraws . The meta - analysis was performed using the Review Manager (®) 5 . 1 software by applying the random effects model . Eighteen studies were included in this review . No study of certolizumab was included . Patients treated with anti - P01375 agents were more likely to display an ASAS 20 response after 12 / 14 weeks ( RR 2 . 21 ; 95 % CI 1 . 91 ; 2 . 56 ) and 24 weeks ( RR 2 . 68 ; 95 % CI 2 . 06 ; 3 . 48 ) compared with controls , which was also true for several other efficacy outcomes . Meta - analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks . DB00051 , infliximab , etanercept , and DB06674 can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis . Safety outcomes deserve further study , especially with respect to long - term follow - ups .\",\n \"Selective P01375 - α inhibitor - induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 - α is a pro - inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune - mediated or inflammatory diseases . P01375 - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long - term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .\",\n \"Golimumab in uveitis previously treated with other anti - P01375 drugs : a retrospective study of three cases from a single centre and literature review . OBJECTIVES : The aim of this paper is to assess the clinical response to DB06674 ( GLM ) in patients with non - infectious uveitis from a single centre that had previously been treated with other anti - P01375 - α drugs . METHODS : A retrospective chart review was carried out of patients with immune - mediated uveitis refractory to standard synthetic immunosuppressive drugs who were treated with GLM at Hospital Universitario Marqués de Valdecilla , Santander ( Spain ) . Patients were included in this study if they had previously been treated with other anti - P01375 - α drugs . A literature review of patients with immune - mediated uveitis undergoing GLM therapy was conducted . RESULTS : Three patients ( 2 men and 1 woman ) were included in this study . Two of them were refractory to other anti - P01375 - α drugs . The median age of patients was 26 years ( range 20 - 42 ) . Uveitis was bilateral in two patients . The underlying diseases were uveitis associated with HLA - Q8TCY5 and psoriasis in one case and sarcoidosis in the other two cases . Improvement of the main ocular parameters following GLM therapy was achieved in all cases . After a median follow - up of 3 ( range 1 - 9 ) months using GLM therapy , none of the patients had experienced new relapses of uveitis . None of them had side effects during treatment with this drug . A literature review disclosed that our observations were in keeping with other reports that showed good response to GLM in 13 of 16 patients with immune - mediated uveitis refractory to other biologic agents . CONCLUSIONS : Although the follow - up was too short in our series , GLM could be an effective and safe therapy for the management of patients with uveitis previously treated with other anti - P01375 - α drugs .\",\n \"NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .\",\n \"The use of biologic therapies in the treatment of rheumatoid arthritis . The use of biologic agents has revolutionized the management of rheumatoid arthritis ( RA ) in the past two decades . These biologic agents directly target molecules and cells involved in the pathogenesis of RA . Biologic agents indeed lead to a better prognosis and clinical remission in patients with RA , especially in patients who are not well - controlled with traditional disease - modifying anti - rheumatic drugs ( DMARDs ) . Currently , five P01375 inhibitors ( infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol ) , an P05231 receptor antagonist ( tocilizumab ) , an IL - 1 receptor antagonist ( anakinra ) , a B cell depleting agent ( rituximab ) and a T cell co - stimulation inhibitor ( abatacept ) have been approved for the treatment of RA . With the increased understanding of the pathogenic mechanisms of RA and advantages in manufacturing biotechnology of pharmaceutical companies , a series of novel biologic therapeutic approaches are being developed . In the present paper , we will summarize the biologic agents currently available to treat RA , and the prospective biologic therapies that might be used in the management of RA in future .\",\n \"Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK23___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK23___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK23___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK23___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .\",\n \"The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD ) 80 / anti - P42081 fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non - neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .\",\n \"___MASK22___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .\",\n \"Apoptosis and the FLIP and NF - kappa B proteins as pharmacodynamic criteria for biosimilar P01375 antagonists . Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale . The imminent expiration of the patents on reference biological products which block the cytokine P01375 - α ( tumor necrosis factor - α ) raises the possibility of bringing so - called biosimilars to the market ( similar to the biologicals of reference products ) . This occurrence is inevitable , but criteria to adequately evaluate these medications are now needed . Even among controversy , there is a demand from publications correlating the pro - apoptotic mechanism of the original P01375 - α antagonists ( etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) in the treatment of rheumatoid arthritis and other diseases . In this article , the authors discuss the possibility of utilizing the pro - apoptotic effect correlated with the regulation of the anti - apoptotic proteins FLIP and NF - κB as new criteria for analyzing the pharmacodynamics of possible biosimilar P01375 - α antagonists which should be submitted to regulatory agencies for evaluation .\",\n \"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .\",\n \"One target , different effects : a comparison of distinct therapeutic antibodies against the same targets . To date , more than 30 antibodies have been approved worldwide for therapeutic use . While the monoclonal antibody market is rapidly growing , the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders . Moreover , antibodies against only five targets ( P01375 - α , P04626 , P11836 , P00533 , and P15692 ) account for more than 80 percent of the worldwide market of therapeutic antibodies . The shortage of novel , clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets , based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another . For example , four antibodies against P01375 - α have been approved by the FDA -- infliximab , adalimumab , DB06674 , and certolizumab pegol -- with many more in clinical and preclinical development . The situation is similar for P04626 , P11836 , P00533 , and P15692 , each having one or more approved antibodies and many more under development . This review discusses the different binding characteristics , mechanisms of action , and biological and clinical activities of multiple monoclonal antibodies against P01375 - α , HER - 2 , P11836 , and P00533 and provides insights into the development of therapeutic antibodies .\",\n \"DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .\",\n \"Can we reduce the dosage of biologics in spondyloarthritis ? P01375 blockers have revolutionized the management of spondyloarthritis ( SpA ) . To date , four anti - TNFα agents ( etanercept , infliximab , adalimumab , DB06674 ) have been approved for the management of ankylosing spondylitis ( AS ) and psoriatic arthritis ( PsA ) . The first objective in the management of AS and PsA with P01375 inhibitors is to reduce disease activity to clinical remission or low disease activity . After remission has been achieved , this state should be maintained as long as possible . However , the financial burden associated with the cost of anti - P01375 agents as well as concerns about their long - term safety suggest reducing the dosage of the drug or discontinuing the therapy in the hopes of drug - free remission . The aim of this review is to examine what has , till now , been published on this topic in axial SpA , which includes AS and non - radiographic axial SpA ( nr - axSpA ) , peripheral SpA and PsA . Discontinuation of therapy in axial SpA is not possible in the majority of patients , while on the contrary , reducing the dosage often is . In some patients with peripheral SpA and PsA it is also possible to discontinue therapy and to achieve drug - free remission .\",\n \"Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .\",\n \"P01375 inhibitors - state of knowledge . P01375 ( P01375 ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 inhibitors in modern therapy . The main safety aspects of P01375 inhibitor administration are described in particular , with special consideration of the available meta - analyses . Finally , perspectives on the next - generation P01375 inhibitors and their use in the clinic are given .\",\n \"___MASK22___ antagonizes P01375 induction of P19320 on endothelial cells by inhibiting mTORC2 . Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells ( ECs ) . Here we report that rapamycin pretreatment reduced the ability of P01375 - treated ECs to capture T cells under conditions of venular flow . This functional change was caused by inhibition of P01375 - induced expression of vascular cell adhesion molecule - 1 ( P19320 ) and could be mimicked by knockdown of mammalian target of rapamycin ( P42345 ) or rictor , but not raptor , implicating mTORC2 as the target of rapamycin for this effect . Mechanistically , mTORC2 acts through Akt to repress Raf1 - Q02750 / 2 - P27361 / 2 signaling , and inhibition of mTORC2 consequently results in hyperactivation of P27361 / 2 . Increased P27361 / 2 activity antagonizes P19320 expression by repressing P01375 induction of the transcription factor P10914 . Preventing activation of P27361 / 2 reduced the ability of rapamycin to inhibit P01375 - induced P19320 expression . In vivo , rapamycin inhibited mTORC2 activity and potentiated activation of P27361 / 2 . These changes correlated with reduced endothelial expression of P01375 - induced P19320 , which was restored via pharmacological inhibition of P27361 / 2 . Functionally , rapamycin reduced infiltration of leukocytes into renal glomeruli , an effect which was partially reversed by inhibition of P27361 / 2 . These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target .\",\n \"Pharmacology of P01375 blockade in rheumatoid arthritis and other chronic inflammatory diseases . P01375 - alpha ( P01375 ) has been unequivocally validated as a therapeutic target in a number of immune - mediated inflammatory disorders ( IMIDs ) . There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF . But approaches to P01375 inhibition differ and currently include mAbs ( infliximab , adalimumab , and DB06674 ) , either chimeric or human in sequence , a PEGylated Fab ' fragment ( certolizumab ) , and an IgG1 - P20333 fusion protein ( etanercept ) . It is emerging that the pharmacological properties of these three anti - P01375 subtypes differ with respect to Fc function , binding of tmTNF and the possible consequences of this , as well as the ability to form complexes . The mode of administration of each agent , clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety .\",\n \"___MASK30___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK30___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .\",\n \"Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .\",\n \"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK35___ and Tissue P00747 Activator in Occluded Arteries .\",\n \"Effect of interferon - gamma and P01375 on P15941 mucin expression in ovarian carcinoma cell lines . In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment , a study was designed to investigate whether the biological response modifiers interferon - gamma ( P01579 ) and tumour necrosis factor - alpha ( P01375 ) could effect the expression of an epitope on the tumour associated P15941 epithelial mucin . Four ovarian carcinoma cell lines showing high ( OAW42 and GG ) and low ( JAM and PE01 ) basal expression of P15941 were treated with 10 - 1000 U / mL of P01579 or P01375 for one or five days . Changes in P15941 expression in cells exposed to P01579 or P01375 were monitored using an ELISA technique with the monoclonal antibody O43633 which reacts with a core protein epitope on the P15941 mucin , and then corrected for the number of viable cells present . P01375 had little effect on P15941 expression , but one or five days exposure to P01579 significantly increased P15941 expression ( p < 0 . 01 ) in all cell lines including the two cell lines that initially showed little or no expression .\",\n \"Spondyloarthritides . The most important clinical features of the spondyloarthritides ( SpA ) are not only inflammatory back pain ( Q9H4E7 ) but also peripheral ( enthesitis ) and extra - articular symptoms . For clinical purposes , two forms related to the predominant clinical manifestation - axial and peripheral SpA - and five subgroups - ankylosing spondylitis ( AS ) , SpA associated with psoriasis and inflammatory bowel disease ( Q9UKU7 ) , reactive arthritis and undifferentiated SpA - are differentiated . Axial SpA including AS is the most frequent subtype of SpA , followed by psoriatic arthritis and undifferentiated SpA , while reactive arthritis and Q9UKU7 - related SpA are less frequent . The prevalence of SpA has been shown to be similar to rheumatoid arthritis . The outcome of the disease is influenced by the degree of disease activity over time , which is mainly related not only to inflammation but also on the structural damage ( new bone formation ) that occurs over time . Treatment options for patients with SpA have been limited for decades . Non - steroidal anti - inflammatory agents are currently considered first choice , since they have shown good amelioration of symptoms in SpA patients especially when suffering by the typical symptom of Q9H4E7 . Furthermore , there is a clear role for regular physiotherapy in AS to prevent loss of spinal mobility . For patients who have insufficiently responded to conventional therapies , four anti - tumour necrosis factor ( P01375 ) agents are available and are approved for the treatment of patients with active AS : infliximab , etanercept , adalimumab and DB06674 . As far as it stands now , P01375 blockers seem to have no influence on new bone formation in AS .\",\n \"New treatments for inflammatory rheumatic disease . As our understanding of the pathogenesis of autoimmune diseases is growing , new therapies are being developed to target disease - specific pathways . Since the introduction of etanercept in 1998 , several biotechnological agents have been developed , most of them indicated in the treatment of rheumatoid arthritis , but also psoriatic arthritis . Most currently available molecules target P01375 - alfa with different strategies ( i . e . , etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) , P05231 ( tocilizumab ) , P16410 ( abatacept ) , and B cells ( rituximab , belimumab ) as they are key mediators in the cascade of inflammation . Further , small molecules have been recently developed to target intracellular signaling , such as Janus Kinases for tofacitinib , the first FDA - approved small molecule for rheumatoid arthritis . Most novel treatments are being developed for arthritis with specific differences between rheumatoid and psoriatic arthritis , as well as for systemic lupus erythematosus , following the approval of belimumab . Finally , biologic therapies are effective also in gout , mainly targeting interleukin - 1 to block the inflammasome . This review article describes the new and upcoming treatment options for rheumatoid arthritis , psoriatic arthritis , systemic lupus erythematosus , and gout to dissect what we should be aware of when discussing these new and promising molecules .\",\n \"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK70___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK70___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .\",\n \"Biologics in the management of ulcerative colitis - comparative safety and efficacy of P01375 - α antagonists . Ulcerative colitis can cause debilitating symptoms and complications such as colonic strictures , colonic dysplasia , colorectal cancer , and toxic megacolon or perforation . Goals of treatment in ulcerative colitis include resolution of gastrointestinal symptoms , healing of colonic mucosa , and prevention of disease complications . Our treatment armamentarium has expanded dramatically over the past 10 years , and we now have multiple biologic agents approved for the treatment of moderate - severe disease , in addition to conventional therapies such as 5 - aminosalicylates , thiopurines , and corticosteroids . In this review , we will provide a detailed discussion of the three tumor necrosis factor - alpha ( P01375 - α ) inhibitors currently approved for treatment of ulcerative colitis : infliximab , adalimumab , and DB06674 . All three agents are effective for inducing and maintaining clinical response and remission in patients with ulcerative colitis , and they have comparable safety profiles . There are no head - to - head trials comparing their efficacy , and the choice of agent is most often based on insurance coverage , route of administration , and patient preference . Combination therapy with an immunomodulator is proven to be more effective than anti - P01375 monotherapy , and patients who lose response to an anti - P01375 agent should undergo dose intensification in order to regain clinical response . Despite therapeutic optimization , a significant percentage of patients will not achieve clinical remission with anti - P01375 agents , and so newer therapies are on the horizon .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK22___","___MASK23___","___MASK2___","___MASK30___","___MASK35___","___MASK56___","___MASK70___","___MASK88___","___MASK92___"],"string":"[\n \"___MASK22___\",\n \"___MASK23___\",\n \"___MASK2___\",\n \"___MASK30___\",\n \"___MASK35___\",\n \"___MASK56___\",\n \"___MASK70___\",\n \"___MASK88___\",\n \"___MASK92___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK23___"},"id":{"kind":"string","value":"MH_train_87"}}},{"rowIdx":88,"cells":{"query":{"kind":"string","value":"interacts_with DB00831?"},"supports":{"kind":"list like","value":["Suppressed Ca2 +/ P62158 / CaMKII - dependent K ( DB00171 ) channel activity in primary afferent neurons mediates hyperalgesia after axotomy . Painful axotomy decreases K ( DB00171 ) channel current ( IK ( DB00171 ) ) in primary afferent neurons . Because cytosolic Ca ( 2 +) signaling is depressed in injured dorsal root ganglia ( Q86YR7 ) neurons , we investigated whether Ca ( 2 +)- calmodulin ( P62158 ) - Ca ( 2 +)/ P62158 - dependent kinase II ( CaMKII ) regulates IK ( DB00171 ) in large Q86YR7 neurons . Immunohistochemistry identified the presence of K ( DB00171 ) channel subunits Q09428 , SUR2 , and Kir6 . 2 but not Kir6 . 1 , and pCaMKII in neurofilament 200 - positive Q86YR7 somata . Single - channel recordings from cell - attached patches revealed that basal and evoked IK ( DB00171 ) by ionomycin , a Ca ( 2 +) ionophore , is activated by CaMKII . In axotomized neurons from rats made hyperalgesic by spinal nerve ligation ( Q16658 ) , basal K ( DB00171 ) channel activity was decreased , and sensitivity to ionomycin was abolished . Basal and Ca ( 2 +)- evoked K ( DB00171 ) channel activity correlated inversely with the degree of hyperalgesia induced by Q16658 in the rats from which the neurons were isolated . Inhibition of IK ( DB00171 ) by glybenclamide , a selective K ( DB00171 ) channel inhibitor , depolarized resting membrane potential ( O94763 ) recorded in perforated whole - cell patches and enhanced neurotransmitter release measured by amperometry . The selective K ( DB00171 ) channel opener diazoxide hyperpolarized the O94763 and attenuated neurotransmitter release . Axotomized neurons from rats made hyperalgesic by Q16658 lost sensitivity to the myristoylated form of autocamtide - 2 - related inhibitory peptide ( AIPm ) , a pseudosubstrate blocker of CaMKII , whereas axotomized neurons from Q16658 animals that failed to develop hyperalgesia showed normal IK ( DB00171 ) inhibition by AIPm . AIPm also depolarized O94763 in control neurons via K ( DB00171 ) channel inhibition . Unitary current conductance and sensitivity of K ( DB00171 ) channels to cytosolic DB00171 and ligands were preserved even after painful nerve injury , thus providing opportunities for selective therapeutic targeting against neuropathic pain .","Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2 + , calmodulin , DB02527 , the catalytic subunit of DB02527 - dependent protein kinase ( CSU ) and some Ca2 + antagonists were studied in chemically ( Triton X - 100 ) skinned coronary smooth muscle . P62158 increased the Ca2 + responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half - maximal activating Ca2 + concentration . DB00831 , a calmodulin antagonist , inhibited Ca2 +- calmodulin - induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2 + concentration . DB08980 , a Ca2 +- antagonist , at 2 x 10 (- 4 ) M produced a significant inhibitory effect , which was reduced by increasing the Ca2 + concentration . From other Ca2 + antagonists tested , W - 7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2 + , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle .","P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK80___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .","Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK10___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK10___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .","___MASK13___ : kinetic and dynamic profile in the treatment of pain . ___MASK13___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK13___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK13___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK13___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .","Endothelins stimulate sodium uptake into rat brain capillary endothelial cells through endothelin A - like receptors . The effect of endothelins ( ETs ) on sodium / hydrogen ( Na +/ H + ) antiport system was examined in cultured rat brain capillary endothelium ( RBEC ) . ET - 1 , P20800 , and P14138 stimulated Na + uptake into RBEC with similar half - maximal stimulation ( EC50 ) values ( 0 . 7 , 0 . 6 , and 1 . 1 nM , respectively ) . This reaction was inhibited by the Na +/ H + antiport inhibitor , N -( ethyl - N - isopropyl )- amiloride ( EIPA ) . The selective endothelin A ( P25101 ) receptor - antagonist ( cyclo - D - DB00150 - D - DB00128 - Pro - D - DB00161 - DB00149 ( BQ123 ) ) , but not endothelin B ( ETB ) receptor - antagonists ( ( Cys11 , Cys15 ) - ET - 1 ( IRL1038 ) or N - cis - 2 , 6 - dimethylpiperidinocarbonyl - L - gamma MeLeu - D - DB00150 ( COOMe )- D - Nle - ONa ( BQ788 ) ) , inhibited both ET - 1 - and P14138 - stimulated Na + uptake , indicating P25101 - receptor mediation . The protein kinase C ( PKC ) activator ( phorbol 12 - myristate 13 - acetate ( PMA ) ) failed to stimulate Na + uptake . The calcium - calmodulin ( P62158 ) inhibitor ( W7 ) reduced ET - 1 - stimulated Na + uptake by 50 % , whereas the PKC inhibitor ( staurosporine ) had no effect , indicating that ET - 1 stimulation of the Na +/ H + antiport system is linked to a P62158 - dependent and PKC - independent pathway .","___MASK69___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK69___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK69___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .","Resistance of P04626 / neu - overexpressing tumor targets to lymphokine - activated - killer - cell - mediated lysis : evidence for deficiency of binding and post - binding events . P04626 / neu - overexpressing tumor cell lines are relatively resistant to lymphokine - activated killer ( Q96QP1 ) cell cytotoxicity when compared to P04626 / neu - nonexpressing lines . P04626 / neu + targets were also resistant to binding by Q96QP1 large granular lymphocytes ( LGL ) as shown by visualization at the single - cell level , a target monolayer binding assay and in \" cold \" target inhibition experiments . P04626 / neu + Q96QP1 - resistant ovarian cell lines demonstrated an absence of P05362 expression while expression of LFA - 3 , N - P62158 , laminin and beta 1 integrins was comparable to that of P04626 / neu - targets . In contrast , the P04626 / neu + breast cell line , SKBR - 3 , which was also resistant to lysis and binding by Q96QP1 LGL , demonstrated normal expression of P05362 . Anti - P05362 antibodies blocked binding and lysis of P04626 / neu - carcinoma targets by Q96QP1 cells , further supporting the notion that lack of P05362 expression on P04626 / neu + cells contributes to their resistance . The modest binding and lysis of P04626 / neu + targets by Q96QP1 cells was significantly inhibited by anti - LFA - 1 antibodies , suggesting the existence of another counter - receptor for LFA - 1 on P04626 / neu + targets . The following also supported deficiencies in post - binding events when P04626 / neu + cells resisted the lytic activity of Q96QP1 cells : ( a ) when the relative resistance to effector cell binding was overcome by exogenous lectin . P04626 / neu + cell lines were still resistant to Q96QP1 cytolysis , and ( b ) P04626 / neu + targets were resistant to perforin - containing granule extracts obtained from the CTLL - R8 cytotoxic lymphocyte cell line . These results indicate that deficiency in effector binding as well as post - binding events contributes to the resistance of P04626 / neu - overexpressing tumor targets to Q96QP1 - cell - mediated lysis .","Bioassay - guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F . cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen ' s egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay - guided fractionation from F . cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S - 180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S - 180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi - target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment .","___MASK8___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK8___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .","[ P62158 - dependent regulation of Ca , Mg - ATPase activity in plasma membranes of the swine myometrium ] . Highly purified plasma membrane ( PM ) preparations of pig myometrium were found to contain 0 . 91 +/- 0 . 22 microgram calmodulin per mg of PM protein . Treatment of membranes with 1 mM EGTA in the presence of 0 . 2 M NaCl causes the diminution of the calmodulin content down to 3 % of the original level . The activity of Ca , Mg - ATPase is thereby decreased by 40 % . Exogenous calmodulin restores the enzyme activity up to 1 . 94 +/- +/- 0 . 30 mumol Pi / mg protein / hour . The maximal activation of Ca , Mg - ATPase is observed with 10 (- 7 ) M calmodulin . P62158 increases the total ATPase activity of myometrium PM without affecting the Mg - ATPase activity . DB00831 ( 20 microM ) diminishes the activating effect of exogenous calmodulin on Ca , Mg - ATPase . P62158 stimulates Ca , Mg - ATPase at low concentrations of Ca2 + ( 10 (- 8 )- 10 (- 6 ) M ) by decreasing Km for Ca2 + from 0 . 4 . 10 (- 6 ) M to 2 . 10 (- 8 ) M as well as by increasing Vmax -- from 0 , 8 to 1 . 42 mumol Pl / mg protein / hour . It is supposed that the activating effect of calmodulin on Ca , Mg - ATPase is based on electrostatic interactions of Ca2 +- free calmodulin with the enzyme .","Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \" CDI \" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .","Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK41___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .","Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .","Products of the unc - 52 gene in Caenorhabditis elegans are homologous to the core protein of the mammalian basement membrane heparan sulfate proteoglycan . Mutations in the unc - 52 gene of Caenorhabditis elegans affect attachment of the myofilament lattice to the muscle cell membrane . Here , we demonstrate that the unc - 52 gene encodes a nematode homolog of perlecan , the mammalian basement membrane heparan sulfate proteoglycan . The longest potential open reading frame of this gene encodes a 2482 - amino - acid protein with a signal peptide and four domains . The first domain is unique to the unc - 52 polypeptide , whereas the three remaining domains contain sequences found in the P01130 ( domain II ) laminin ( domain III ) and N - P62158 ( domain IV ) . We have identified three alternatively spliced transcripts that encode different carboxy - terminal sequences . The two larger transcripts encode proteins containing all or part of domain IV , whereas the smaller transcript encodes a shortened polypeptide that completely lacks domain IV . We have determined that the disorganized muscle phenotype observed in unc - 52 ( st196 ) animals is caused by the insertion of a Tc1 transposon into domain IV . Two monoclonal antibodies that recognize an extracellular component of all contractile tissues in C . elegans fail to stain embryos homozygous for a lethal unc - 52 allele . We have mapped the epitopes recognized by both monoclonal antibodies to a region of domain IV in the unc - 52 - encoded protein sequence .","Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK95___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .","Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK57___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .","Traumatic brain injury - induced acute gene expression changes in rat cerebral cortex identified by GeneChip analysis . Proper CNS function depends on concerted expression of thousands of genes in a controlled and timely manner . Traumatic brain injury ( TBI ) in mammals results in neuronal death and neurological dysfunction , which might be mediated by altered expression of several genes . By employing a CNS - specific GeneChip and real - time polymerase chain reaction ( PCR ) , the present study analyzed the gene expression changes in adult rat cerebral cortex in the first 24 hr after a controlled cortical impact injury . Many functional families of genes not previously implicated in TBI - induced brain damage are altered in the injured cortex . These include up - regulated transcription factors ( O14543 , O60674 , P35610 - 3 , Q03060 , P10914 , SMN , silencer factor - B , ANIA - 3 , ANIA - 4 , and DB09106 - 1 ) and signal transduction pathways ( cpg21 , Narp , and P09455 ) and down - regulated transmitter release mechanisms ( CITRON , synaptojanin II , ras - related rab3 , neurexin - 1beta , and SNAP25A and - B ) , kinases ( IP - 3 - kinase , Pak1 , Ca ( 2 +)/ P62158 - dependent protein kinases ) , and ion channels ( K (+) channels TWIK , RK5 , X62839 , and Na (+) channel I ) . In addition , several genes previously shown to play a role in TBI pathophysiology , including proinflammatory genes , proapoptotic genes , heat shock proteins , immediate early genes , neuropeptides , and glutamate receptor subunits , were also observed to be altered in the injured cortex . Real - time PCR analysis confirmed the GeneChip data for many of these transcripts . The novel physiologically relevant gene expression changes observed here might explain some of the molecular mechanisms of TBI - induced neuronal damage .","[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK60___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin ."],"string":"[\n \"Suppressed Ca2 +/ P62158 / CaMKII - dependent K ( DB00171 ) channel activity in primary afferent neurons mediates hyperalgesia after axotomy . Painful axotomy decreases K ( DB00171 ) channel current ( IK ( DB00171 ) ) in primary afferent neurons . Because cytosolic Ca ( 2 +) signaling is depressed in injured dorsal root ganglia ( Q86YR7 ) neurons , we investigated whether Ca ( 2 +)- calmodulin ( P62158 ) - Ca ( 2 +)/ P62158 - dependent kinase II ( CaMKII ) regulates IK ( DB00171 ) in large Q86YR7 neurons . Immunohistochemistry identified the presence of K ( DB00171 ) channel subunits Q09428 , SUR2 , and Kir6 . 2 but not Kir6 . 1 , and pCaMKII in neurofilament 200 - positive Q86YR7 somata . Single - channel recordings from cell - attached patches revealed that basal and evoked IK ( DB00171 ) by ionomycin , a Ca ( 2 +) ionophore , is activated by CaMKII . In axotomized neurons from rats made hyperalgesic by spinal nerve ligation ( Q16658 ) , basal K ( DB00171 ) channel activity was decreased , and sensitivity to ionomycin was abolished . Basal and Ca ( 2 +)- evoked K ( DB00171 ) channel activity correlated inversely with the degree of hyperalgesia induced by Q16658 in the rats from which the neurons were isolated . Inhibition of IK ( DB00171 ) by glybenclamide , a selective K ( DB00171 ) channel inhibitor , depolarized resting membrane potential ( O94763 ) recorded in perforated whole - cell patches and enhanced neurotransmitter release measured by amperometry . The selective K ( DB00171 ) channel opener diazoxide hyperpolarized the O94763 and attenuated neurotransmitter release . Axotomized neurons from rats made hyperalgesic by Q16658 lost sensitivity to the myristoylated form of autocamtide - 2 - related inhibitory peptide ( AIPm ) , a pseudosubstrate blocker of CaMKII , whereas axotomized neurons from Q16658 animals that failed to develop hyperalgesia showed normal IK ( DB00171 ) inhibition by AIPm . AIPm also depolarized O94763 in control neurons via K ( DB00171 ) channel inhibition . Unitary current conductance and sensitivity of K ( DB00171 ) channels to cytosolic DB00171 and ligands were preserved even after painful nerve injury , thus providing opportunities for selective therapeutic targeting against neuropathic pain .\",\n \"Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2 + , calmodulin , DB02527 , the catalytic subunit of DB02527 - dependent protein kinase ( CSU ) and some Ca2 + antagonists were studied in chemically ( Triton X - 100 ) skinned coronary smooth muscle . P62158 increased the Ca2 + responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half - maximal activating Ca2 + concentration . DB00831 , a calmodulin antagonist , inhibited Ca2 +- calmodulin - induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2 + concentration . DB08980 , a Ca2 +- antagonist , at 2 x 10 (- 4 ) M produced a significant inhibitory effect , which was reduced by increasing the Ca2 + concentration . From other Ca2 + antagonists tested , W - 7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2 + , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle .\",\n \"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK80___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .\",\n \"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK10___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK10___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .\",\n \"___MASK13___ : kinetic and dynamic profile in the treatment of pain . ___MASK13___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK13___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK13___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK13___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .\",\n \"Endothelins stimulate sodium uptake into rat brain capillary endothelial cells through endothelin A - like receptors . The effect of endothelins ( ETs ) on sodium / hydrogen ( Na +/ H + ) antiport system was examined in cultured rat brain capillary endothelium ( RBEC ) . ET - 1 , P20800 , and P14138 stimulated Na + uptake into RBEC with similar half - maximal stimulation ( EC50 ) values ( 0 . 7 , 0 . 6 , and 1 . 1 nM , respectively ) . This reaction was inhibited by the Na +/ H + antiport inhibitor , N -( ethyl - N - isopropyl )- amiloride ( EIPA ) . The selective endothelin A ( P25101 ) receptor - antagonist ( cyclo - D - DB00150 - D - DB00128 - Pro - D - DB00161 - DB00149 ( BQ123 ) ) , but not endothelin B ( ETB ) receptor - antagonists ( ( Cys11 , Cys15 ) - ET - 1 ( IRL1038 ) or N - cis - 2 , 6 - dimethylpiperidinocarbonyl - L - gamma MeLeu - D - DB00150 ( COOMe )- D - Nle - ONa ( BQ788 ) ) , inhibited both ET - 1 - and P14138 - stimulated Na + uptake , indicating P25101 - receptor mediation . The protein kinase C ( PKC ) activator ( phorbol 12 - myristate 13 - acetate ( PMA ) ) failed to stimulate Na + uptake . The calcium - calmodulin ( P62158 ) inhibitor ( W7 ) reduced ET - 1 - stimulated Na + uptake by 50 % , whereas the PKC inhibitor ( staurosporine ) had no effect , indicating that ET - 1 stimulation of the Na +/ H + antiport system is linked to a P62158 - dependent and PKC - independent pathway .\",\n \"___MASK69___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK69___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK69___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .\",\n \"Resistance of P04626 / neu - overexpressing tumor targets to lymphokine - activated - killer - cell - mediated lysis : evidence for deficiency of binding and post - binding events . P04626 / neu - overexpressing tumor cell lines are relatively resistant to lymphokine - activated killer ( Q96QP1 ) cell cytotoxicity when compared to P04626 / neu - nonexpressing lines . P04626 / neu + targets were also resistant to binding by Q96QP1 large granular lymphocytes ( LGL ) as shown by visualization at the single - cell level , a target monolayer binding assay and in \\\" cold \\\" target inhibition experiments . P04626 / neu + Q96QP1 - resistant ovarian cell lines demonstrated an absence of P05362 expression while expression of LFA - 3 , N - P62158 , laminin and beta 1 integrins was comparable to that of P04626 / neu - targets . In contrast , the P04626 / neu + breast cell line , SKBR - 3 , which was also resistant to lysis and binding by Q96QP1 LGL , demonstrated normal expression of P05362 . Anti - P05362 antibodies blocked binding and lysis of P04626 / neu - carcinoma targets by Q96QP1 cells , further supporting the notion that lack of P05362 expression on P04626 / neu + cells contributes to their resistance . The modest binding and lysis of P04626 / neu + targets by Q96QP1 cells was significantly inhibited by anti - LFA - 1 antibodies , suggesting the existence of another counter - receptor for LFA - 1 on P04626 / neu + targets . The following also supported deficiencies in post - binding events when P04626 / neu + cells resisted the lytic activity of Q96QP1 cells : ( a ) when the relative resistance to effector cell binding was overcome by exogenous lectin . P04626 / neu + cell lines were still resistant to Q96QP1 cytolysis , and ( b ) P04626 / neu + targets were resistant to perforin - containing granule extracts obtained from the CTLL - R8 cytotoxic lymphocyte cell line . These results indicate that deficiency in effector binding as well as post - binding events contributes to the resistance of P04626 / neu - overexpressing tumor targets to Q96QP1 - cell - mediated lysis .\",\n \"Bioassay - guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F . cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen ' s egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay - guided fractionation from F . cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S - 180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S - 180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi - target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment .\",\n \"___MASK8___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK8___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .\",\n \"[ P62158 - dependent regulation of Ca , Mg - ATPase activity in plasma membranes of the swine myometrium ] . Highly purified plasma membrane ( PM ) preparations of pig myometrium were found to contain 0 . 91 +/- 0 . 22 microgram calmodulin per mg of PM protein . Treatment of membranes with 1 mM EGTA in the presence of 0 . 2 M NaCl causes the diminution of the calmodulin content down to 3 % of the original level . The activity of Ca , Mg - ATPase is thereby decreased by 40 % . Exogenous calmodulin restores the enzyme activity up to 1 . 94 +/- +/- 0 . 30 mumol Pi / mg protein / hour . The maximal activation of Ca , Mg - ATPase is observed with 10 (- 7 ) M calmodulin . P62158 increases the total ATPase activity of myometrium PM without affecting the Mg - ATPase activity . DB00831 ( 20 microM ) diminishes the activating effect of exogenous calmodulin on Ca , Mg - ATPase . P62158 stimulates Ca , Mg - ATPase at low concentrations of Ca2 + ( 10 (- 8 )- 10 (- 6 ) M ) by decreasing Km for Ca2 + from 0 . 4 . 10 (- 6 ) M to 2 . 10 (- 8 ) M as well as by increasing Vmax -- from 0 , 8 to 1 . 42 mumol Pl / mg protein / hour . It is supposed that the activating effect of calmodulin on Ca , Mg - ATPase is based on electrostatic interactions of Ca2 +- free calmodulin with the enzyme .\",\n \"Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \\\" CDI \\\" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .\",\n \"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK41___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .\",\n \"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .\",\n \"Products of the unc - 52 gene in Caenorhabditis elegans are homologous to the core protein of the mammalian basement membrane heparan sulfate proteoglycan . Mutations in the unc - 52 gene of Caenorhabditis elegans affect attachment of the myofilament lattice to the muscle cell membrane . Here , we demonstrate that the unc - 52 gene encodes a nematode homolog of perlecan , the mammalian basement membrane heparan sulfate proteoglycan . The longest potential open reading frame of this gene encodes a 2482 - amino - acid protein with a signal peptide and four domains . The first domain is unique to the unc - 52 polypeptide , whereas the three remaining domains contain sequences found in the P01130 ( domain II ) laminin ( domain III ) and N - P62158 ( domain IV ) . We have identified three alternatively spliced transcripts that encode different carboxy - terminal sequences . The two larger transcripts encode proteins containing all or part of domain IV , whereas the smaller transcript encodes a shortened polypeptide that completely lacks domain IV . We have determined that the disorganized muscle phenotype observed in unc - 52 ( st196 ) animals is caused by the insertion of a Tc1 transposon into domain IV . Two monoclonal antibodies that recognize an extracellular component of all contractile tissues in C . elegans fail to stain embryos homozygous for a lethal unc - 52 allele . We have mapped the epitopes recognized by both monoclonal antibodies to a region of domain IV in the unc - 52 - encoded protein sequence .\",\n \"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK95___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .\",\n \"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK57___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .\",\n \"Traumatic brain injury - induced acute gene expression changes in rat cerebral cortex identified by GeneChip analysis . Proper CNS function depends on concerted expression of thousands of genes in a controlled and timely manner . Traumatic brain injury ( TBI ) in mammals results in neuronal death and neurological dysfunction , which might be mediated by altered expression of several genes . By employing a CNS - specific GeneChip and real - time polymerase chain reaction ( PCR ) , the present study analyzed the gene expression changes in adult rat cerebral cortex in the first 24 hr after a controlled cortical impact injury . Many functional families of genes not previously implicated in TBI - induced brain damage are altered in the injured cortex . These include up - regulated transcription factors ( O14543 , O60674 , P35610 - 3 , Q03060 , P10914 , SMN , silencer factor - B , ANIA - 3 , ANIA - 4 , and DB09106 - 1 ) and signal transduction pathways ( cpg21 , Narp , and P09455 ) and down - regulated transmitter release mechanisms ( CITRON , synaptojanin II , ras - related rab3 , neurexin - 1beta , and SNAP25A and - B ) , kinases ( IP - 3 - kinase , Pak1 , Ca ( 2 +)/ P62158 - dependent protein kinases ) , and ion channels ( K (+) channels TWIK , RK5 , X62839 , and Na (+) channel I ) . In addition , several genes previously shown to play a role in TBI pathophysiology , including proinflammatory genes , proapoptotic genes , heat shock proteins , immediate early genes , neuropeptides , and glutamate receptor subunits , were also observed to be altered in the injured cortex . Real - time PCR analysis confirmed the GeneChip data for many of these transcripts . The novel physiologically relevant gene expression changes observed here might explain some of the molecular mechanisms of TBI - induced neuronal damage .\",\n \"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK60___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK10___","___MASK13___","___MASK41___","___MASK57___","___MASK60___","___MASK69___","___MASK80___","___MASK8___","___MASK95___"],"string":"[\n \"___MASK10___\",\n \"___MASK13___\",\n \"___MASK41___\",\n \"___MASK57___\",\n \"___MASK60___\",\n \"___MASK69___\",\n \"___MASK80___\",\n \"___MASK8___\",\n \"___MASK95___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK80___"},"id":{"kind":"string","value":"MH_train_88"}}},{"rowIdx":89,"cells":{"query":{"kind":"string","value":"interacts_with DB01235?"},"supports":{"kind":"list like","value":["Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .","Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK29___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","Detection of anti - isoniazid and anti - cytochrome P450 antibodies in patients with isoniazid - induced liver failure . Isoniazid ( ___MASK52___ ) - induced hepatotoxicity remains one of the most common causes of drug - induced idiosyncratic liver injury and liver failure . This form of liver injury is not believed to be immune - mediated because it is not usually associated with fever or rash , does not recur more rapidly on rechallenge , and previous studies have failed to identify anti - ___MASK52___ antibodies ( Abs ) . In this study , we found Abs present in sera of 15 of 19 cases of ___MASK52___ - induced liver failure . Anti - ___MASK52___ Abs were present in 8 sera ; 11 had anti - cytochrome P450 ( CYP ) 2E1 Abs , 14 had Abs against P05181 modified by ___MASK52___ , 14 had anti - P08684 antibodies , and 10 had anti - P11712 Abs . ___MASK52___ was found to form covalent adducts with P05181 , P08684 , and P11712 . None of these Abs were detected in sera from ___MASK52___ - treated controls without significant liver injury . The presence of a range of antidrug and autoAbs has been observed in other drug - induced liver injury that is presumed to be immune mediated . CONCLUSION : These data provide strong evidence that ___MASK52___ induces an immune response that causes ___MASK52___ - induced liver injury .","P28702 polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients . It has been suggested that the retinoid X receptor beta ( P28702 ) gene is a risk factor for Wegener ' s granulomatosis . We addressed if there is a functional difference in the response to retinoic acid ( RA ) and vitamin D in Antineutrophil cytoplasmic antibody ( ANCA ) associated systemic vasculitis ( AASV ) patients and if this was associated with P28702 genotypes . TNFalpha and P22301 production were measured in whole blood assay from AASV patients ( n = 51 ) and healthy controls ( HC , n = 67 ) . One micromolar of 1 , 25 -( OH )( 2 ) D3 , 9 - cis RA ( 9c - RA ) or all - trans RA ( ___MASK47___ ) was added to the assay . Genotyping was performed for exons 7 and 2 of the P28702 gene and for a microsatellite in vicinity of the P28702 gene . Lipopolysaccharide ( LPS ) mediated TNFalpha production and P22301 were significantly lower in patients . Addition of 1 , 25 -( OH )( 2 ) D3 , ___MASK47___ or 9c - RA , blunted TNFalpha production , more pronounced in patients . Although all three compounds inhibited P22301 production significantly in HC , only 1 , 25 -( OH )( 2 ) D3 was found to be effective in patients . Allele distribution of the P28702 microsatellite differed significantly between patients and HC . This was not found for the SNP in exons 2 and 7 . Genotype of the latter correlated with the ability of 1 , 25 -( OH )( 2 ) D3 and ___MASK47___ to inhibit P22301 production . We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients . Since the inhibition of TNFalpha was more effective in patients , vitamin D supplementation might be an additional therapeutical approach .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK53___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","___MASK76___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK76___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK76___ is a promising pharmacological tool in the treatment of renal edema .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","P09038 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington ' s disease . There is no satisfactory treatment for Huntington ' s disease ( HD ) , a hereditary neurodegenerative disorder that produces chorea , dementia , and death . One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors ( neurogenesis ) and their migration into damaged regions of the brain . Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis , we treated HD transgenic R6 / 2 mice from 8 weeks of age until death by s . c . administration of P09038 . P09038 increased the number of proliferating cells in the subventricular zone by approximately 30 % in wild - type mice , and by approximately 150 % in HD transgenic R6 / 2 mice . P09038 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6 / 2 mice . In the striatum , these neurons were Q9UD71 - expressing medium spiny neurons , consistent with the phenotype of neurons lost in HD . P09038 was neuroprotective as well , because it blocked cell death induced by mutant expanded Htt in primary striatal cultures . P09038 also reduced polyglutamine aggregates , improved motor performance , and extended lifespan by approximately 20 % . We conclude that P09038 improves neurological deficits and longevity in a transgenic mouse model of HD , and that its neuroprotective and neuroproliferative effects may contribute to this improvement .","Effects of chronic AVP P30518 blockade in congestive heart failure in sheep . Comparison with chronic P12821 inhibition .","[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .","Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .","Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .","The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .","Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .","The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .","Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .","[ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6 - week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7 . 15 +/- 1 . 5 y . ) with no thrombotic complications were included into the study . All children were clinically steroid - sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin - antithrombin complexes ( TAT ) , serum levels of D - dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0 . 05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0 . 05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in \" prothrombotic state \" in P01308 patients .","Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 , Q01959 , Q13639 , P21917 , P14416 , P28223 , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 , P21397 and P23560 . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .","Human chromosome 3 and pig chromosome 13 show complete synteny conservation but extensive gene - order differences . A comparative map of human chromosome 3 ( HSA 3 ) and pig chromosome 13 ( SSC 13 ) was constructed using physically assigned pig sequence - tagged sites ( STSs ) . Pig STSs representing 11 HSA 3 genes , including v - P04049 murine leukemia viral oncogene homolog 1 ( P04049 ) , retinoic acid beta receptor ( P10826 ) , cholecystokinin ( CCK ) , pituitary transcription factor 1 ( P28069 ) , ceruloplasmin ( CP ) , guanine nucleotide binding protein , alpha - inhibiting polypeptide 2 ( P04899 ) , sucrase - isomaltase ( SI ) , rhodopsin ( P08100 ) , dopamine receptor D3 ( P35462 ) , growth - associated protein 43 ( P17677 ) , and somatostatin ( P61278 ) , were developed . Ten pig STSs were regionally mapped using a somatic cell hybrid panel ( SCHP ) to SSC 13 with 80 - 100 % concordance . Large - insert probes were obtained by screening a pig yeast artificial chromosome ( YAC ) library with primers for each STS . Several YACs were identified for P35462 , P17677 , P28069 , P08100 , SI , and P61278 for fluorescence in situ hybridization ( Q5TCZ1 ) mapping . Single gene and bi - color Q5TCZ1 with each pairwise combination were used to further define the gene order on SSC 13 . While these data confirm chromosome painting results showing that HSA 3 probes hybridize to a major portion of SSC 13 , they also demonstrate extensive gene - order differences between man and pig within this large conserved synteny group . Interestingly , several conserved chromosomal regions have been detected between pig and mouse that are not conserved between man and mouse , suggesting that the SSC 13 gene arrangement may be the closest to that of the ancestral eutherian chromosome .","Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .","The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK83___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","Increased blood pressure and loss of anp - induced natriuresis in mice lacking Q9UD71 gene . Atrial natriuretic peptide ( P01160 ) is an important regulator of sodium metabolism and indirectly of blood pressure . Evidence has accumulated that P01160 regulates sodium metabolism through a cascade of steps involving an increase in the level of cGMP , activation of cGMP - dependent protein kinase ( PKG ) , and inhibition of renal tubular Na + , K +- ATPase activity . One of the major substrates for PKG is Q9UD71 . In the present study we observed that P01160 does not induce natriuresis in mice that lack Q9UD71 . In contrast , there was a 4 - fold increase in urinary sodium excretion following P01160 administration to wild type mice . P01160 as well as Zaprinast , a selective inhibitor of cGMP phosophodiesterase , inhibited renal Na + , K +- ATPase activity in wild type mice but had no such effect in mice lacking Q9UD71 . Mean arterial blood pressure , measured in conscious animals , was significantly increased in Q9UD71 deficient mice as compared to wild type mice . The results confirm that Q9UD71 acts as a third messenger in the P01160 signaling pathway in renal tissue and suggest an important role of Q9UD71 in the maintenance of normal blood pressure .","Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .","Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .","Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .","P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .","The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .","DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .","Association of dopamine - related gene alleles , smoking behavior and decline in FEV1 in subjects with P48444 : findings from the lung health study . Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease ( P48444 ) . Specific dopamine related gene alleles have previously been found to be associated with smoking initiation , maintenance and cessation . We investigated the association between specific dopamine related gene alleles and both change in smoking behavior and lung function change over time in individuals with mild - to - moderate P48444 . Subjects included a subset of participants in the Lung Health Study ( LHS ) , a smoking intervention study in smokers with mild to moderate P48444 . Smoking status was determined and lung function performed at baseline and annually for 5 years . In post - hoc analyses , we assessed the association of the dopamine receptor ( P14416 ) TaqI A1 (+) allele ( A1A1 , A1A2 genotypes ) and A1 (-) allele ( A2A2 genotype ) , and the dopamine transporter ( Q01959 ) 9R (+) allele ( 9R9R and 9R10R genotypes ) and 9R (-) allele ( 10R10R genotype ) with both changes in smoking status and lung function in a subset of LHS subjects . No significant associations were noted between variants in these genes and success in smoking cessation . However , in exploratory analyses that did not adjust for multiple comparisons , sustained male ( but not female ) quitters with the P14416 A1 (-) allele and / or the Q01959 9R (+) allele showed an accelerated decline in Q99581 ( 1 ) similar to that of continuing smokers over 5 years after quitting smoking . These preliminary findings suggest that dopamine - related genes may play a role in the progression of P48444 , at least in the subset of male ex - smokers whose disease continues to progress despite sustained quitting , and warrants additional confirmatory and mechanistic studies .","Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK47___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK47___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .","Readjusting the localization of long QT syndrome gene on chromosome 11p15 . Long QT syndrome ( LQT ) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia . A first locus for LQT has been identified on chromosome 11p15 . 5 ( LQT1 ) , closely linked to P01112 . To refine the location of LQT1 , microsatellites were genotyped in 8 French families and the following order was determined : tel - P01112 - P21917 - D11S922 - D11S4046 - P01344 - P01308 - TH - D11S1318 - D11S1323 - D11S1338 - D11S90 9 - D11S1346 - cen . By haplotype analysis , 12 crossing - over events were identified in affected and unaffected subjects , delineating the LQT1 candidate region to 7 cM . This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to P01112 .","Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK52___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK52___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK52___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK52___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK52___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK52___ increased the protein expression of hepatic P05181 and ___MASK52___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK52___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK52___ and RFP - induced hepatotoxicity .","Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .","Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK31___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .","Dopaminergic , serotonergic , and oxytonergic candidate genes associated with infant attachment security and disorganization ? In search of main and interaction effects . BACKGROUND AND METHODS : In two birth cohort studies with genetic , sensitive parenting , and attachment data of more than 1 , 000 infants in total , we tested main and interaction effects of candidate genes involved in the dopamine , serotonin , and oxytocin systems ( P21917 , P14416 , P21964 , 5 - HTT , P30559 ) on attachment security and disorganization . Parenting was assessed using observational rating scales for parental sensitivity ( Ainsworth , Bell , & Stayton , 1974 ) , and infant attachment was assessed with the Strange Situation Procedure . RESULTS : We found no consistent additive genetic associations for attachment security and attachment disorganization . However , specific tests revealed evidence for a codominant risk model for P21964 Val158Met , consistent across both samples . Children with the DB00161 / DB00134 genotype showed higher disorganization scores ( combined effect size d = . 22 , CI = . 10 -. 34 , p < . 001 ) . Gene - by - environment interaction effects were not replicable across the two samples . CONCLUSIONS : This unexpected finding might be explained by a broader range of plasticity in heterozygotes , which may increase susceptibility to environmental influences or to dysregulation of emotional arousal . This study is unique in combining the two largest attachment cohorts with molecular genetic and observed rearing environment data to date .","Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .","Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .","Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .","P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .","DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .","Fibroblast growth factor - 2 in hyperplastic pituitaries of D2R knockout female mice . P14416 ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 ) and its receptor , P11362 , comparatively in pituitaries from KO and wild - type ( WT ) female mice . We also evaluated P09038 subcellular localization and P09038 effects on pituitary function . P09038 - induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 - stimulated release was higher in KO . P09038 stimulated pituitary cellular proliferation ( MTS assay and [( 3 ) H ] thymidine incorporation ) , with no differences between genotypes . P09038 concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0 . 00001 and 0 . 00014 ) . Immunofluorescence histochemistry showed less P09038 in pituitaries from KO females and revealed a distinct P09038 localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0 . 018 ) . However , when stimulated with P09038 , a significantly higher increment of P29323 phosphorylation was evidenced in KO cells ( P < or = 0 . 02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 levels , with an increased distribution in the nucleus , and increased P11362 levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine - resistant prolactinomas , which will make tumor - specific therapy possible .","Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .","Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .","Therapy with interferon - beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis . OBJECTIVE : To investigate the endogenous dopaminergic / adrenergic system of lymphocytes in multiple sclerosis ( MS ) patients during treatment with interferon ( IFN ) - beta . METHODS : Patients with relapsing - remitting MS undergoing IFN - beta treatment were prospectively studied during the first year of treatment . Circulating lymphocytes were obtained at baseline and after 1 , 3 , 6 and 12 months of treatment and assayed for catecholamine ( CA ) production and mRNA expression of tyrosine hydroxylase ( TH , the rate - limiting enzyme in the synthesis of CA ) , beta ( 2 )- adrenoceptors ( AR ) and D2 , D3 and D5 dopaminergic receptors ( DR ) . RESULTS : In cells from patients treated with IFN - beta for 12 months the production of CA hugely increased and was less sensitive to P01579 - induced inhibition . Expression of mRNA for TH , beta ( 2 )- AR and P21918 was already enhanced after 1 month and further increased up to 6 - 12 months of treatment . On the contrary , P14416 mRNA progressively decreased and P35462 mRNA did not significantly change over the whole study period . CONCLUSIONS : In MS patients IFN - beta treatment enhances the ability of lymphocytes to produce CA , and induces extensive modifications of both beta ( 2 )- AR and DR - operated pathways . The clinical relevance of these effects deserves consideration .","Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .","A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK50___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .","AP - 2beta represses P21728 gene transcription in neuro2a cells . Expression of the P21728 in brain is restricted to specific neuronal populations . To investigate the mechanism of this selective expression , we localized a silencer upstream of the human D ( 1A ) gene and identified its binding transcription factor in the D ( 1A )- negative neural cell line Neuro2a . Using deletion CAT analysis , we narrowed this silencer to the region between nucleotides - 561 and - 532 relative to the CAP site . This 30 - bp region , designated D1AS1 , contains a sequence homologous to the P05549 binding site and binds to a factor that also interacts with the P05549 consensus sequence . In gel supershift assays , this factor is recognized by anti - AP - 2beta antibody . Co - transfection of Neuro2a cells with an AP - 2beta expression vector repressed the basal CAT activity of D ( 1A ) promoter - reporter plasmids in a D1AS1 - dependent manner . RT - PCR analysis indicated that , among P05549 family members , Neuro2a cells express only AP - 2beta . Furthermore , co - transfection of these cells with decoy oligonucleotides corresponding to the D1AS1 sequence de - repressed the D ( 1A ) gene promoter . Unlike in Neuro2a cells , AP - 2beta could not repress the D ( 1A ) promoter in the D ( 1A )- positive neural cell line , NS20Y . In addition , the expression of AP - 2beta in different brain regions does not inversely correlate with that of P21728 . These observations taken together indicate that AP - 2beta is a repressive transcription factor that acts on the D1AS1 silencer of the P21728 gene via some cell - specific mechanism ( s ) in Neuro2a .","Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .","Differential treatment regimen - related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain . Animal studies suggest differential effects of cannabinoids on dopamine - related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence . The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid , HU210 , on dopamine receptor density in adolescent and adult rats . Adolescent ( postnatal day ( P01160 ) 35 ) and adult ( P01160 70 ) rats received a single dose of 100μg / kg HU210 or 25 , 50 or 100μg / kg HU210 for 4 or 14 days . P21728 ( D1R ) or D2 receptor ( D2R ) density was measured in the medial and lateral ( CPUL ) caudate putamen , nucleus accumbens , olfactory tubercle ( TU ) and substantia nigra ( D1R only ) using in vitro autoradiography . D1R and D2R densities were 1 . 6 - 1 . 7 - and 1 . 1 - 1 . 4 - fold higher respectively in adolescent control rats compared to adults . In adult rats , D1R density was increased by 1 . 2 - and 1 . 3 - fold ( p < 0 . 05 ) in CPUL and TU respectively compared to controls , after 14 days of HU210 treatment . A significant overall effect of treatment ( p < 0 . 05 ) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210 . In adolescents , an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0 . 0026 ) but no changes in D1R or D2R densities were observed in other treatment groups . These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment .","The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .","Effects of chronic ' Binge ' cocaine administration on plasma DB01285 and corticosterone levels in mice deficient in Q9UD71 . The product of the Q9UD71 gene mediates intracellular signals initiated by the binding of dopamine to its receptors . Cocaine administration leads to increased activation of dopamine receptors , and causes activation of the stress - responsive hypothalamic - pituitary - adrenal ( Q9Y251 ) axis . We determined the effects of chronic ' binge ' pattern cocaine on Q9Y251 activity in mice containing a targeted disruption of the Q9UD71 gene . Mice received three daily injections of cocaine ( 15 mg / kg / injection ) for 14 days , and were sacrificed 30 min after the last injection . We measured the levels of plasma adrenocorticotropin ( DB01285 ) and corticosterone which reflect Q9Y251 activity . In wild - type controls , ' binge ' cocaine administration significantly increased plasma DB01285 and corticosterone levels . In contrast , Q9UD71 - deficient mice failed to show a significant elevation of either plasma DB01285 or corticosterone levels following ' binge ' cocaine . The results indicate that Q9UD71 plays a role in mediating the stimulatory effects of cocaine on the Q9Y251 axis .","Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK13___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .","Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK47___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK47___ .","Identification and characterization of mouse Erbb2 gene in silico . The Q9UD71 - Q14849 - O15273 - PNMT - MGC9753 - P04626 - MGC14832 - Q14451 locus on human chromosome 17q12 is frequently amplified in human gastric and breast cancer . We have recently identified and characterized human MGC9753 ( also known as wild - type CAB2 ) and mouse Mgc9753 . Here , we identified and characterized mouse Erbb2 gene by using bioinformatics . BLAST programs revealed that mouse AK031099 cDNA was derived from mouse Erbb2 gene . Because AK031099 cDNA showed 806 C --> A nucleotide substitution compared with mouse genome draft sequences and mouse Erbb2 ESTs , the nucleotide sequence of mouse Erbb2 cDNA was determined in silico by correcting 806 A of AK031099 cDNA to C . Nucleotide position 48 - 3818 of mouse Erbb2 cDNA was the coding region . Mouse Erbb2 gene , consisting of 27 exons , was located within the Ppp1r1b - Grb7 locus on the mouse chromosome 11 . Mouse Erbb2 protein ( 1256 aa ) showed 87 . 5 % total - amino - acid identity with human P04626 protein , and 95 . 2 % total - amino - acid identity with rat Erbb2 protein . Mouse Ppp1r1b - Grb7 locus and human Ppp1r1b - Grb7 locus were evolutionarily conserved in the order and the orientation of genes therein . Nucleotide and amino - acid substitution rates of Neurod2 located centromeric to the Ppp1r1b - Grb7 locus were significantly lower than others within the Ppp1r1b - Grb7 locus . This is the first report on the complete coding sequence of mouse Erbb2 gene as well as on the comprehensive comparison of Ppp1r1b - Grb7 locus within the human and mouse genomes .","Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice . The genetically selected long attack latency ( P38571 ) and short attack latency ( SAL ) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus - pituitary - adrenocortical ( Q9Y251 ) - axis . Serial analysis of gene expression ( Q9NXZ1 ) was used to generate a hippocampal expression profile of almost 30 000 genes in P38571 and SAL mice . Using Q9NXZ1 , we found differential expression of 191 genes . Among these were genes involved in growth , signal transduction , and cell metabolism . The Q9NXZ1 study was supported by GeneChip analysis ( Affymetrix ) . Strikingly , both Q9NXZ1 and GeneChips showed a higher expression of numerous cytoskeleton genes , such as cofilin and several tubulin isotypes in P38571 mice . P38571 mice also showed a higher expression of several calmodulin - related genes and genes encoding components of a MAPK cascade , namely raf - related oncogene and P28482 . The findings were confirmed by in situ hybridization . Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf / P29323 pathway that may be related to structural differences in the hippocampus of P38571 and SAL mice . As stress - related disorders , such as depression , are also linked to differential regulation of the Q9Y251 - axis and the serotonergic system and are associated with altered hippocampal morphology , differential regulation of these genes may be involved in the pathogenesis of these diseases .","Expression and prognostic relevance of activated extracellular - regulated kinases ( P27361 / 2 ) in breast cancer . Extracellular - regulated kinases ( P27361 , P28482 ) play important roles in the malignant behaviour of breast cancer cells in vitro . In our present study , 148 clinical breast cancer samples ( 120 cases with follow - up data ) were studied for the expression of P27361 , P28482 and their phosphorylated forms p - P27361 and p - P28482 by immunoblotting , and p - P27361 / 2 expression in corresponding paraffin sections was analysed by immunohistochemistry . The results were correlated with established clinical and histological prognostic parameters , follow - up data and expression of seven cell - cycle regulatory proteins as well as P03956 , P14780 , P05121 and AP - 1 transcription factors , which had been analysed before . High p - P27361 expression as determined by immunoblots correlated significantly with a low frequency of recurrences and infrequent fatal outcome ( P = 0 . 007 and 0 . 008 ) and was an independent indicator of long relapse - free and overall survival in multivariate analysis . By immunohistochemistry , strong p - P29323 staining in tumour cells was associated with early stages ( P = 0 . 020 ) , negative nodal status ( P = 0 . 003 ) and long recurrence - free survival ( P = 0 . 017 ) . In contrast , expression of the unphosphorylated kinases P27361 and P28482 was not associated with clinical and histological prognostic parameters , except a positive correlation with oestrogen receptor status . Comparison with the expression of formerly analysed cell - cycle - and invasion - associated proteins corroborates our conclusion that activation of P27361 and P28482 is not associated with enhanced proliferation and invasion of mammary carcinomas .","___MASK31___ - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple - negative breast cancer cells . ___MASK31___ , a dual epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) kinase inhibitor , showed clinical benefits in advanced P04626 - positive breast cancer patients . Because some triple - negative breast cancers ( TNBCs ) frequently overexpress P00533 , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event - free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple - negative MDA - MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib - increased motility was attributed by the elevation of P00533 through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 ) . Strikingly , independent of its kinase activity , the elevated P00533 at least partly stabilized P35354 expression by enhancing the binding of Q15717 to P35354 mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA - MB - 231 cells by upregulating P00533 and P35354 through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib - based treatment . These findings also shed new light on the molecular mechanism of P35354 mRNA stabilization by P00533 in a kinase - independent manner .","Targeted deletion of P28482 in cardiomyocytes attenuates hypertrophic response but provokes pathological stress induced cardiac dysfunction . Mitogen - activated protein kinases ( MAPKs ) are involved in the regulation of cardiac hypertrophy and myocyte survival . Extracellular signal regulated protein kinase 1 and 2 ( P27361 / 2 ) are key components in the MAPK signaling pathways . Dysfunction of P27361 / 2 in congenital heart diseases ( Noonan syndrome and LEOPARD syndrome ) leads to cardiac hypertrophy . P28482 contributes 70 % of protein content to total P27361 / 2 content in myocardium ; however , the specific role of P28482 in regulating cardiac hypertrophy is yet to be further defined . To investigate the specific role of P28482 played in the cardiomyocytes , we generated and examined mice with cardiomyocyte - specific deletion of the erk2 gene ( P28482 ( cko ) mice ) . Following short - term pathological hypertrophic stresses , the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross - sectional area of individual myocytes , downregulation of hypertrophic foetal gene markers ( P01160 and DB04899 ) , and less interstitial fibrosis . However , increased cardiomyocyte apoptosis was observed . Upon prolonged stimulation , P28482 ( cko ) mice developed deterioration in cardiac function . However , absence of P28482 did not affect physiological hypertrophy induced by 4weeks of swimming exercise . These results revealed an essential role for P28482 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death .","P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .","P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .","Multiple endocytic signals in the C - terminal tail of the cystic fibrosis transmembrane conductance regulator . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is a DB02527 - dependent protein kinase ( PKA ) - activated chloride channel that is localized to the plasma membrane and endosomal compartment . Endosomal targeting of P13569 is attributed to the DB00135 ( 1424 )- based internalization signal , identified in the C - terminal tail of the channel . Mutation of the DB00135 ( 1424 ) residue could partly inhibit the endocytosis of P13569 and its association with the adapter protein P05549 . To reveal additional endosomal targeting signals , site - directed mutagenesis of both a chimaera , composed of a truncated form of interleukin 2 receptor alpha chain ( TacT ) and the C - terminal tail of P13569 ( Ct ) , and the full - length P13569 was performed . Morphological and functional assays revealed the presence of multiple internalization motifs at the C - terminus , consisting of a phenylalanine - based motif ( DB00120 ( 1413 ) ) and a bipartite endocytic signal , comprising a tyrosine ( DB00135 ( 1424 ) ) and a di - DB00149 - based ( DB00149 ( 1430 )- DB00149 ) motif . Whereas the replacement of any one of the three internalization motifs with alanine prevented the endocytosis of the TacT - Ct chimaera , mutagenesis of DB00120 ( 1413 )- DB00149 impaired the biosynthetic processing of P13569 , indicating that DB00120 ( 1413 ) is indispensable for the native structure of P13569 . In contrast , replacement of DB00149 ( 1430 )- DB00149 - and DB00135 ( 1424 )- based signals with alanine increased the cell - surface density of both the chimaeras and P13569 in an additive manner . These results suggest that the internalization of P13569 is regulated by multiple endocytic sorting signals .","Dynamic simulations of pathways downstream of P00533 - family , including mutations and treatments : concordance with experimental results . The pathways downstream of ErbB - family proteins are very important in BC , especially when considering treatment with onco - protein inhibitors . We studied and implemented dynamic simulations of four downstream pathways and described the fragment of the signaling network we evaluated as a Molecular Interaction Map . Our simulations , enacted using Ordinary Differential Equations , involved 242 modified species and complexes , 279 reversible reactions and 111 catalytic reactions . Mutations within a single pathway tended to be mutually exclusive ; only inhibitors acting at , or downstream ( not upstream ) , of a given mutation were active . A double alteration along two distinct pathways required the inhibition of both pathways . We started an analysis of sensitivity / robustness of our network , and we systematically introduced several individual fluctuations of total concentrations of independent molecular species . Only very few cases showed significant sensitivity . We transduced the ErbB2 over - expressing BC line , BT474 , with the P01112 ( V12 ) mutant , then treated it with ErbB - family and phosphorylated MEK ( MEKPP ) inhibitors , ___MASK31___ and U0126 , respectively . Experimental and simulation results were highly concordant , showing statistical significance for both pathways and for two respective endpoints , i . e . phosphorylated active forms of P29323 and Akt , p one tailed = . 0072 and = . 0022 , respectively . Working with a complex 39 basic species signaling network region , this technology facilitates both comprehension and effective , efficient and accurate modeling and data interpretation . Dynamic network simulations we performed proved to be both practical and valuable for a posteriori comprehension of biological networks and signaling , thereby greatly facilitating handling , and thus complete exploitation , of biological data ."],"string":"[\n \"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .\",\n \"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \\\" correctors \\\" such as ___MASK29___ ( VX - 809 ) that improve P13569 maturation and trafficking and \\\" potentiators \\\" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"Detection of anti - isoniazid and anti - cytochrome P450 antibodies in patients with isoniazid - induced liver failure . Isoniazid ( ___MASK52___ ) - induced hepatotoxicity remains one of the most common causes of drug - induced idiosyncratic liver injury and liver failure . This form of liver injury is not believed to be immune - mediated because it is not usually associated with fever or rash , does not recur more rapidly on rechallenge , and previous studies have failed to identify anti - ___MASK52___ antibodies ( Abs ) . In this study , we found Abs present in sera of 15 of 19 cases of ___MASK52___ - induced liver failure . Anti - ___MASK52___ Abs were present in 8 sera ; 11 had anti - cytochrome P450 ( CYP ) 2E1 Abs , 14 had Abs against P05181 modified by ___MASK52___ , 14 had anti - P08684 antibodies , and 10 had anti - P11712 Abs . ___MASK52___ was found to form covalent adducts with P05181 , P08684 , and P11712 . None of these Abs were detected in sera from ___MASK52___ - treated controls without significant liver injury . The presence of a range of antidrug and autoAbs has been observed in other drug - induced liver injury that is presumed to be immune mediated . CONCLUSION : These data provide strong evidence that ___MASK52___ induces an immune response that causes ___MASK52___ - induced liver injury .\",\n \"P28702 polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients . It has been suggested that the retinoid X receptor beta ( P28702 ) gene is a risk factor for Wegener ' s granulomatosis . We addressed if there is a functional difference in the response to retinoic acid ( RA ) and vitamin D in Antineutrophil cytoplasmic antibody ( ANCA ) associated systemic vasculitis ( AASV ) patients and if this was associated with P28702 genotypes . TNFalpha and P22301 production were measured in whole blood assay from AASV patients ( n = 51 ) and healthy controls ( HC , n = 67 ) . One micromolar of 1 , 25 -( OH )( 2 ) D3 , 9 - cis RA ( 9c - RA ) or all - trans RA ( ___MASK47___ ) was added to the assay . Genotyping was performed for exons 7 and 2 of the P28702 gene and for a microsatellite in vicinity of the P28702 gene . Lipopolysaccharide ( LPS ) mediated TNFalpha production and P22301 were significantly lower in patients . Addition of 1 , 25 -( OH )( 2 ) D3 , ___MASK47___ or 9c - RA , blunted TNFalpha production , more pronounced in patients . Although all three compounds inhibited P22301 production significantly in HC , only 1 , 25 -( OH )( 2 ) D3 was found to be effective in patients . Allele distribution of the P28702 microsatellite differed significantly between patients and HC . This was not found for the SNP in exons 2 and 7 . Genotype of the latter correlated with the ability of 1 , 25 -( OH )( 2 ) D3 and ___MASK47___ to inhibit P22301 production . We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients . Since the inhibition of TNFalpha was more effective in patients , vitamin D supplementation might be an additional therapeutical approach .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK53___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"___MASK76___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK76___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK76___ is a promising pharmacological tool in the treatment of renal edema .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"P09038 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington ' s disease . There is no satisfactory treatment for Huntington ' s disease ( HD ) , a hereditary neurodegenerative disorder that produces chorea , dementia , and death . One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors ( neurogenesis ) and their migration into damaged regions of the brain . Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis , we treated HD transgenic R6 / 2 mice from 8 weeks of age until death by s . c . administration of P09038 . P09038 increased the number of proliferating cells in the subventricular zone by approximately 30 % in wild - type mice , and by approximately 150 % in HD transgenic R6 / 2 mice . P09038 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6 / 2 mice . In the striatum , these neurons were Q9UD71 - expressing medium spiny neurons , consistent with the phenotype of neurons lost in HD . P09038 was neuroprotective as well , because it blocked cell death induced by mutant expanded Htt in primary striatal cultures . P09038 also reduced polyglutamine aggregates , improved motor performance , and extended lifespan by approximately 20 % . We conclude that P09038 improves neurological deficits and longevity in a transgenic mouse model of HD , and that its neuroprotective and neuroproliferative effects may contribute to this improvement .\",\n \"Effects of chronic AVP P30518 blockade in congestive heart failure in sheep . Comparison with chronic P12821 inhibition .\",\n \"[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .\",\n \"Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .\",\n \"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .\",\n \"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .\",\n \"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .\",\n \"The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .\",\n \"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .\",\n \"[ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6 - week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7 . 15 +/- 1 . 5 y . ) with no thrombotic complications were included into the study . All children were clinically steroid - sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin - antithrombin complexes ( TAT ) , serum levels of D - dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0 . 05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0 . 05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in \\\" prothrombotic state \\\" in P01308 patients .\",\n \"Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 , Q01959 , Q13639 , P21917 , P14416 , P28223 , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 , P21397 and P23560 . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .\",\n \"Human chromosome 3 and pig chromosome 13 show complete synteny conservation but extensive gene - order differences . A comparative map of human chromosome 3 ( HSA 3 ) and pig chromosome 13 ( SSC 13 ) was constructed using physically assigned pig sequence - tagged sites ( STSs ) . Pig STSs representing 11 HSA 3 genes , including v - P04049 murine leukemia viral oncogene homolog 1 ( P04049 ) , retinoic acid beta receptor ( P10826 ) , cholecystokinin ( CCK ) , pituitary transcription factor 1 ( P28069 ) , ceruloplasmin ( CP ) , guanine nucleotide binding protein , alpha - inhibiting polypeptide 2 ( P04899 ) , sucrase - isomaltase ( SI ) , rhodopsin ( P08100 ) , dopamine receptor D3 ( P35462 ) , growth - associated protein 43 ( P17677 ) , and somatostatin ( P61278 ) , were developed . Ten pig STSs were regionally mapped using a somatic cell hybrid panel ( SCHP ) to SSC 13 with 80 - 100 % concordance . Large - insert probes were obtained by screening a pig yeast artificial chromosome ( YAC ) library with primers for each STS . Several YACs were identified for P35462 , P17677 , P28069 , P08100 , SI , and P61278 for fluorescence in situ hybridization ( Q5TCZ1 ) mapping . Single gene and bi - color Q5TCZ1 with each pairwise combination were used to further define the gene order on SSC 13 . While these data confirm chromosome painting results showing that HSA 3 probes hybridize to a major portion of SSC 13 , they also demonstrate extensive gene - order differences between man and pig within this large conserved synteny group . Interestingly , several conserved chromosomal regions have been detected between pig and mouse that are not conserved between man and mouse , suggesting that the SSC 13 gene arrangement may be the closest to that of the ancestral eutherian chromosome .\",\n \"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .\",\n \"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK83___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"Increased blood pressure and loss of anp - induced natriuresis in mice lacking Q9UD71 gene . Atrial natriuretic peptide ( P01160 ) is an important regulator of sodium metabolism and indirectly of blood pressure . Evidence has accumulated that P01160 regulates sodium metabolism through a cascade of steps involving an increase in the level of cGMP , activation of cGMP - dependent protein kinase ( PKG ) , and inhibition of renal tubular Na + , K +- ATPase activity . One of the major substrates for PKG is Q9UD71 . In the present study we observed that P01160 does not induce natriuresis in mice that lack Q9UD71 . In contrast , there was a 4 - fold increase in urinary sodium excretion following P01160 administration to wild type mice . P01160 as well as Zaprinast , a selective inhibitor of cGMP phosophodiesterase , inhibited renal Na + , K +- ATPase activity in wild type mice but had no such effect in mice lacking Q9UD71 . Mean arterial blood pressure , measured in conscious animals , was significantly increased in Q9UD71 deficient mice as compared to wild type mice . The results confirm that Q9UD71 acts as a third messenger in the P01160 signaling pathway in renal tissue and suggest an important role of Q9UD71 in the maintenance of normal blood pressure .\",\n \"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .\",\n \"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .\",\n \"Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .\",\n \"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .\",\n \"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .\",\n \"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .\",\n \"Association of dopamine - related gene alleles , smoking behavior and decline in FEV1 in subjects with P48444 : findings from the lung health study . Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease ( P48444 ) . Specific dopamine related gene alleles have previously been found to be associated with smoking initiation , maintenance and cessation . We investigated the association between specific dopamine related gene alleles and both change in smoking behavior and lung function change over time in individuals with mild - to - moderate P48444 . Subjects included a subset of participants in the Lung Health Study ( LHS ) , a smoking intervention study in smokers with mild to moderate P48444 . Smoking status was determined and lung function performed at baseline and annually for 5 years . In post - hoc analyses , we assessed the association of the dopamine receptor ( P14416 ) TaqI A1 (+) allele ( A1A1 , A1A2 genotypes ) and A1 (-) allele ( A2A2 genotype ) , and the dopamine transporter ( Q01959 ) 9R (+) allele ( 9R9R and 9R10R genotypes ) and 9R (-) allele ( 10R10R genotype ) with both changes in smoking status and lung function in a subset of LHS subjects . No significant associations were noted between variants in these genes and success in smoking cessation . However , in exploratory analyses that did not adjust for multiple comparisons , sustained male ( but not female ) quitters with the P14416 A1 (-) allele and / or the Q01959 9R (+) allele showed an accelerated decline in Q99581 ( 1 ) similar to that of continuing smokers over 5 years after quitting smoking . These preliminary findings suggest that dopamine - related genes may play a role in the progression of P48444 , at least in the subset of male ex - smokers whose disease continues to progress despite sustained quitting , and warrants additional confirmatory and mechanistic studies .\",\n \"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK47___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK47___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .\",\n \"Readjusting the localization of long QT syndrome gene on chromosome 11p15 . Long QT syndrome ( LQT ) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia . A first locus for LQT has been identified on chromosome 11p15 . 5 ( LQT1 ) , closely linked to P01112 . To refine the location of LQT1 , microsatellites were genotyped in 8 French families and the following order was determined : tel - P01112 - P21917 - D11S922 - D11S4046 - P01344 - P01308 - TH - D11S1318 - D11S1323 - D11S1338 - D11S90 9 - D11S1346 - cen . By haplotype analysis , 12 crossing - over events were identified in affected and unaffected subjects , delineating the LQT1 candidate region to 7 cM . This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to P01112 .\",\n \"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK52___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK52___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK52___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK52___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK52___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK52___ increased the protein expression of hepatic P05181 and ___MASK52___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK52___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK52___ and RFP - induced hepatotoxicity .\",\n \"Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .\",\n \"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK31___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .\",\n \"Dopaminergic , serotonergic , and oxytonergic candidate genes associated with infant attachment security and disorganization ? In search of main and interaction effects . BACKGROUND AND METHODS : In two birth cohort studies with genetic , sensitive parenting , and attachment data of more than 1 , 000 infants in total , we tested main and interaction effects of candidate genes involved in the dopamine , serotonin , and oxytocin systems ( P21917 , P14416 , P21964 , 5 - HTT , P30559 ) on attachment security and disorganization . Parenting was assessed using observational rating scales for parental sensitivity ( Ainsworth , Bell , & Stayton , 1974 ) , and infant attachment was assessed with the Strange Situation Procedure . RESULTS : We found no consistent additive genetic associations for attachment security and attachment disorganization . However , specific tests revealed evidence for a codominant risk model for P21964 Val158Met , consistent across both samples . Children with the DB00161 / DB00134 genotype showed higher disorganization scores ( combined effect size d = . 22 , CI = . 10 -. 34 , p < . 001 ) . Gene - by - environment interaction effects were not replicable across the two samples . CONCLUSIONS : This unexpected finding might be explained by a broader range of plasticity in heterozygotes , which may increase susceptibility to environmental influences or to dysregulation of emotional arousal . This study is unique in combining the two largest attachment cohorts with molecular genetic and observed rearing environment data to date .\",\n \"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .\",\n \"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .\",\n \"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .\",\n \"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .\",\n \"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .\",\n \"Fibroblast growth factor - 2 in hyperplastic pituitaries of D2R knockout female mice . P14416 ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 ) and its receptor , P11362 , comparatively in pituitaries from KO and wild - type ( WT ) female mice . We also evaluated P09038 subcellular localization and P09038 effects on pituitary function . P09038 - induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 - stimulated release was higher in KO . P09038 stimulated pituitary cellular proliferation ( MTS assay and [( 3 ) H ] thymidine incorporation ) , with no differences between genotypes . P09038 concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0 . 00001 and 0 . 00014 ) . Immunofluorescence histochemistry showed less P09038 in pituitaries from KO females and revealed a distinct P09038 localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0 . 018 ) . However , when stimulated with P09038 , a significantly higher increment of P29323 phosphorylation was evidenced in KO cells ( P < or = 0 . 02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 levels , with an increased distribution in the nucleus , and increased P11362 levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine - resistant prolactinomas , which will make tumor - specific therapy possible .\",\n \"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .\",\n \"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .\",\n \"Therapy with interferon - beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis . OBJECTIVE : To investigate the endogenous dopaminergic / adrenergic system of lymphocytes in multiple sclerosis ( MS ) patients during treatment with interferon ( IFN ) - beta . METHODS : Patients with relapsing - remitting MS undergoing IFN - beta treatment were prospectively studied during the first year of treatment . Circulating lymphocytes were obtained at baseline and after 1 , 3 , 6 and 12 months of treatment and assayed for catecholamine ( CA ) production and mRNA expression of tyrosine hydroxylase ( TH , the rate - limiting enzyme in the synthesis of CA ) , beta ( 2 )- adrenoceptors ( AR ) and D2 , D3 and D5 dopaminergic receptors ( DR ) . RESULTS : In cells from patients treated with IFN - beta for 12 months the production of CA hugely increased and was less sensitive to P01579 - induced inhibition . Expression of mRNA for TH , beta ( 2 )- AR and P21918 was already enhanced after 1 month and further increased up to 6 - 12 months of treatment . On the contrary , P14416 mRNA progressively decreased and P35462 mRNA did not significantly change over the whole study period . CONCLUSIONS : In MS patients IFN - beta treatment enhances the ability of lymphocytes to produce CA , and induces extensive modifications of both beta ( 2 )- AR and DR - operated pathways . The clinical relevance of these effects deserves consideration .\",\n \"Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .\",\n \"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK50___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .\",\n \"AP - 2beta represses P21728 gene transcription in neuro2a cells . Expression of the P21728 in brain is restricted to specific neuronal populations . To investigate the mechanism of this selective expression , we localized a silencer upstream of the human D ( 1A ) gene and identified its binding transcription factor in the D ( 1A )- negative neural cell line Neuro2a . Using deletion CAT analysis , we narrowed this silencer to the region between nucleotides - 561 and - 532 relative to the CAP site . This 30 - bp region , designated D1AS1 , contains a sequence homologous to the P05549 binding site and binds to a factor that also interacts with the P05549 consensus sequence . In gel supershift assays , this factor is recognized by anti - AP - 2beta antibody . Co - transfection of Neuro2a cells with an AP - 2beta expression vector repressed the basal CAT activity of D ( 1A ) promoter - reporter plasmids in a D1AS1 - dependent manner . RT - PCR analysis indicated that , among P05549 family members , Neuro2a cells express only AP - 2beta . Furthermore , co - transfection of these cells with decoy oligonucleotides corresponding to the D1AS1 sequence de - repressed the D ( 1A ) gene promoter . Unlike in Neuro2a cells , AP - 2beta could not repress the D ( 1A ) promoter in the D ( 1A )- positive neural cell line , NS20Y . In addition , the expression of AP - 2beta in different brain regions does not inversely correlate with that of P21728 . These observations taken together indicate that AP - 2beta is a repressive transcription factor that acts on the D1AS1 silencer of the P21728 gene via some cell - specific mechanism ( s ) in Neuro2a .\",\n \"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .\",\n \"Differential treatment regimen - related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain . Animal studies suggest differential effects of cannabinoids on dopamine - related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence . The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid , HU210 , on dopamine receptor density in adolescent and adult rats . Adolescent ( postnatal day ( P01160 ) 35 ) and adult ( P01160 70 ) rats received a single dose of 100μg / kg HU210 or 25 , 50 or 100μg / kg HU210 for 4 or 14 days . P21728 ( D1R ) or D2 receptor ( D2R ) density was measured in the medial and lateral ( CPUL ) caudate putamen , nucleus accumbens , olfactory tubercle ( TU ) and substantia nigra ( D1R only ) using in vitro autoradiography . D1R and D2R densities were 1 . 6 - 1 . 7 - and 1 . 1 - 1 . 4 - fold higher respectively in adolescent control rats compared to adults . In adult rats , D1R density was increased by 1 . 2 - and 1 . 3 - fold ( p < 0 . 05 ) in CPUL and TU respectively compared to controls , after 14 days of HU210 treatment . A significant overall effect of treatment ( p < 0 . 05 ) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210 . In adolescents , an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0 . 0026 ) but no changes in D1R or D2R densities were observed in other treatment groups . These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment .\",\n \"The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .\",\n \"Effects of chronic ' Binge ' cocaine administration on plasma DB01285 and corticosterone levels in mice deficient in Q9UD71 . The product of the Q9UD71 gene mediates intracellular signals initiated by the binding of dopamine to its receptors . Cocaine administration leads to increased activation of dopamine receptors , and causes activation of the stress - responsive hypothalamic - pituitary - adrenal ( Q9Y251 ) axis . We determined the effects of chronic ' binge ' pattern cocaine on Q9Y251 activity in mice containing a targeted disruption of the Q9UD71 gene . Mice received three daily injections of cocaine ( 15 mg / kg / injection ) for 14 days , and were sacrificed 30 min after the last injection . We measured the levels of plasma adrenocorticotropin ( DB01285 ) and corticosterone which reflect Q9Y251 activity . In wild - type controls , ' binge ' cocaine administration significantly increased plasma DB01285 and corticosterone levels . In contrast , Q9UD71 - deficient mice failed to show a significant elevation of either plasma DB01285 or corticosterone levels following ' binge ' cocaine . The results indicate that Q9UD71 plays a role in mediating the stimulatory effects of cocaine on the Q9Y251 axis .\",\n \"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK13___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .\",\n \"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK47___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK47___ .\",\n \"Identification and characterization of mouse Erbb2 gene in silico . The Q9UD71 - Q14849 - O15273 - PNMT - MGC9753 - P04626 - MGC14832 - Q14451 locus on human chromosome 17q12 is frequently amplified in human gastric and breast cancer . We have recently identified and characterized human MGC9753 ( also known as wild - type CAB2 ) and mouse Mgc9753 . Here , we identified and characterized mouse Erbb2 gene by using bioinformatics . BLAST programs revealed that mouse AK031099 cDNA was derived from mouse Erbb2 gene . Because AK031099 cDNA showed 806 C --> A nucleotide substitution compared with mouse genome draft sequences and mouse Erbb2 ESTs , the nucleotide sequence of mouse Erbb2 cDNA was determined in silico by correcting 806 A of AK031099 cDNA to C . Nucleotide position 48 - 3818 of mouse Erbb2 cDNA was the coding region . Mouse Erbb2 gene , consisting of 27 exons , was located within the Ppp1r1b - Grb7 locus on the mouse chromosome 11 . Mouse Erbb2 protein ( 1256 aa ) showed 87 . 5 % total - amino - acid identity with human P04626 protein , and 95 . 2 % total - amino - acid identity with rat Erbb2 protein . Mouse Ppp1r1b - Grb7 locus and human Ppp1r1b - Grb7 locus were evolutionarily conserved in the order and the orientation of genes therein . Nucleotide and amino - acid substitution rates of Neurod2 located centromeric to the Ppp1r1b - Grb7 locus were significantly lower than others within the Ppp1r1b - Grb7 locus . This is the first report on the complete coding sequence of mouse Erbb2 gene as well as on the comprehensive comparison of Ppp1r1b - Grb7 locus within the human and mouse genomes .\",\n \"Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice . The genetically selected long attack latency ( P38571 ) and short attack latency ( SAL ) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus - pituitary - adrenocortical ( Q9Y251 ) - axis . Serial analysis of gene expression ( Q9NXZ1 ) was used to generate a hippocampal expression profile of almost 30 000 genes in P38571 and SAL mice . Using Q9NXZ1 , we found differential expression of 191 genes . Among these were genes involved in growth , signal transduction , and cell metabolism . The Q9NXZ1 study was supported by GeneChip analysis ( Affymetrix ) . Strikingly , both Q9NXZ1 and GeneChips showed a higher expression of numerous cytoskeleton genes , such as cofilin and several tubulin isotypes in P38571 mice . P38571 mice also showed a higher expression of several calmodulin - related genes and genes encoding components of a MAPK cascade , namely raf - related oncogene and P28482 . The findings were confirmed by in situ hybridization . Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf / P29323 pathway that may be related to structural differences in the hippocampus of P38571 and SAL mice . As stress - related disorders , such as depression , are also linked to differential regulation of the Q9Y251 - axis and the serotonergic system and are associated with altered hippocampal morphology , differential regulation of these genes may be involved in the pathogenesis of these diseases .\",\n \"Expression and prognostic relevance of activated extracellular - regulated kinases ( P27361 / 2 ) in breast cancer . Extracellular - regulated kinases ( P27361 , P28482 ) play important roles in the malignant behaviour of breast cancer cells in vitro . In our present study , 148 clinical breast cancer samples ( 120 cases with follow - up data ) were studied for the expression of P27361 , P28482 and their phosphorylated forms p - P27361 and p - P28482 by immunoblotting , and p - P27361 / 2 expression in corresponding paraffin sections was analysed by immunohistochemistry . The results were correlated with established clinical and histological prognostic parameters , follow - up data and expression of seven cell - cycle regulatory proteins as well as P03956 , P14780 , P05121 and AP - 1 transcription factors , which had been analysed before . High p - P27361 expression as determined by immunoblots correlated significantly with a low frequency of recurrences and infrequent fatal outcome ( P = 0 . 007 and 0 . 008 ) and was an independent indicator of long relapse - free and overall survival in multivariate analysis . By immunohistochemistry , strong p - P29323 staining in tumour cells was associated with early stages ( P = 0 . 020 ) , negative nodal status ( P = 0 . 003 ) and long recurrence - free survival ( P = 0 . 017 ) . In contrast , expression of the unphosphorylated kinases P27361 and P28482 was not associated with clinical and histological prognostic parameters , except a positive correlation with oestrogen receptor status . Comparison with the expression of formerly analysed cell - cycle - and invasion - associated proteins corroborates our conclusion that activation of P27361 and P28482 is not associated with enhanced proliferation and invasion of mammary carcinomas .\",\n \"___MASK31___ - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple - negative breast cancer cells . ___MASK31___ , a dual epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) kinase inhibitor , showed clinical benefits in advanced P04626 - positive breast cancer patients . Because some triple - negative breast cancers ( TNBCs ) frequently overexpress P00533 , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event - free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple - negative MDA - MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib - increased motility was attributed by the elevation of P00533 through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 ) . Strikingly , independent of its kinase activity , the elevated P00533 at least partly stabilized P35354 expression by enhancing the binding of Q15717 to P35354 mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA - MB - 231 cells by upregulating P00533 and P35354 through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib - based treatment . These findings also shed new light on the molecular mechanism of P35354 mRNA stabilization by P00533 in a kinase - independent manner .\",\n \"Targeted deletion of P28482 in cardiomyocytes attenuates hypertrophic response but provokes pathological stress induced cardiac dysfunction . Mitogen - activated protein kinases ( MAPKs ) are involved in the regulation of cardiac hypertrophy and myocyte survival . Extracellular signal regulated protein kinase 1 and 2 ( P27361 / 2 ) are key components in the MAPK signaling pathways . Dysfunction of P27361 / 2 in congenital heart diseases ( Noonan syndrome and LEOPARD syndrome ) leads to cardiac hypertrophy . P28482 contributes 70 % of protein content to total P27361 / 2 content in myocardium ; however , the specific role of P28482 in regulating cardiac hypertrophy is yet to be further defined . To investigate the specific role of P28482 played in the cardiomyocytes , we generated and examined mice with cardiomyocyte - specific deletion of the erk2 gene ( P28482 ( cko ) mice ) . Following short - term pathological hypertrophic stresses , the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross - sectional area of individual myocytes , downregulation of hypertrophic foetal gene markers ( P01160 and DB04899 ) , and less interstitial fibrosis . However , increased cardiomyocyte apoptosis was observed . Upon prolonged stimulation , P28482 ( cko ) mice developed deterioration in cardiac function . However , absence of P28482 did not affect physiological hypertrophy induced by 4weeks of swimming exercise . These results revealed an essential role for P28482 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death .\",\n \"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .\",\n \"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .\",\n \"Multiple endocytic signals in the C - terminal tail of the cystic fibrosis transmembrane conductance regulator . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is a DB02527 - dependent protein kinase ( PKA ) - activated chloride channel that is localized to the plasma membrane and endosomal compartment . Endosomal targeting of P13569 is attributed to the DB00135 ( 1424 )- based internalization signal , identified in the C - terminal tail of the channel . Mutation of the DB00135 ( 1424 ) residue could partly inhibit the endocytosis of P13569 and its association with the adapter protein P05549 . To reveal additional endosomal targeting signals , site - directed mutagenesis of both a chimaera , composed of a truncated form of interleukin 2 receptor alpha chain ( TacT ) and the C - terminal tail of P13569 ( Ct ) , and the full - length P13569 was performed . Morphological and functional assays revealed the presence of multiple internalization motifs at the C - terminus , consisting of a phenylalanine - based motif ( DB00120 ( 1413 ) ) and a bipartite endocytic signal , comprising a tyrosine ( DB00135 ( 1424 ) ) and a di - DB00149 - based ( DB00149 ( 1430 )- DB00149 ) motif . Whereas the replacement of any one of the three internalization motifs with alanine prevented the endocytosis of the TacT - Ct chimaera , mutagenesis of DB00120 ( 1413 )- DB00149 impaired the biosynthetic processing of P13569 , indicating that DB00120 ( 1413 ) is indispensable for the native structure of P13569 . In contrast , replacement of DB00149 ( 1430 )- DB00149 - and DB00135 ( 1424 )- based signals with alanine increased the cell - surface density of both the chimaeras and P13569 in an additive manner . These results suggest that the internalization of P13569 is regulated by multiple endocytic sorting signals .\",\n \"Dynamic simulations of pathways downstream of P00533 - family , including mutations and treatments : concordance with experimental results . The pathways downstream of ErbB - family proteins are very important in BC , especially when considering treatment with onco - protein inhibitors . We studied and implemented dynamic simulations of four downstream pathways and described the fragment of the signaling network we evaluated as a Molecular Interaction Map . Our simulations , enacted using Ordinary Differential Equations , involved 242 modified species and complexes , 279 reversible reactions and 111 catalytic reactions . Mutations within a single pathway tended to be mutually exclusive ; only inhibitors acting at , or downstream ( not upstream ) , of a given mutation were active . A double alteration along two distinct pathways required the inhibition of both pathways . We started an analysis of sensitivity / robustness of our network , and we systematically introduced several individual fluctuations of total concentrations of independent molecular species . Only very few cases showed significant sensitivity . We transduced the ErbB2 over - expressing BC line , BT474 , with the P01112 ( V12 ) mutant , then treated it with ErbB - family and phosphorylated MEK ( MEKPP ) inhibitors , ___MASK31___ and U0126 , respectively . Experimental and simulation results were highly concordant , showing statistical significance for both pathways and for two respective endpoints , i . e . phosphorylated active forms of P29323 and Akt , p one tailed = . 0072 and = . 0022 , respectively . Working with a complex 39 basic species signaling network region , this technology facilitates both comprehension and effective , efficient and accurate modeling and data interpretation . Dynamic network simulations we performed proved to be both practical and valuable for a posteriori comprehension of biological networks and signaling , thereby greatly facilitating handling , and thus complete exploitation , of biological data .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK13___","___MASK29___","___MASK31___","___MASK47___","___MASK50___","___MASK52___","___MASK53___","___MASK76___","___MASK83___"],"string":"[\n \"___MASK13___\",\n \"___MASK29___\",\n \"___MASK31___\",\n \"___MASK47___\",\n \"___MASK50___\",\n \"___MASK52___\",\n \"___MASK53___\",\n \"___MASK76___\",\n \"___MASK83___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK52___"},"id":{"kind":"string","value":"MH_train_89"}}},{"rowIdx":90,"cells":{"query":{"kind":"string","value":"interacts_with DB08896?"},"supports":{"kind":"list like","value":["Determination of ancestral allele for possible human cancer - associated polymorphisms . To determine ancestral allele in possible cancer - associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 ( alias IL - 1RA ) variable number tandem repeat ( VNTR ) ; P04818 ( previously TS ) VNTR ; AR CAG repeat ; dinucleotide repeats of P22309 , IGF1 , P01579 ( alias P01579 ) , P03372 ( alias P03372 ) , and P00533 ] and 9 single nucleotide polymorphisms ( P03956 - 1607 1G / 2G , P08254 - 1171 5A / 6A , O15527 Ser326Cys , P05091 Gly487Lys , P04637 Arg72Pro , Q9UNQ0 Gln141Lys , P16455 Leu84Phe , P04179 Ala - 9Val , and P42898 Ala222Val ) . No chimpanzee polymorphism corresponded to human P18510 VNTR ; the ancestral allele was a repeat lost in humans . Dinucleotide repeat polymorphisms of IGF1 , P01579 , P03372 , and P00533 were shared by chimpanzees , but the length of repeats tended to be longer in humans than in chimpanzees . This tendency was particularly evident for IGF1 . All of the SNPs tested are human - specific nucleotide changes . The ancestral allele 7A was shown to be lost in P08254 - 1171 5A / 6A . Thus , all of the possible cancer - associated polymorphisms tested have human - specific alleles , and the ancestral allele is lost in three polymorphisms ( P18510 VNTR , P22309 CA repeat , and P08254 - 1171 5A / 6A ) , suggesting a possible involvement of human - specific alleles in cancer susceptibility .","Contribution of cubilin and amnionless to processing and membrane targeting of cubilin - amnionless complex . O60494 is a peripheral apical membrane receptor for multiple ligands that are taken up in several absorptive epithelia . Recently , amnionless ( Q9BXJ7 ) was identified to form a functional receptor complex with cubilin . By expression in transfected polarized MDCK cells of Q9BXJ7 and several cubilin fragments , including a functional \" mini \" version of cubilin , the processing , sorting , and membrane anchoring of the complex to the apical membrane were investigated . The results show that truncation mutants , including the N - terminal domain of cubilin , did not appear at the plasma membrane but instead were retained in the endoplasmic reticulum or partially secreted into the medium . Coexpression with Q9BXJ7 led to efficient transport to the apical cell surface of the cubilin constructs , which included the P01133 domains , and prevented release into the medium . Q9BXJ7 co - precipitated with cubilin and co - localized with cubilin at the apical cell surface . Apical sorting was observed for a broad set of nonoverlapping cubilin fragments without the N - terminal region , in the absence of Q9BXJ7 . The preference for apical sorting disappeared when glycosylation was inhibited by tunicamycin . In conclusion , it is shown that both units contribute to the processing of the cubilin - Q9BXJ7 complex to the apical membrane : Q9BXJ7 interacts with the P01133 domains of cubilin and is responsible for membrane attachment and export of the complex from the endoplasmic reticulum , whereas the extracellular cubilin molecule is responsible for apical sorting of the complex in a carbohydrate - dependent manner .","Suppression of proliferation and migration in highly - metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly - metastatic lung cancer , the leading cause of cancer - related deaths in the world . In this study , we synthesized a new compound ethyl 6 - bromocoumarin - 3 - carboxylyl L - theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly - metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase - 3 and P09874 but also reduces the protein expressions of Bcl - 2 , cyclin D1 , P17948 and NF - κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly - metastatic tumor growth and reduces the tumor weight by 61 . 6 % in tumor - bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR - Akt - NF - κB signaling pathways ; TBrC may have a wide therapeutic and / or adjuvant therapeutic application in the treatment of lung cancer .","The preclinical development of regorafenib for the treatment of colorectal cancer . INTRODUCTION : The DB01367 - RAF - MEK - P29323 pathway is one of the best characterized kinase cascades . During the exploration of small molecules that inhibit P04049 kinase , regorafenib ( DB08896 ) was discovered as a multikinase inhibitor which demonstrated anti - cancer , anti - angiogenic , and apoptotic activities in metastatic colorectal cancer . This was not the first multikinase inhibitor discovered for the disease ; indeed , before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012 , sorafenib ( BAY 43 - 9006 ) had already been developed to be the first in the world as a multikinase inhibitor for malignancy . Indeed , the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile , both as a kinase inhibitor as well as in its clinical application . AREAS COVERED : In this drug discovery case history , the authors review the design , discovery , and development of both regorafenib and sorafenib from back in the 1990s . Furthermore , the authors highlight the drug ' s anti - cancer and anti - angiogenic properties as well as its efficacy , safety pharmacology and toxicology based on FDA documents . EXPERT OPINION : In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently , our understanding of drug discovery , the approaches for kinase profiling , and technologies needed for their development are paramount . Indeed , the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics . Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive .","Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .","Activity of nilotinib ( Q9BXJ7 - 107 ) alone in advanced gastrointestinal stromal tumors progressing on imatinib and sunitinib . Case report . ___MASK45___ is a novel tyrosine kinase inhibitor targeting P10721 ( CD117 ) , P09619 and P11274 - P00519 and inhibiting the proliferation of both imatinib - sensitive and imatinib - resistant cells in vitro . ___MASK45___ , alone or in combination with imatinib , has promising activity in imatinib - resistant patients with advanced gastrointestinal stromal tumors ( GISTs ) , including those who progressed on sunitinib and other tyrosine kinase inhibitors . We describe the beneficial effect of nilotinib 400 mg b . i . d . orally in a 53 - year - old patient with metastatic GISTs who had radiologically confirmed disease progression on both imatinib ( 800 mg / day ) and sunitinib ( 50 mg / day ) . A positron emission tomography - computerized tomography evaluation showed marked decreases in ( 18 ) F - DB09150 uptake in the liver and mesentery region after 3 months of therapy with nilotinib . ___MASK45___ is an option for patients with advanced GISTs progressing on both imatinib and sunitinib .","The effects of five alkaloids from Bulbus Fritillariae on the concentration of DB02527 in P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid . The aim of this study was to investigate the effects of five alkaloids , namely verticine , verticinone , imperialine , imperialine - 3beta - D - glucoside , and puqietinone , purified from Bulbus Fritillariae and used as an antitussive drug in traditional Chinese medicine , on their antimuscarinic M ( 2 ) function and the DB02527 level of P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid . By transfecting the P29320 cells with the method of calcium phosphate co - precipitation and screening with G418 , the cells stably expressing M ( 2 ) receptor were identified . The expression of M ( 2 ) receptor in P29320 cells was confirmed by both RT - PCR and western blot . The DB02527 level in the treated cells was analyzed with RIA method ( ( 125 ) I - DB02527 P10721 ) . And the results suggested that the five alkaloids could significantly elevate the DB02527 concentration in the P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid ( p < 0 . 01 ) .","Functional cross talk between P61073 and P09619 on glioblastoma cells is essential for migration . Glioblastoma ( GBM ) is the most common and aggressive form of brain tumor , characterized by high migratory behavior and infiltration in brain parenchyma which render classic therapeutic approach ineffective . The migratory behaviour of GBM cells could be conditioned by a number of tissue - and glioma - derived cytokines and growth factors . Although the pro - migratory action of P48061 on GBM cells in vitro and in vivo is recognized , the molecular mechanisms involved are not clearly identified . In fact the signaling pathways involved in the pro - migratory action of P48061 may differ in individual glioblastoma and integrate with those resulting from abnormal expression and activation of growth factor receptors . In this study we investigated whether some of the receptor tyrosine kinases commonly expressed in GBM cells could cooperate with P48061 / P61073 in their migratory behavior . Our results show a functional cross - talk between P61073 and P09619 which appears to be essential for GBM chemotaxis .","DB08896 for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi - target inhibitor . Intracellular signals for cancer cell growth , proliferation , migration , and survival are frequently triggered by protein tyrosine kinases ( TKs ) . The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes . However , intrinsic resistance may limit the benefit of these drugs , and multiple escape routes compensate for the inhibited signaling . The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents . In this scenario , regorafenib has emerged as a novel , orally active , multitarget compound with potent activity against a number of angiogenic and stromal TKs , including vascular endothelial growth factor receptor 2 ( P35968 ) , tyrosine kinase with immunoglobulin - like and P01133 - like domains 2 ( P35590 - 2 ) , fibroblast growth factor receptor 1 ( P11362 ) , and platelet - derived growth factor receptor ( P09619 ) . Moreover , the drug has the capability of blocking P10721 , P07949 and V600 mutant P15056 . Starting from interesting preclinical results , this review describes the clinical development of regorafenib in gastrointestinal malignancies , focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors .","Casitas B - lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases . In addition to overexpression and the occurrence of activating mutations , receptors can be aberrantly activated by impaired downregulation . In this study , we show that an oncogenic mutant of the ubiquitin ligase casitas B - lineage lymphoma ( P22681 ; CBLΔexon8 ) , which is found in acute myeloid leukemia patients , predominantly cooperates with receptor tyrosine kinase ( RTK ) class III receptors ( P16234 , P09619 , P10721 , and P36888 ) , but not with non - class III RTKs or cytokine receptors , to induce P08700 - independent growth of Ba / P13726 cells . In cells coexpressing RTK class III / CBLΔexon8 , receptor internalization was delayed , and cells were protected from apoptosis after cytokine withdrawal . Ligand - stimulated Ba / P13726 cells and acute myeloid leukemia cell lines coexpressing the P22681 deletion mutant and P36888 showed enhanced AKT phosphorylation . Combined pharmacologic inhibition of the PI3K / AKT pathway and P36888 had an additive effect on cell proliferation . The transforming potential of the P22681 mutant was completely abolished by the mutation of the P22681 PTB domain and was decreased by the mutation of tyrosines 589 and 591 in the juxtamembrane domain of P36888 . A constitutively active P31749 mutant ( E17K ) recapitulated the phenotype induced by the P22681 deletion mutant in Ba / P13726 cells . This study reveals P36888 - P22681 interaction sites and the AKT pathway as critical mediators of transformation by oncogenic P22681 mutants .","[ New insights into hypereosinophilic syndromes ] . Hypereosinophilic syndrome ( DB09106 ) is characterized by chronic unexplained eosinophilia with organ involvement . The concept of DB09106 as a single disease entity is being challenged by the recent identification of multiple underlying molecular mechanisms . DB09106 can directly affect the eosinophil lineage ( often linked to a fusion gene Q6UN15 - P16234 , and corresponding in this case to chronic eosinophilic leukemia ) , or the lymphoid lineage , where eosinophilia is secondary to expansion of a T cell subset overproducing interleukin - 5 , a cytokine involved in eosinophilopoiesis . These recent discoveries have legitimized the use of tyrosine kinase inhibitors such as imatinib , which , by inhibiting P16234 , have transformed the prognosis of chronic eosinophilic leukemia , and also the use of monoclonal anti - P05113 antibodies , which are promising treatment for steroid - dependent DB09106 .","[ ___MASK36___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK36___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","Mast cells and eosinophils in mastocytosis , chronic eosinophilic leukemia , and non - clonal disorders . Mast cells and eosinophils often travel in the same biologic circles . In non - clonal states , such as allergic and inflammatory conditions , cell - to - cell contact and the pleiotropic actions of multiple cytokines and chemokines , derived from local tissues or mast cells themselves , foster the co - recruitment of these cells to the same geographic cellular niche . While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis , these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors . The dysregulated tyrosine kinases , D816V P10721 and Q6UN15 - P16234 , are the prototypic oncogenic lesions resulting in systemic mastocytosis ( SM ) and chronic eosinophilic leukemia , respectively . We review the pathobiology of these myeloproliferative neoplasms ( MPNs ) with a focus on the relationship between mast cells and eosinophils , and discuss murine models , which further elucidate how the phenotype of these diseases can be influenced by stem cell factor ( P21583 ) and expression of the potent eosinophilopoietic cytokine , interleukin - 5 ( P05113 ) . Therapy of SM and Q6UN15 - P16234 - positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed .","Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .","Phosphorylation of calmodulin by the epidermal - growth - factor - receptor tyrosine kinase . An epidermal - growth - factor ( P01133 )- receptor preparation isolated by calmodulin - affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin . P62158 phosphorylation was enhanced 3 - 8 - fold by P01133 , was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2 + . Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues . Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99 , located in the third calcium - binding domain of calmodulin , as the phosphorylated residue . Stoichiometric measurements show a 32P / calmodulin molar ratio of approximately 1 when optimal phosphorylation conditions are used .","Critical appraisal of the use of regorafenib in the management of colorectal cancer . The lack of valid clinical management options for patients affected by metastatic colorectal cancer , which has progressed after all approved standard treatments , has lead to research into new active molecules . DB08896 is an oral small - molecule multi kinase inhibitor , binding to several intracellular kinases , with powerful inhibitory activity against vascular endothelial growth factor receptors ( P17948 , P35968 , and P35916 ) , platelet - derived growth factor receptor , fibroblast growth factor receptor 1 , Raf , P35590 - 2 , and the kinases P10721 , P07949 , and P15056 . The antitumor activity of regorafenib has been tested in vitro and in vivo , and inhibition of tumor growth has been observed in several cancer models , particularly colorectal cancer and gastrointestinal stromal tumors . The most frequent adverse events of grade 3 or higher related to regorafenib were hand - foot skin reaction , fatigue , diarrhea , hypertension , and rash or desquamation . Only a few Phase I - II trials , and most recently a Phase III trial in pretreated colorectal cancer , have been carried out to date . Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy . At this point in time , regorafenib is the first small - molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients .","Inhibition of proliferation and migration of luminal and claudin - low breast cancer cells by P09619 inhibitors . BACKGROUND : Platelet - derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 in murine and human luminal - like and claudin - low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal - like and claudin - low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells .","Lessons learned from the irinotecan metabolic pathway . ___MASK88___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK88___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK88___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .","Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .","Cord blood stem - cell - derived dendritic cells generate potent antigen - specific immune responses and anti - tumour effects . The aim of the present study was to investigate whether CBSCs [ ( umbilical ) cord blood stem cells ] can be a new source of DCs ( dendritic cells ) , which can generate more potent antigen - specific immune responses and anti - tumour effects . CBSCs and PBMCs ( peripheral blood mononuclear cells ) were collected , cultured and differentiated into DCs . Surface markers , secreting cytokines , antigen - presentation activity , antigen - specific cell - mediated immunity and cytotoxic killing effects induced by these two DC origins were evaluated and compared . CBSCs were expanded ~ 17 - fold by ex vivo culture . The expression of surface markers in CBSC - derived DCs were higher than those in PBMC - derived DCs treated with LPS ( lipopolysaccharide ) . The CBSC - derived DCs mainly secreted IL ( interleukin )- 6 , P22301 and P01375 ( tumour necrosis factor ) - α , whereas PBMC - derived DCs mainly secreted P05113 and IFN ( interferon )- γ . The CBSC - derived DCs had better antigen - presentation abilities when stimulated with LPS or P01375 - α , induced higher numbers of IFN - γ - secreting antigen - specific CD8 + T - cells , as assessed using an ELISpot ( enzyme - linked immunosorbent spot ) assay , and stimulated more potent antigen - specific CTL ( cytotoxic T - cell ) activities ( P < 0 . 01 , one - way Q9UNW9 ) . CBSC - derived DCs had quicker and greater P29323 ( extracellular - signal - regulated kinase ) and Akt phosphorylation , and weaker p38 phosphorylation , than PBMC - derived DCs when stimulated with LPS . In conclusion , CBSC - derived DCs have the ability to induce stronger antigen - specific immunity and more potent anti - tumour effects and therefore could be a good source of DCs for use in DC - based cancer vaccines and immunotherapy .","The interleukin - 5 / receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras - P04049 - Q96HU1 kinase and the Jak - P35610 pathways in eosinophils . We have shown that the interaction of interleukin ( IL ) - 5 with the receptor activates Lyn tyrosine kinase within 1 min and Jak2 tyrosine kinase within 1 - 3 min . P05113 also stimulates GTP binding to P01112 . The signal is subsequently propagated through the activation of P04049 , MEK , and Q96HU1 kinases as shown by their increased autophosphorylation in vitro and phosphorylation in situ . Jak2 kinase has been shown to phosphorylate P35610 nuclear proteins . The activation of P35610 nuclear factors was studied by electrophoretic mobility shift assay using a gamma activation site ( GAS ) probe . We found that P05113 induces two GAS - binding proteins in eosinophils , one of which is P42224 . We conclude that P05113 induced signals are propagated through two distinct pathways : ( 1 ) Lyn --> Ras --> P04049 --> MEK --> Q96HU1 kinase and ( 2 ) Jak2 --> P42224 .","[ Genetic and epigenetic changes in colorectal cancer and genetic testing for personalized medicine ] . Recent studies have uncovered molecular pathways of colorectal cancer , including the chromosomal instability pathway and microsatellite pathway . In addition , according to genetic and epigenetic profiles , colorectal cancer can be subclassified into 3 distinct groups , named the CpG island methylator phenotype ( CIMP ) 1 , CIMP2 , and CIMP negative . CIMP1 is characterized by MSI and P15056 mutations and rare P01116 and p53 mutations . CIMP2 is associated with P01116 mutations and rare MSI , P15056 , or p53 mutations . CIMP negative cases have a high rate of p53 mutations and lower rates of MSI or mutations of P15056 or P01116 . Regarding genetic testing for personalized medicine for colorectal cancer , uridine disphosphate glucuronosyl transferase 1 ( UGT1 ) and P01116 tests are available . ___MASK88___ is one of the most effective chemotherapeutic agents in the treatment of metastatic colorectal cancer . The prodrug irinotecan is biotransformed by carboxylesterase into its active metabolite SN - 38 , which is inactivated by UGT1 into the inactive compound SN - 38G . Here we discuss P22309 gene polymorphism as a predictor of toxicity . The epidermal growth factor ( P00533 ) plays an important role in the development and progression of colorectal cancer . P01116 serves as a mediator between extracellular ligand binding and intracellular transduction of signals from P00533 to the nucleus . Activating P01116 mutations has been identified as a predictor of resistance to P00533 - directed antibodies such as cetuximab . Here we discuss the current understanding of P01116 mutations and the therapeutic effect of cetuximab .","P09874 deletion promotes subventricular zone neural stem cells toward a glial fate . Identification of critical factors involved in oligodendroglial fate specification from endogenous neural stem cells is relevant to the development of therapeutic interventions that aim to promote remyelination . Here we report a novel role of the DNA repair protein poly - ADP - ribose polymerase - 1 ( P09874 ) in regulating the neural stem cell profile in the postnatal mouse forebrain subventricular zone ( SVZ ) . We observed increased expression of Sox2 and Sox10 in the SVZ of postnatal day 11 ( P11 ) P09874 knockout mice . This increase corresponded to increased Olig2 expression in Sox2 - positive cells of the P09874 knockout mouse SVZ and decreased Map2abc expression compared with Sox2 / Olig2 and Sox2 / Map2abc expression in wild - type mice . We noted enhanced expression of proliferating oligodendrocyte progenitor cells ( OPCs ) at the expense of proliferating neuroblasts in the SVZ of P09874 knockout mice , by using Olig1 / Ki67 / O43602 , Q99942 / Ki67 / O43602 , and P09619 / BrdU / TuJ1 immunofluorescence labeling . In addition , the percentage of BrdU / Olig2 double - labeled cells increased in the SVZ and corpus callosum of P09874 knockout mice compared with wild - type mice . We also observed a decrease in O43602 - positive cells without a decrease in the overall SVZ area in P09874 knockout mice , further indicating a switch from neuroblast to OPC fate . P09874 knockout mice displayed thinning of MBP expression in the corpus callosum and external capsule , suggesting that the enhanced OPC proliferation in the SVZ might compensate for deficiency in myelination . Together , our results show that P09874 deletion promotes SVZ neural stem cells toward a glial fate and suggest that future studies target P09874 as a potential therapeutic strategy for demyelinating diseases .","Peptide - based targeting of the platelet - derived growth factor receptor beta . PURPOSE : The aim of this work is to identify new ligands targeting the platelet - derived growth factor receptor beta ( PDGFRβ ) . PROCEDURES : Biopanning was carried out with a 12 - amino - acid phage display library against the recombinant extracellular domain of PDGFRβ . The identified peptide P09619 - P1 was chemically synthesized and labeled with ( 125 ) I or ( 131 ) I . In vitro studies were performed on the PDGFRβ - expressing cell lines BxPC3 and MCF7 and on PDGFRβ - transfected P29320 cells in comparison to negative control wtHEK293 and CaIX - transfected P29320 cells . Biodistribution experiments were performed in Balb / c nude mice , carrying subcutaneously BxPC3 tumors . RESULTS : In vitro studies demonstrated a higher binding to BxPC3 , MCF7 , and PDGFRβ - tr - P29320 cells in comparison to negative control cell lines . Binding was inhibited up to 90 % by the unlabeled P09619 - P1 peptide . Organ distribution studies revealed a higher accumulation in BxPC3 tumors than in most organs . CONCLUSIONS : P09619 - P1 is a promising candidate for targeting human PDGFRβ .","DB08896 ( DB08896 ) : stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma . The introduction of targeted therapies , specifically those that target the P15692 receptor ( VEGFR ) , PDGF receptor ( P09619 ) and the P42345 pathways , has significantly changed the approach to patients with unresectable renal cell cancer ( RCC ) . However , drug resistance develops through bypassing of targeted pathways . DB08896 ( DB08896 ) is a novel bi - aryl urea compound that has potential anti - tumour activity in RCC , as along with targeting P15692 and PDGF receptors , it targets additional kinases associated with alternative pathways of angiogenesis and resistance to P15692 - targeted drugs . Based on a phase II clinical trial , the efficacy outcome of regorafenib in the first - line setting of unresectable RCC appears comparable that of other targeted first - line drugs . However , testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects . Further assessment of regorafenib should exploit the drug ' s ability to inhibit mechanisms of escape from anti - angiogenic treatment through biomarker - driven clinical trials .","Isolation of mouse DB05914 on the basis of expression of Sca - 1 and P09619 - α . Platelet - derived growth factor receptor α ( P09619 - α ) and stem cell antigen 1 ( Sca - 1 ) have recently been identified as selective markers of mouse DB05914 ( MSCs ) . P09619 - α (+) Sca - 1 (+) ( PαS ) MSCs have augmented growth potential and robust tri - lineage differentiation compared with standard culture - selected MSCs . In addition , the selective isolation of PαS MSCs avoids cellular contamination that can complicate other methods . Here we describe in detail our protocol to isolate PαS MSCs using flow cytometry . In brief , the tibia and femora are isolated and crushed using a pestle and mortar . The crushed bones are then chopped and incubated for 1 h at 37 ° C in 20 ml of DMEM containing 0 . 2 % ( wt / vol ) collagenase . The cell suspension is filtered before red blood cell lysis and incubated with the following antibodies : allophycocyanin ( P25054 ) - conjugated P09619 - α , FITC - conjugated Sca - 1 , phycoerythrin ( PE ) - conjugated P08575 and Ter119 . Appropriate gates are constructed on a cell sorter to exclude dead cells and lineage ( P08575 (+) Ter - 119 (+) ) - positive cells . Approximately 10 , 000 PαS MSCs may then be isolated per mouse . The total protocol takes ~ 7 h to complete .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK1___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )","Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .","Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK43___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK43___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK43___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .","DB08896 in metastatic colorectal cancer . DB08896 is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis ( P17948 , 2 , 3 ; angiopoietin - 1 receptor ) , oncogenesis ( stem cell growth factor receptor ; P07949 ; P15056 including BRAFV600E ) , and tumor microenvironment ( P09619 - β and FGFR ) . Based on data from the Phase III CORRECT study , regorafenib stands as a further option for patient affected by metastatic colorectal cancer who have exhausted previous available therapies . Its multi - targeted effect might explain activity in advanced lines of treatment , when cancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance , but also makes difficult to identify predictive biomarkers . In this article we examine preclinical as well as clinical data of regorafenib in the therapy of metastatic colorectal cancer , challenges for potential markers of efficacy and its role in the treatment algorithm .","Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK43___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK43___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .","Timing of the hepatic arterial phase at DB08884 - enhanced hepatic dynamic Q9BWK5 : comparison of the test - injection and the fixed - time delay method . PURPOSE : To compare the fixed - time - and the test - injection method with respect to the image quality of hypervascular hepatocellular carcinoma ( HCC ) and the adequacy of timing of the hepatic arterial phase ( HAP ) in DB08884 ( EOB ) enhanced Q9BWK5 . MATERIALS AND METHODS : We studied 63 patients with computed tomography ( CT ) - proven hypervascular HCC : 30 ( group 1 ) were scanned HAP using the fixed - time delay method ( protocol 1 ) ; in the other 33 ( group 2 ) , we applied the test - injection method ( protocol 2 ) . We compared the protocols with respect with tumor - to - liver contrast ( TLC ) , contrast - to - noise - ratio ( P21554 ) , and relative enhancement of the liver and tumor ( Q04864 , P07949 ) during HAP . Two radiologists compared the adequacy of HAP , image contrast , image noise , and overall image quality . RESULTS : Under protocol 2 , TLC , P21554 , and Q04864 and P07949 of hypervascular HCC were significantly higher ( P < 0 . 01 ) . The proportion of optimal HAP was significantly higher for protocol 2 than protocol 1 ( P < 0 . 01 ) . The visual score of the image contrast and the overall image quality were significantly higher in group 2 than group 1 ( P = 0 . 02 and P = 0 . 01 , respectively ) . CONCLUSION : At EOB - enhanced hepatic dynamic Q9BWK5 , the test - injection method yielded better image quality of hypervascular HCC and improved adequacy of timing of HAP .","Nerve growth factor activation of the extracellular signal - regulated kinase pathway is modulated by Ca ( 2 +) and calmodulin . Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons . Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA , which leads to the activation of several intracellular signaling pathways . Once activated , TrkA also allows for a rapid and moderate increase in intracellular calcium levels , which would contribute to the effects triggered by nerve growth factor in neurons . In this report , we analyzed the relationship of calcium to the activation of the Ras / extracellular signal - regulated kinase pathway in PC12 cells . We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal - regulated kinases after TrkA stimulation . We analyzed the elements of the pathway that lead to this activation , and we observed that calmodulin antagonists completely block the initial P04049 activation without affecting the function of upstream elements , such as Ras , Grb2 , Shc , and Trk . We have broadened our study to other stimuli that activate extracellular signal - regulated kinases through tyrosine kinase receptors , and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons . P62158 seems to regulate the full activation of P04049 after Ras activation , since functional Ras is necessary for P04049 activation after nerve growth factor stimulation and calmodulin - Sepharose is able to precipitate P04049 in a calcium - dependent manner .","___MASK45___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .","DB08896 . DB08896 ( DB08896 , Stivarga ® ) is an oral diphenylurea multikinase inhibitor that targets angiogenic ( P17948 - 3 , Q02763 ) , stromal ( P09619 - β , FGFR ) , and oncogenic receptor tyrosine kinases ( P10721 , P07949 , and RAF ) . DB08896 is the first small - molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies . Consequently , regorafenib was FDA approved for this indication . In addition , regorafenib treatment resulted in a significant improvement in progression - free survival ( PFS ) compared with placebo in patients with metastatic gastrointestinal stromal tumors ( GIST ) after progression on standard treatments and is also an FDA approved indication . Currently , regorafenib is examined in several clinical trials ( mostly phase II ) in different tumor entities , including renal cell carcinoma ( RCC ) , hepatocellular carcinoma ( HCC ) , and soft tissue sarcoma ( STS ) .","The development of regorafenib and its current and potential future role in cancer therapy . DB08896 is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types , in preclinical and clinical studies . Preclinical data show inhibitory activity of angiogenic , stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1 , 2 and 3 , tyrosine - protein kinase receptor P35590 - 2 , platelet - derived growth factor receptor β , fibroblast growth factor receptor 1 , proto - oncogene tyrosine - protein kinase receptor Ret , mast / stem cell growth factor receptor Kit , P04049 and wild - type and V600E mutant serine / threonine - protein kinase B - raf . Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3 - weeks - on / 1 - week - off schedule , or 100 mg daily on a continuous schedule , with adverse effects typical of other multikinase inhibitors . Phase II studies demonstrated clinical benefit in a variety of tumor types , mostly associated with prolonged stable disease . Phase III studies include the CORRECT trial , which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies . There is still much work to be done to determine the role of regorafenib in the future of cancer therapy . This review will focus on the development of regorafenib , from early preclinical work through phase I , II and III trials , as well as highlighting the current role and potential future directions of this novel agent .","Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .","Oncogenes in melanoma : an update . Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage . P15056 , P01111 , and P10721 are three well - known oncogenes involved in melanoma pathogenesis . Targeting of mutated P15056 kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients , underscoring the particular role of this oncogene in melanoma biology . However , recurrences regularly occur within several months , which supposedly involve further oncogenes . Moreover , oncogenic driver mutations have not been described for up to 30 % of all melanomas . In order to obtain a more complete picture of the mutational landscape of melanoma , more recent studies used high - throughput DNA sequencing technologies . A number of new oncogene candidates such as P28482 / 2 , Q15303 , Q12879 , Q14832 , P63000 , and Q70Z35 were identified . Their particular role in melanoma biology is currently under investigation . Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments . However , these findings await further validation in clinical studies . This review provides an overview on well - known melanoma oncogenes and new oncogene candidates , based on recent high - throughput sequencing studies . The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area . The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future .","The role of HIV - related chemokine receptors and chemokines in human erythropoiesis in vitro . In order to better define the role of HIV - related chemokines in human erythropoiesis we studied : A ) the expression of chemokine receptors , both on human P28906 (+) cells which include erythroid progenitors and on more mature erythroid cells ; B ) the functionality of these receptors by calcium flux , chemotaxis assay and phosphorylation of mitogen - activated protein kinases ( MAPK ) Q8NFH3 / 44 ( P27361 / P28482 ) and AKT , and finally C ) the influence of chemokines on BFU - E formation . We found that HIV - related chemokine receptor P61073 , but not P51681 , is detectable on human P28906 (+) BFU - E cells . P61073 surface expression decreased during erythroid maturation , although P61073 mRNA was still present in cells isolated from differentiated erythroid colonies . P48061 , a P61073 ligand , induced calcium flux and phosphorylation of MAPK ( Q8NFH3 / 44 ) and AKT in P28906 (+) P10721 (+) bone marrow mononuclear cells which contain BFU - E , as well as chemotactic activity of both human P28906 (+) BFU - E progenitors and erythroid cells isolated from day 2 - 6 BFU - E colonies . Responsiveness to P48061 decreased when the cells differentiated to the point of surface expression of the erythroid - specific marker P02724 . In contrast , the P51681 ligands ( macrophage inflammatory protein - 1alpha [ MIP - 1alpha ] , MIP - 1beta , and RANTES ) did not activate calcium flux , MAPK and AKT phosphorylation or chemotaxis of P28906 (+) P10721 (+) cells or cells isolated from the BFU - E colonies . Interestingly , none of the chemokines tested in this study had any effect on BFU - E colony formation . In conclusion , only P61073 is functional , and its specific ligand P48061 may therefore play an important role in the homing and / or retention of early erythroid precursors in the bone marrow environment .","Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .","DB08896 for cancer . INTRODUCTION : DB08896 ( DB08896 ) is a novel , orally active , diphenylurea multikinase inhibitor of P17948 - 3 , c - P10721 , P35590 - 2 , P09619 - β , P11362 , P07949 , RAF - 1 , P15056 and p38 Q96HU1 kinase . AREAS COVERED : This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies . The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile . Current clinical developments , especially in colorectal cancer ( CRC ) and gastrointestinal stromal tumor ( GIST ) , are addressed . Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed . EXPERT OPINION : DB08896 ( DB08896 ) is a novel , orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed . The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets . DB08896 has promising antineoplastic activity in various tumor types . Two large , randomized Phase III pivotal registration studies in patients with GIST and CRC , respectively , already completed enrolment , with final results being awaited . Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing . Moreover , regorafenib has recently been granted Orphan Drug Status for GIST tumors and ' fast track ' status for both GIST and CRC by the FDA .","P14416 signaling dynamics of dopamine D2 - neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS1R ) receptor - receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor - receptor interactions in Parkinson ' s disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET ( 2 ) ) evidence has for the first time been obtained in the current study for the existence of both D2LR / NTS1R and D2SR / NTS1R heteromers in living HEK293T cells . Through confocal laser microscopy the NTS1R ( GFP2 ) and D2R ( YFP ) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and / or LRA ) in the two participating receptors which may contribute to the formation of the D2R / NTS1R heteromers by participating in guide - clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 / 2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor - receptor interactions in the D2LR - NTS1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) .","Association of DNA repair gene polymorphisms with response to platinum - based doublet chemotherapy in patients with non - small - cell lung cancer . PURPOSE : To identify polymorphisms in DNA repair genes that affect responses to platinum - based doublet chemotherapy in patients with non - small - cell lung cancer ( NSCLC ) . PATIENTS AND METHODS : In total , 640 patients with NSCLC who received platinum - based doublet chemotherapy in the National Cancer Center Hospital in Japan from 2000 to 2008 and whose responses were evaluated by Response Evaluation Criteria in Solid Tumors ( RECIST ) participated in a study of the association between response and genotypes for 30 single nucleotide polymorphisms ( SNPs ) in 27 DNA repair genes . Candidate SNPs were selected in a discovery set of 201 patients , and their associations were validated in an independent set of 439 patients by prespecified P value criteria . RESULTS : Homozygotes for the minor allele P04637 - 72Pro of the Arg72Pro SNP in the P04637 gene showed a better response rate ( 54 . 3 % ) than those for the major allele P04637 - 72Arg ( 29 . 1 % ; P = 4 . 4 × 10 (- 5 ) ) irrespective of therapeutic regimens , and minor allele homozygotes had significantly longer progression - free and overall survivals than major allele homozygotes ( hazard ratio [ HR ] , 0 . 85 ; 95 % CI , 0 . 74 to 0 . 98 ; P = . 020 ; and HR , 0 . 86 ; 95 % CI , 0 . 74 to 0 . 99 ; P = . 039 ) . Minor allele carriers for SNP Lys940Arg in the poly ( ADP - ribose ) polymerase 1 ( P09874 ) gene showed a better response rate to the paclitaxel regimen ( 45 . 8 % ) than to the gemcitabine regimen ( 10 . 5 % ; P for interaction = . 019 ) . CONCLUSION : Polymorphisms in the P04637 and P09874 genes are involved in inter - individual differences in the response to platinum - based doublet chemotherapy in patients with NSCLC .","Molecular profiling in the treatment of colorectal cancer : focus on regorafenib . Metastatic colorectal cancer ( mCRC ) is a highly heterogeneous disease . Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies , including anti - P00533 antibodies , cetuximab and panitumumab , and P15692 inhibitors , bevacizumab , ramucirumab , and aflibercept . The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments , such as DB01367 mutation profiling for P00533 antibodies . DB08896 is a multikinase inhibitor currently used as late line therapy for mCRC . The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized . Here , we review currently available clinical evidence of mCRC molecular profiling , such as DB01367 , P15056 , and P22897 testing , and its role in targeted therapies with special focus on regorafenib treatment .","AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK69___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .","___MASK45___ : a phenylamino - pyrimidine derivative with activity against P11274 - P00519 , P10721 and P09619 kinases . The P11274 - P00519 kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia ( CML ) . However , mutations within the P00519 kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib . Multiple distinct P11274 - P00519 kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported . ___MASK45___ is a tyrosine kinase inhibitor 30 - fold more potent than imatinib against P11274 - P00519 kinase . ___MASK45___ is active against a wide range of imatinib - resistant P11274 - P00519 mutant isoforms , except for T315I . Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting . Studies addressing the activity of nilotinib in newly - diagnosed patients with CML are underway . Furthermore , nilotinib is a potent inhibitor of P10721 and P09619 kinases . Here , we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by P10721 and / or P09619 mutant kinases , such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia .","DB08896 for treatment of advanced gastrointestinal stromal tumors . INTRODUCTION : Gastrointestinal stromal tumors ( GISTs ) are abdominal sarcomas which are extremely refractory to chemotherapy treatment . The treatment of GISTs has been revolutionized by use of P10721 / platelet - derived growth factor receptor - α ( P16234 ) kinase inhibitors . Unfortunately , most tumors develop resistance to front - line ( imatinib ) or second - line ( sunitinib ) therapy . DB08896 , a P10721 / P16234 / vascular endothelial growth factor receptor ( VEGFR ) oral kinase inhibitor , has been shown to improve progression - free survival in the third - or fourth - line setting . AREAS COVERED : This review covers the preclinical and clinical studies of regorafenib for treatment of GIST . A literature search on regorafenib was carried out using the PubMed database up to October 2013 . EXPERT OPINION : Currently , imatinib and sunitinib represent the only proven first - and second - line therapies , respectively , for advanced GISTs . Based on the results of a Phase III study , regorafenib is now established as the only proven third - line therapy . DB08896 activity in this setting is believed to be due to its activity against oncogenic forms of P10721 / P16234 . Although side effects are common with this agent , they can be effectively managed with a combination of supportive care , dose interruptions / reductions . The toxicity profile is similar to other oral kinase inhibitors with anti - VEGFR activity . DB08896 is mainly metabolized by P08684 , and concomitant use of strong inducers / inhibitors of this enzyme should be avoided .","Role of P15056 in thyroid oncogenesis . P15056 , a cytoplasmic serine - threonine protein kinase , plays a critical role in cell signaling as an activator within the mitogen - activated protein kinase ( MAPK ) pathway . The most common P15056 mutation is the V600E transversion , which causes constitutive kinase activity . This mutation has been found in a multitude of human cancers , including both papillary thyroid cancer ( PTC ) and papillary - derived anaplastic thyroid cancer ( ATC ) , in which it initiates follicular cell transformation . With such a high frequency of P15056 mutations in PTC ( 44 % ) and PTC - derived ATC ( 24 % ) , research in P15056 ( V600E ) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence . P15056 ( V600E ) in PTC has also provided valuable prognostic information , as its presence has been correlated with more aggressive and iodine - resistant phenotypes . Such findings have initiated research in targeting oncogenic P15056 in cancer therapeutics . Although multiple phase II clinical trials in patients with iodine - refractory metastatic PTC have shown significant efficacy for sorafenib , a first - generation P15056 inhibitor , the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib . Additionally , preclinical and clinical studies investigating combination therapy with agents such as selective ( PLX 4032 ) and potent ( DB08896 and ARQ 736 ) small - molecule P15056 inhibitors and Q96HU1 / extracellular signal - regulated kinase ( P29323 ) kinase inhibitors ( AZD6244 ) hold great promise in the treatment of P15056 ( V600E ) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC .","Management of regorafenib - related toxicities : a review . DB08896 ( Stivarga , DB08896 ; Bayer Pharma AG , Berlin , Germany ) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 ( P35968 ) , P17948 , P35916 , fibroblast growth factor receptor 1 ( P11362 ) , RAF , P10721 , P07949 and P15056 . Its antiangiogenic effect is greater than that of its related drug , sorafenib . DB08896 has been approved by the US Food and Drug Administration ( FDA ) for the treatment of metastatic colorectal cancer ( mCRC ) in patients who have failed treatment with fluoropyrimidine , oxaliplatin and irinotecan based chemotherapy , an anti - P15692 therapy and , if P01116 wild type , an anti - P00533 therapy . The FDA based this approval on data from the CORRECT trial , which showed the efficacy of regorafenib compared with placebo . The most common grade 3 - 4 adverse reactions with the drug are hand foot skin reactions ( HFSR ) , diarrhea , hypertension and fatigue . This review discusses the efficacy data , and the incidence and management of regorafenib ' s toxicities .","Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK60___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .","Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .","Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .","AM251 induces apoptosis and G2 / M cell cycle arrest in A375 human melanoma cells . Human cutaneous melanoma is an aggressive and chemotherapy - resistant type of cancer . AM251 is a cannabinoid type 1 ( P21554 ) receptor antagonist / inverse agonist with off - target antitumor activity against pancreatic and colon cancer cells . The current study aimed to characterize the in - vitro antimelanoma activity of AM251 . The P15056 V600E mutant melanoma cell line , A375 , was used as an in - vitro model system . Characterization tools included a cell viability assay , nuclear morphology assessment , gene expression , western blot , flow cytometry with P08758 - FITC / 7 - AAD double staining , cell cycle analyses , and measurements of changes in intracellular DB02527 and calcium concentrations . AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability . AM251 , at a concentration that approximates the IC50 , downregulated genes encoding antiapoptotic proteins ( P10415 and survivin ) and increased transcription levels of proapoptotic Q07812 , induced alteration of P08758 reactivity , DNA fragmentation , chromatin condensation in the cell nuclei , and G2 / M phase arrest . AM251 also induced a 40 % increase in the basal DB02527 levels , but it did not affect intracellular calcium concentrations . The involvement of Q9Y2T6 , O75762 , and P35354 in the AM251 mechanism of action was excluded . The combination of AM251 with celecoxib produced a synergistic antitumor activity , although the mechanism underlying this effect remains to be elucidated . This study provides the first evidence of a proapoptotic effect and G2 / M cell cycle arrest of AM251 on A375 cells . This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma .","Order of genes on human chromosome 5q with respect to 5q interstitial deletions . Using ( a ) somatic cell hybrids retaining partial chromosome 5 and ( b ) clinical samples from patients with acquired deletions of the long arm of chromosome 5 , combined with chromosome 5 - linked DNA probes , some of which exhibited RFLPs , we have determined the order of a series of genes on chromosome 5 . The order established is 5pter ---- MLVI - 2 ---- cen ---- P07686 ---- P00374 ---- Pi227 - --- cp12 . 6 ---- ( P05113 , P05112 ) ---- P08700 ---- P04141 ---- P05230 ---- ( P07333 , P09619 ) ---- ( treC , ADRBR ) ---- ( Q5SW96 - Q13585 , P09603 ) ---- qter . The suggested order and orientation for the closely linked P08700 / P04141 gene pair is cen ---- 5 ' P08700 3 ' ---- 5 ' P04141 3 ' ---- qter , on the basis of analysis of the P04141 rearrangement in HL60 DNA . The map position of the GRL locus , which was consistent with both somatic cell hybrid and 5q - analyses , was telomeric to P04141 and centromeric to P07333 / P09619 , near P05230 . Long - range restriction - enzyme analysis of 5q - DNAs did not detect rearrangements of 5q - linked probes except in HL60 DNA , but it did reveal putative long - range RFLPs of several loci . RFLPs for GRL , Pi227 , cp12 . 6 , P08700 , and P07333 can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions .","G protein - coupled receptor kinase - 3 - deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses . Chemokine receptor interactions coordinate leukocyte migration in inflammation . Chemokine receptors are GPCRs that when activated , are phosphorylated by GRKs to turn off G protein - mediated signaling yet recruit additional signaling machinery . Recently , P35626 was identified as a negative regulator of P48061 / P61073 signaling that is defective in human WHIM syndrome . Here , we report that P35626 -/- mice exhibit numerous features of human WHIM , such as impaired P48061 - mediated desensitization , enhanced P61073 signaling to P29323 activation , altered granulocyte migration , and a mild myelokathexis . Moreover , P35626 -/- protects mice from two acute models of inflammatory arthritis ( K / BxN serum transfer and CAIA ) . In these granulocyte - dependent disease models , protection of P35626 -/- mice is mediated by retention of cells in the marrow , fewer circulating granulocytes in the peripheral blood , and reduced granulocytes in the joints during active inflammation . In contrast to WHIM , P35626 -/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia . Thus , we conclude that the loss of P35626 - mediated regulation of P48061 / P61073 signaling contributes to some , but not all , of the complete WHIM phenotype and that P35626 inhibition may be beneficial in the treatment of inflammatory arthritis .","N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .","Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .","Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK75___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .","P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .","DB08896 ( DB08896 ) : a new oral multikinase inhibitor of angiogenic , stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Angiogenesis , a critical driver of tumor development , is controlled by interconnected signaling pathways . Vascular endothelial growth factor receptor ( VEGFR ) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature . DB08896 ( DB08896 ) , a novel oral multikinase inhibitor , potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays . Furthermore , regorafenib inhibits additional angiogenic kinases ( P17948 / 3 , platelet - derived growth factor receptor - β and fibroblast growth factor receptor 1 ) and the mutant oncogenic kinases P10721 , P07949 and B - RAF . The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast - enhanced magnetic resonance imaging . DB08896 administered once orally at 10 mg / kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts . In a daily ( qd )× 4 dosing study , the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition ( TGI ) . A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd × 5 dosing at 10 and 30 mg / kg . DB08896 exhibited potent dose - dependent TGI in various preclinical human xenograft models in mice , with tumor shrinkages observed in breast MDA - MB - 231 and renal 786 - O carcinoma models . Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki - 67 and phosphorylated extracellular regulated kinases 1 / 2 . These data demonstrate that regorafenib is a well - tolerated , orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies .","Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .","Biological and molecular effects of small molecule kinase inhibitors on low - passage human colorectal cancer cell lines . Low - passage cancer cell lines are versatile tools to study tumor cell biology . Here , we have employed four such cell lines , established from primary tumors of colorectal cancer ( CRC ) patients , to evaluate effects of the small molecule kinase inhibitors ( SMI ) vemurafenib , trametinib , perifosine , and regorafenib in an in vitro setting . The mutant P15056 ( V600E / V600K ) inhibitor vemurafenib , but also the Q02750 / 2 inhibitor trametinib efficiently inhibited DNA synthesis , signaling through P27361 / 2 and expression of genes downstream of P27361 / 2 in P15056 mutant cells only . In case of the AKT inhibitor perifosine , three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant . The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of P01116 , P15056 , P42336 , and P04637 mutations . DB08896 action was associated with broad - range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK / P29323 signaling . In vemurafenib - sensitive cells , the antiproliferative effect of vemurafenib was enhanced by the other SMI . Together , our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low - passage CRC cell lines as preclinical models ."],"string":"[\n \"Determination of ancestral allele for possible human cancer - associated polymorphisms . To determine ancestral allele in possible cancer - associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 ( alias IL - 1RA ) variable number tandem repeat ( VNTR ) ; P04818 ( previously TS ) VNTR ; AR CAG repeat ; dinucleotide repeats of P22309 , IGF1 , P01579 ( alias P01579 ) , P03372 ( alias P03372 ) , and P00533 ] and 9 single nucleotide polymorphisms ( P03956 - 1607 1G / 2G , P08254 - 1171 5A / 6A , O15527 Ser326Cys , P05091 Gly487Lys , P04637 Arg72Pro , Q9UNQ0 Gln141Lys , P16455 Leu84Phe , P04179 Ala - 9Val , and P42898 Ala222Val ) . No chimpanzee polymorphism corresponded to human P18510 VNTR ; the ancestral allele was a repeat lost in humans . Dinucleotide repeat polymorphisms of IGF1 , P01579 , P03372 , and P00533 were shared by chimpanzees , but the length of repeats tended to be longer in humans than in chimpanzees . This tendency was particularly evident for IGF1 . All of the SNPs tested are human - specific nucleotide changes . The ancestral allele 7A was shown to be lost in P08254 - 1171 5A / 6A . Thus , all of the possible cancer - associated polymorphisms tested have human - specific alleles , and the ancestral allele is lost in three polymorphisms ( P18510 VNTR , P22309 CA repeat , and P08254 - 1171 5A / 6A ) , suggesting a possible involvement of human - specific alleles in cancer susceptibility .\",\n \"Contribution of cubilin and amnionless to processing and membrane targeting of cubilin - amnionless complex . O60494 is a peripheral apical membrane receptor for multiple ligands that are taken up in several absorptive epithelia . Recently , amnionless ( Q9BXJ7 ) was identified to form a functional receptor complex with cubilin . By expression in transfected polarized MDCK cells of Q9BXJ7 and several cubilin fragments , including a functional \\\" mini \\\" version of cubilin , the processing , sorting , and membrane anchoring of the complex to the apical membrane were investigated . The results show that truncation mutants , including the N - terminal domain of cubilin , did not appear at the plasma membrane but instead were retained in the endoplasmic reticulum or partially secreted into the medium . Coexpression with Q9BXJ7 led to efficient transport to the apical cell surface of the cubilin constructs , which included the P01133 domains , and prevented release into the medium . Q9BXJ7 co - precipitated with cubilin and co - localized with cubilin at the apical cell surface . Apical sorting was observed for a broad set of nonoverlapping cubilin fragments without the N - terminal region , in the absence of Q9BXJ7 . The preference for apical sorting disappeared when glycosylation was inhibited by tunicamycin . In conclusion , it is shown that both units contribute to the processing of the cubilin - Q9BXJ7 complex to the apical membrane : Q9BXJ7 interacts with the P01133 domains of cubilin and is responsible for membrane attachment and export of the complex from the endoplasmic reticulum , whereas the extracellular cubilin molecule is responsible for apical sorting of the complex in a carbohydrate - dependent manner .\",\n \"Suppression of proliferation and migration in highly - metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly - metastatic lung cancer , the leading cause of cancer - related deaths in the world . In this study , we synthesized a new compound ethyl 6 - bromocoumarin - 3 - carboxylyl L - theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly - metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase - 3 and P09874 but also reduces the protein expressions of Bcl - 2 , cyclin D1 , P17948 and NF - κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly - metastatic tumor growth and reduces the tumor weight by 61 . 6 % in tumor - bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR - Akt - NF - κB signaling pathways ; TBrC may have a wide therapeutic and / or adjuvant therapeutic application in the treatment of lung cancer .\",\n \"The preclinical development of regorafenib for the treatment of colorectal cancer . INTRODUCTION : The DB01367 - RAF - MEK - P29323 pathway is one of the best characterized kinase cascades . During the exploration of small molecules that inhibit P04049 kinase , regorafenib ( DB08896 ) was discovered as a multikinase inhibitor which demonstrated anti - cancer , anti - angiogenic , and apoptotic activities in metastatic colorectal cancer . This was not the first multikinase inhibitor discovered for the disease ; indeed , before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012 , sorafenib ( BAY 43 - 9006 ) had already been developed to be the first in the world as a multikinase inhibitor for malignancy . Indeed , the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile , both as a kinase inhibitor as well as in its clinical application . AREAS COVERED : In this drug discovery case history , the authors review the design , discovery , and development of both regorafenib and sorafenib from back in the 1990s . Furthermore , the authors highlight the drug ' s anti - cancer and anti - angiogenic properties as well as its efficacy , safety pharmacology and toxicology based on FDA documents . EXPERT OPINION : In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently , our understanding of drug discovery , the approaches for kinase profiling , and technologies needed for their development are paramount . Indeed , the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics . Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive .\",\n \"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .\",\n \"Activity of nilotinib ( Q9BXJ7 - 107 ) alone in advanced gastrointestinal stromal tumors progressing on imatinib and sunitinib . Case report . ___MASK45___ is a novel tyrosine kinase inhibitor targeting P10721 ( CD117 ) , P09619 and P11274 - P00519 and inhibiting the proliferation of both imatinib - sensitive and imatinib - resistant cells in vitro . ___MASK45___ , alone or in combination with imatinib , has promising activity in imatinib - resistant patients with advanced gastrointestinal stromal tumors ( GISTs ) , including those who progressed on sunitinib and other tyrosine kinase inhibitors . We describe the beneficial effect of nilotinib 400 mg b . i . d . orally in a 53 - year - old patient with metastatic GISTs who had radiologically confirmed disease progression on both imatinib ( 800 mg / day ) and sunitinib ( 50 mg / day ) . A positron emission tomography - computerized tomography evaluation showed marked decreases in ( 18 ) F - DB09150 uptake in the liver and mesentery region after 3 months of therapy with nilotinib . ___MASK45___ is an option for patients with advanced GISTs progressing on both imatinib and sunitinib .\",\n \"The effects of five alkaloids from Bulbus Fritillariae on the concentration of DB02527 in P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid . The aim of this study was to investigate the effects of five alkaloids , namely verticine , verticinone , imperialine , imperialine - 3beta - D - glucoside , and puqietinone , purified from Bulbus Fritillariae and used as an antitussive drug in traditional Chinese medicine , on their antimuscarinic M ( 2 ) function and the DB02527 level of P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid . By transfecting the P29320 cells with the method of calcium phosphate co - precipitation and screening with G418 , the cells stably expressing M ( 2 ) receptor were identified . The expression of M ( 2 ) receptor in P29320 cells was confirmed by both RT - PCR and western blot . The DB02527 level in the treated cells was analyzed with RIA method ( ( 125 ) I - DB02527 P10721 ) . And the results suggested that the five alkaloids could significantly elevate the DB02527 concentration in the P29320 cells transfected with muscarinic M ( 2 ) receptor plasmid ( p < 0 . 01 ) .\",\n \"Functional cross talk between P61073 and P09619 on glioblastoma cells is essential for migration . Glioblastoma ( GBM ) is the most common and aggressive form of brain tumor , characterized by high migratory behavior and infiltration in brain parenchyma which render classic therapeutic approach ineffective . The migratory behaviour of GBM cells could be conditioned by a number of tissue - and glioma - derived cytokines and growth factors . Although the pro - migratory action of P48061 on GBM cells in vitro and in vivo is recognized , the molecular mechanisms involved are not clearly identified . In fact the signaling pathways involved in the pro - migratory action of P48061 may differ in individual glioblastoma and integrate with those resulting from abnormal expression and activation of growth factor receptors . In this study we investigated whether some of the receptor tyrosine kinases commonly expressed in GBM cells could cooperate with P48061 / P61073 in their migratory behavior . Our results show a functional cross - talk between P61073 and P09619 which appears to be essential for GBM chemotaxis .\",\n \"DB08896 for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi - target inhibitor . Intracellular signals for cancer cell growth , proliferation , migration , and survival are frequently triggered by protein tyrosine kinases ( TKs ) . The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes . However , intrinsic resistance may limit the benefit of these drugs , and multiple escape routes compensate for the inhibited signaling . The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents . In this scenario , regorafenib has emerged as a novel , orally active , multitarget compound with potent activity against a number of angiogenic and stromal TKs , including vascular endothelial growth factor receptor 2 ( P35968 ) , tyrosine kinase with immunoglobulin - like and P01133 - like domains 2 ( P35590 - 2 ) , fibroblast growth factor receptor 1 ( P11362 ) , and platelet - derived growth factor receptor ( P09619 ) . Moreover , the drug has the capability of blocking P10721 , P07949 and V600 mutant P15056 . Starting from interesting preclinical results , this review describes the clinical development of regorafenib in gastrointestinal malignancies , focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors .\",\n \"Casitas B - lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases . In addition to overexpression and the occurrence of activating mutations , receptors can be aberrantly activated by impaired downregulation . In this study , we show that an oncogenic mutant of the ubiquitin ligase casitas B - lineage lymphoma ( P22681 ; CBLΔexon8 ) , which is found in acute myeloid leukemia patients , predominantly cooperates with receptor tyrosine kinase ( RTK ) class III receptors ( P16234 , P09619 , P10721 , and P36888 ) , but not with non - class III RTKs or cytokine receptors , to induce P08700 - independent growth of Ba / P13726 cells . In cells coexpressing RTK class III / CBLΔexon8 , receptor internalization was delayed , and cells were protected from apoptosis after cytokine withdrawal . Ligand - stimulated Ba / P13726 cells and acute myeloid leukemia cell lines coexpressing the P22681 deletion mutant and P36888 showed enhanced AKT phosphorylation . Combined pharmacologic inhibition of the PI3K / AKT pathway and P36888 had an additive effect on cell proliferation . The transforming potential of the P22681 mutant was completely abolished by the mutation of the P22681 PTB domain and was decreased by the mutation of tyrosines 589 and 591 in the juxtamembrane domain of P36888 . A constitutively active P31749 mutant ( E17K ) recapitulated the phenotype induced by the P22681 deletion mutant in Ba / P13726 cells . This study reveals P36888 - P22681 interaction sites and the AKT pathway as critical mediators of transformation by oncogenic P22681 mutants .\",\n \"[ New insights into hypereosinophilic syndromes ] . Hypereosinophilic syndrome ( DB09106 ) is characterized by chronic unexplained eosinophilia with organ involvement . The concept of DB09106 as a single disease entity is being challenged by the recent identification of multiple underlying molecular mechanisms . DB09106 can directly affect the eosinophil lineage ( often linked to a fusion gene Q6UN15 - P16234 , and corresponding in this case to chronic eosinophilic leukemia ) , or the lymphoid lineage , where eosinophilia is secondary to expansion of a T cell subset overproducing interleukin - 5 , a cytokine involved in eosinophilopoiesis . These recent discoveries have legitimized the use of tyrosine kinase inhibitors such as imatinib , which , by inhibiting P16234 , have transformed the prognosis of chronic eosinophilic leukemia , and also the use of monoclonal anti - P05113 antibodies , which are promising treatment for steroid - dependent DB09106 .\",\n \"[ ___MASK36___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK36___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"Mast cells and eosinophils in mastocytosis , chronic eosinophilic leukemia , and non - clonal disorders . Mast cells and eosinophils often travel in the same biologic circles . In non - clonal states , such as allergic and inflammatory conditions , cell - to - cell contact and the pleiotropic actions of multiple cytokines and chemokines , derived from local tissues or mast cells themselves , foster the co - recruitment of these cells to the same geographic cellular niche . While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis , these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors . The dysregulated tyrosine kinases , D816V P10721 and Q6UN15 - P16234 , are the prototypic oncogenic lesions resulting in systemic mastocytosis ( SM ) and chronic eosinophilic leukemia , respectively . We review the pathobiology of these myeloproliferative neoplasms ( MPNs ) with a focus on the relationship between mast cells and eosinophils , and discuss murine models , which further elucidate how the phenotype of these diseases can be influenced by stem cell factor ( P21583 ) and expression of the potent eosinophilopoietic cytokine , interleukin - 5 ( P05113 ) . Therapy of SM and Q6UN15 - P16234 - positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed .\",\n \"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .\",\n \"Phosphorylation of calmodulin by the epidermal - growth - factor - receptor tyrosine kinase . An epidermal - growth - factor ( P01133 )- receptor preparation isolated by calmodulin - affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin . P62158 phosphorylation was enhanced 3 - 8 - fold by P01133 , was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2 + . Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues . Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99 , located in the third calcium - binding domain of calmodulin , as the phosphorylated residue . Stoichiometric measurements show a 32P / calmodulin molar ratio of approximately 1 when optimal phosphorylation conditions are used .\",\n \"Critical appraisal of the use of regorafenib in the management of colorectal cancer . The lack of valid clinical management options for patients affected by metastatic colorectal cancer , which has progressed after all approved standard treatments , has lead to research into new active molecules . DB08896 is an oral small - molecule multi kinase inhibitor , binding to several intracellular kinases , with powerful inhibitory activity against vascular endothelial growth factor receptors ( P17948 , P35968 , and P35916 ) , platelet - derived growth factor receptor , fibroblast growth factor receptor 1 , Raf , P35590 - 2 , and the kinases P10721 , P07949 , and P15056 . The antitumor activity of regorafenib has been tested in vitro and in vivo , and inhibition of tumor growth has been observed in several cancer models , particularly colorectal cancer and gastrointestinal stromal tumors . The most frequent adverse events of grade 3 or higher related to regorafenib were hand - foot skin reaction , fatigue , diarrhea , hypertension , and rash or desquamation . Only a few Phase I - II trials , and most recently a Phase III trial in pretreated colorectal cancer , have been carried out to date . Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy . At this point in time , regorafenib is the first small - molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients .\",\n \"Inhibition of proliferation and migration of luminal and claudin - low breast cancer cells by P09619 inhibitors . BACKGROUND : Platelet - derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 in murine and human luminal - like and claudin - low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal - like and claudin - low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells .\",\n \"Lessons learned from the irinotecan metabolic pathway . ___MASK88___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK88___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK88___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .\",\n \"Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .\",\n \"Cord blood stem - cell - derived dendritic cells generate potent antigen - specific immune responses and anti - tumour effects . The aim of the present study was to investigate whether CBSCs [ ( umbilical ) cord blood stem cells ] can be a new source of DCs ( dendritic cells ) , which can generate more potent antigen - specific immune responses and anti - tumour effects . CBSCs and PBMCs ( peripheral blood mononuclear cells ) were collected , cultured and differentiated into DCs . Surface markers , secreting cytokines , antigen - presentation activity , antigen - specific cell - mediated immunity and cytotoxic killing effects induced by these two DC origins were evaluated and compared . CBSCs were expanded ~ 17 - fold by ex vivo culture . The expression of surface markers in CBSC - derived DCs were higher than those in PBMC - derived DCs treated with LPS ( lipopolysaccharide ) . The CBSC - derived DCs mainly secreted IL ( interleukin )- 6 , P22301 and P01375 ( tumour necrosis factor ) - α , whereas PBMC - derived DCs mainly secreted P05113 and IFN ( interferon )- γ . The CBSC - derived DCs had better antigen - presentation abilities when stimulated with LPS or P01375 - α , induced higher numbers of IFN - γ - secreting antigen - specific CD8 + T - cells , as assessed using an ELISpot ( enzyme - linked immunosorbent spot ) assay , and stimulated more potent antigen - specific CTL ( cytotoxic T - cell ) activities ( P < 0 . 01 , one - way Q9UNW9 ) . CBSC - derived DCs had quicker and greater P29323 ( extracellular - signal - regulated kinase ) and Akt phosphorylation , and weaker p38 phosphorylation , than PBMC - derived DCs when stimulated with LPS . In conclusion , CBSC - derived DCs have the ability to induce stronger antigen - specific immunity and more potent anti - tumour effects and therefore could be a good source of DCs for use in DC - based cancer vaccines and immunotherapy .\",\n \"The interleukin - 5 / receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras - P04049 - Q96HU1 kinase and the Jak - P35610 pathways in eosinophils . We have shown that the interaction of interleukin ( IL ) - 5 with the receptor activates Lyn tyrosine kinase within 1 min and Jak2 tyrosine kinase within 1 - 3 min . P05113 also stimulates GTP binding to P01112 . The signal is subsequently propagated through the activation of P04049 , MEK , and Q96HU1 kinases as shown by their increased autophosphorylation in vitro and phosphorylation in situ . Jak2 kinase has been shown to phosphorylate P35610 nuclear proteins . The activation of P35610 nuclear factors was studied by electrophoretic mobility shift assay using a gamma activation site ( GAS ) probe . We found that P05113 induces two GAS - binding proteins in eosinophils , one of which is P42224 . We conclude that P05113 induced signals are propagated through two distinct pathways : ( 1 ) Lyn --> Ras --> P04049 --> MEK --> Q96HU1 kinase and ( 2 ) Jak2 --> P42224 .\",\n \"[ Genetic and epigenetic changes in colorectal cancer and genetic testing for personalized medicine ] . Recent studies have uncovered molecular pathways of colorectal cancer , including the chromosomal instability pathway and microsatellite pathway . In addition , according to genetic and epigenetic profiles , colorectal cancer can be subclassified into 3 distinct groups , named the CpG island methylator phenotype ( CIMP ) 1 , CIMP2 , and CIMP negative . CIMP1 is characterized by MSI and P15056 mutations and rare P01116 and p53 mutations . CIMP2 is associated with P01116 mutations and rare MSI , P15056 , or p53 mutations . CIMP negative cases have a high rate of p53 mutations and lower rates of MSI or mutations of P15056 or P01116 . Regarding genetic testing for personalized medicine for colorectal cancer , uridine disphosphate glucuronosyl transferase 1 ( UGT1 ) and P01116 tests are available . ___MASK88___ is one of the most effective chemotherapeutic agents in the treatment of metastatic colorectal cancer . The prodrug irinotecan is biotransformed by carboxylesterase into its active metabolite SN - 38 , which is inactivated by UGT1 into the inactive compound SN - 38G . Here we discuss P22309 gene polymorphism as a predictor of toxicity . The epidermal growth factor ( P00533 ) plays an important role in the development and progression of colorectal cancer . P01116 serves as a mediator between extracellular ligand binding and intracellular transduction of signals from P00533 to the nucleus . Activating P01116 mutations has been identified as a predictor of resistance to P00533 - directed antibodies such as cetuximab . Here we discuss the current understanding of P01116 mutations and the therapeutic effect of cetuximab .\",\n \"P09874 deletion promotes subventricular zone neural stem cells toward a glial fate . Identification of critical factors involved in oligodendroglial fate specification from endogenous neural stem cells is relevant to the development of therapeutic interventions that aim to promote remyelination . Here we report a novel role of the DNA repair protein poly - ADP - ribose polymerase - 1 ( P09874 ) in regulating the neural stem cell profile in the postnatal mouse forebrain subventricular zone ( SVZ ) . We observed increased expression of Sox2 and Sox10 in the SVZ of postnatal day 11 ( P11 ) P09874 knockout mice . This increase corresponded to increased Olig2 expression in Sox2 - positive cells of the P09874 knockout mouse SVZ and decreased Map2abc expression compared with Sox2 / Olig2 and Sox2 / Map2abc expression in wild - type mice . We noted enhanced expression of proliferating oligodendrocyte progenitor cells ( OPCs ) at the expense of proliferating neuroblasts in the SVZ of P09874 knockout mice , by using Olig1 / Ki67 / O43602 , Q99942 / Ki67 / O43602 , and P09619 / BrdU / TuJ1 immunofluorescence labeling . In addition , the percentage of BrdU / Olig2 double - labeled cells increased in the SVZ and corpus callosum of P09874 knockout mice compared with wild - type mice . We also observed a decrease in O43602 - positive cells without a decrease in the overall SVZ area in P09874 knockout mice , further indicating a switch from neuroblast to OPC fate . P09874 knockout mice displayed thinning of MBP expression in the corpus callosum and external capsule , suggesting that the enhanced OPC proliferation in the SVZ might compensate for deficiency in myelination . Together , our results show that P09874 deletion promotes SVZ neural stem cells toward a glial fate and suggest that future studies target P09874 as a potential therapeutic strategy for demyelinating diseases .\",\n \"Peptide - based targeting of the platelet - derived growth factor receptor beta . PURPOSE : The aim of this work is to identify new ligands targeting the platelet - derived growth factor receptor beta ( PDGFRβ ) . PROCEDURES : Biopanning was carried out with a 12 - amino - acid phage display library against the recombinant extracellular domain of PDGFRβ . The identified peptide P09619 - P1 was chemically synthesized and labeled with ( 125 ) I or ( 131 ) I . In vitro studies were performed on the PDGFRβ - expressing cell lines BxPC3 and MCF7 and on PDGFRβ - transfected P29320 cells in comparison to negative control wtHEK293 and CaIX - transfected P29320 cells . Biodistribution experiments were performed in Balb / c nude mice , carrying subcutaneously BxPC3 tumors . RESULTS : In vitro studies demonstrated a higher binding to BxPC3 , MCF7 , and PDGFRβ - tr - P29320 cells in comparison to negative control cell lines . Binding was inhibited up to 90 % by the unlabeled P09619 - P1 peptide . Organ distribution studies revealed a higher accumulation in BxPC3 tumors than in most organs . CONCLUSIONS : P09619 - P1 is a promising candidate for targeting human PDGFRβ .\",\n \"DB08896 ( DB08896 ) : stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma . The introduction of targeted therapies , specifically those that target the P15692 receptor ( VEGFR ) , PDGF receptor ( P09619 ) and the P42345 pathways , has significantly changed the approach to patients with unresectable renal cell cancer ( RCC ) . However , drug resistance develops through bypassing of targeted pathways . DB08896 ( DB08896 ) is a novel bi - aryl urea compound that has potential anti - tumour activity in RCC , as along with targeting P15692 and PDGF receptors , it targets additional kinases associated with alternative pathways of angiogenesis and resistance to P15692 - targeted drugs . Based on a phase II clinical trial , the efficacy outcome of regorafenib in the first - line setting of unresectable RCC appears comparable that of other targeted first - line drugs . However , testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects . Further assessment of regorafenib should exploit the drug ' s ability to inhibit mechanisms of escape from anti - angiogenic treatment through biomarker - driven clinical trials .\",\n \"Isolation of mouse DB05914 on the basis of expression of Sca - 1 and P09619 - α . Platelet - derived growth factor receptor α ( P09619 - α ) and stem cell antigen 1 ( Sca - 1 ) have recently been identified as selective markers of mouse DB05914 ( MSCs ) . P09619 - α (+) Sca - 1 (+) ( PαS ) MSCs have augmented growth potential and robust tri - lineage differentiation compared with standard culture - selected MSCs . In addition , the selective isolation of PαS MSCs avoids cellular contamination that can complicate other methods . Here we describe in detail our protocol to isolate PαS MSCs using flow cytometry . In brief , the tibia and femora are isolated and crushed using a pestle and mortar . The crushed bones are then chopped and incubated for 1 h at 37 ° C in 20 ml of DMEM containing 0 . 2 % ( wt / vol ) collagenase . The cell suspension is filtered before red blood cell lysis and incubated with the following antibodies : allophycocyanin ( P25054 ) - conjugated P09619 - α , FITC - conjugated Sca - 1 , phycoerythrin ( PE ) - conjugated P08575 and Ter119 . Appropriate gates are constructed on a cell sorter to exclude dead cells and lineage ( P08575 (+) Ter - 119 (+) ) - positive cells . Approximately 10 , 000 PαS MSCs may then be isolated per mouse . The total protocol takes ~ 7 h to complete .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK1___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .\",\n \"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK43___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK43___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK43___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .\",\n \"DB08896 in metastatic colorectal cancer . DB08896 is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis ( P17948 , 2 , 3 ; angiopoietin - 1 receptor ) , oncogenesis ( stem cell growth factor receptor ; P07949 ; P15056 including BRAFV600E ) , and tumor microenvironment ( P09619 - β and FGFR ) . Based on data from the Phase III CORRECT study , regorafenib stands as a further option for patient affected by metastatic colorectal cancer who have exhausted previous available therapies . Its multi - targeted effect might explain activity in advanced lines of treatment , when cancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance , but also makes difficult to identify predictive biomarkers . In this article we examine preclinical as well as clinical data of regorafenib in the therapy of metastatic colorectal cancer , challenges for potential markers of efficacy and its role in the treatment algorithm .\",\n \"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK43___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK43___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .\",\n \"Timing of the hepatic arterial phase at DB08884 - enhanced hepatic dynamic Q9BWK5 : comparison of the test - injection and the fixed - time delay method . PURPOSE : To compare the fixed - time - and the test - injection method with respect to the image quality of hypervascular hepatocellular carcinoma ( HCC ) and the adequacy of timing of the hepatic arterial phase ( HAP ) in DB08884 ( EOB ) enhanced Q9BWK5 . MATERIALS AND METHODS : We studied 63 patients with computed tomography ( CT ) - proven hypervascular HCC : 30 ( group 1 ) were scanned HAP using the fixed - time delay method ( protocol 1 ) ; in the other 33 ( group 2 ) , we applied the test - injection method ( protocol 2 ) . We compared the protocols with respect with tumor - to - liver contrast ( TLC ) , contrast - to - noise - ratio ( P21554 ) , and relative enhancement of the liver and tumor ( Q04864 , P07949 ) during HAP . Two radiologists compared the adequacy of HAP , image contrast , image noise , and overall image quality . RESULTS : Under protocol 2 , TLC , P21554 , and Q04864 and P07949 of hypervascular HCC were significantly higher ( P < 0 . 01 ) . The proportion of optimal HAP was significantly higher for protocol 2 than protocol 1 ( P < 0 . 01 ) . The visual score of the image contrast and the overall image quality were significantly higher in group 2 than group 1 ( P = 0 . 02 and P = 0 . 01 , respectively ) . CONCLUSION : At EOB - enhanced hepatic dynamic Q9BWK5 , the test - injection method yielded better image quality of hypervascular HCC and improved adequacy of timing of HAP .\",\n \"Nerve growth factor activation of the extracellular signal - regulated kinase pathway is modulated by Ca ( 2 +) and calmodulin . Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons . Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA , which leads to the activation of several intracellular signaling pathways . Once activated , TrkA also allows for a rapid and moderate increase in intracellular calcium levels , which would contribute to the effects triggered by nerve growth factor in neurons . In this report , we analyzed the relationship of calcium to the activation of the Ras / extracellular signal - regulated kinase pathway in PC12 cells . We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal - regulated kinases after TrkA stimulation . We analyzed the elements of the pathway that lead to this activation , and we observed that calmodulin antagonists completely block the initial P04049 activation without affecting the function of upstream elements , such as Ras , Grb2 , Shc , and Trk . We have broadened our study to other stimuli that activate extracellular signal - regulated kinases through tyrosine kinase receptors , and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons . P62158 seems to regulate the full activation of P04049 after Ras activation , since functional Ras is necessary for P04049 activation after nerve growth factor stimulation and calmodulin - Sepharose is able to precipitate P04049 in a calcium - dependent manner .\",\n \"___MASK45___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .\",\n \"DB08896 . DB08896 ( DB08896 , Stivarga ® ) is an oral diphenylurea multikinase inhibitor that targets angiogenic ( P17948 - 3 , Q02763 ) , stromal ( P09619 - β , FGFR ) , and oncogenic receptor tyrosine kinases ( P10721 , P07949 , and RAF ) . DB08896 is the first small - molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies . Consequently , regorafenib was FDA approved for this indication . In addition , regorafenib treatment resulted in a significant improvement in progression - free survival ( PFS ) compared with placebo in patients with metastatic gastrointestinal stromal tumors ( GIST ) after progression on standard treatments and is also an FDA approved indication . Currently , regorafenib is examined in several clinical trials ( mostly phase II ) in different tumor entities , including renal cell carcinoma ( RCC ) , hepatocellular carcinoma ( HCC ) , and soft tissue sarcoma ( STS ) .\",\n \"The development of regorafenib and its current and potential future role in cancer therapy . DB08896 is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types , in preclinical and clinical studies . Preclinical data show inhibitory activity of angiogenic , stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1 , 2 and 3 , tyrosine - protein kinase receptor P35590 - 2 , platelet - derived growth factor receptor β , fibroblast growth factor receptor 1 , proto - oncogene tyrosine - protein kinase receptor Ret , mast / stem cell growth factor receptor Kit , P04049 and wild - type and V600E mutant serine / threonine - protein kinase B - raf . Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3 - weeks - on / 1 - week - off schedule , or 100 mg daily on a continuous schedule , with adverse effects typical of other multikinase inhibitors . Phase II studies demonstrated clinical benefit in a variety of tumor types , mostly associated with prolonged stable disease . Phase III studies include the CORRECT trial , which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies . There is still much work to be done to determine the role of regorafenib in the future of cancer therapy . This review will focus on the development of regorafenib , from early preclinical work through phase I , II and III trials , as well as highlighting the current role and potential future directions of this novel agent .\",\n \"Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .\",\n \"Oncogenes in melanoma : an update . Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage . P15056 , P01111 , and P10721 are three well - known oncogenes involved in melanoma pathogenesis . Targeting of mutated P15056 kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients , underscoring the particular role of this oncogene in melanoma biology . However , recurrences regularly occur within several months , which supposedly involve further oncogenes . Moreover , oncogenic driver mutations have not been described for up to 30 % of all melanomas . In order to obtain a more complete picture of the mutational landscape of melanoma , more recent studies used high - throughput DNA sequencing technologies . A number of new oncogene candidates such as P28482 / 2 , Q15303 , Q12879 , Q14832 , P63000 , and Q70Z35 were identified . Their particular role in melanoma biology is currently under investigation . Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments . However , these findings await further validation in clinical studies . This review provides an overview on well - known melanoma oncogenes and new oncogene candidates , based on recent high - throughput sequencing studies . The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area . The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future .\",\n \"The role of HIV - related chemokine receptors and chemokines in human erythropoiesis in vitro . In order to better define the role of HIV - related chemokines in human erythropoiesis we studied : A ) the expression of chemokine receptors , both on human P28906 (+) cells which include erythroid progenitors and on more mature erythroid cells ; B ) the functionality of these receptors by calcium flux , chemotaxis assay and phosphorylation of mitogen - activated protein kinases ( MAPK ) Q8NFH3 / 44 ( P27361 / P28482 ) and AKT , and finally C ) the influence of chemokines on BFU - E formation . We found that HIV - related chemokine receptor P61073 , but not P51681 , is detectable on human P28906 (+) BFU - E cells . P61073 surface expression decreased during erythroid maturation , although P61073 mRNA was still present in cells isolated from differentiated erythroid colonies . P48061 , a P61073 ligand , induced calcium flux and phosphorylation of MAPK ( Q8NFH3 / 44 ) and AKT in P28906 (+) P10721 (+) bone marrow mononuclear cells which contain BFU - E , as well as chemotactic activity of both human P28906 (+) BFU - E progenitors and erythroid cells isolated from day 2 - 6 BFU - E colonies . Responsiveness to P48061 decreased when the cells differentiated to the point of surface expression of the erythroid - specific marker P02724 . In contrast , the P51681 ligands ( macrophage inflammatory protein - 1alpha [ MIP - 1alpha ] , MIP - 1beta , and RANTES ) did not activate calcium flux , MAPK and AKT phosphorylation or chemotaxis of P28906 (+) P10721 (+) cells or cells isolated from the BFU - E colonies . Interestingly , none of the chemokines tested in this study had any effect on BFU - E colony formation . In conclusion , only P61073 is functional , and its specific ligand P48061 may therefore play an important role in the homing and / or retention of early erythroid precursors in the bone marrow environment .\",\n \"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .\",\n \"DB08896 for cancer . INTRODUCTION : DB08896 ( DB08896 ) is a novel , orally active , diphenylurea multikinase inhibitor of P17948 - 3 , c - P10721 , P35590 - 2 , P09619 - β , P11362 , P07949 , RAF - 1 , P15056 and p38 Q96HU1 kinase . AREAS COVERED : This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies . The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile . Current clinical developments , especially in colorectal cancer ( CRC ) and gastrointestinal stromal tumor ( GIST ) , are addressed . Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed . EXPERT OPINION : DB08896 ( DB08896 ) is a novel , orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed . The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets . DB08896 has promising antineoplastic activity in various tumor types . Two large , randomized Phase III pivotal registration studies in patients with GIST and CRC , respectively , already completed enrolment , with final results being awaited . Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing . Moreover , regorafenib has recently been granted Orphan Drug Status for GIST tumors and ' fast track ' status for both GIST and CRC by the FDA .\",\n \"P14416 signaling dynamics of dopamine D2 - neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS1R ) receptor - receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor - receptor interactions in Parkinson ' s disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET ( 2 ) ) evidence has for the first time been obtained in the current study for the existence of both D2LR / NTS1R and D2SR / NTS1R heteromers in living HEK293T cells . Through confocal laser microscopy the NTS1R ( GFP2 ) and D2R ( YFP ) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and / or LRA ) in the two participating receptors which may contribute to the formation of the D2R / NTS1R heteromers by participating in guide - clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 / 2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor - receptor interactions in the D2LR - NTS1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) .\",\n \"Association of DNA repair gene polymorphisms with response to platinum - based doublet chemotherapy in patients with non - small - cell lung cancer . PURPOSE : To identify polymorphisms in DNA repair genes that affect responses to platinum - based doublet chemotherapy in patients with non - small - cell lung cancer ( NSCLC ) . PATIENTS AND METHODS : In total , 640 patients with NSCLC who received platinum - based doublet chemotherapy in the National Cancer Center Hospital in Japan from 2000 to 2008 and whose responses were evaluated by Response Evaluation Criteria in Solid Tumors ( RECIST ) participated in a study of the association between response and genotypes for 30 single nucleotide polymorphisms ( SNPs ) in 27 DNA repair genes . Candidate SNPs were selected in a discovery set of 201 patients , and their associations were validated in an independent set of 439 patients by prespecified P value criteria . RESULTS : Homozygotes for the minor allele P04637 - 72Pro of the Arg72Pro SNP in the P04637 gene showed a better response rate ( 54 . 3 % ) than those for the major allele P04637 - 72Arg ( 29 . 1 % ; P = 4 . 4 × 10 (- 5 ) ) irrespective of therapeutic regimens , and minor allele homozygotes had significantly longer progression - free and overall survivals than major allele homozygotes ( hazard ratio [ HR ] , 0 . 85 ; 95 % CI , 0 . 74 to 0 . 98 ; P = . 020 ; and HR , 0 . 86 ; 95 % CI , 0 . 74 to 0 . 99 ; P = . 039 ) . Minor allele carriers for SNP Lys940Arg in the poly ( ADP - ribose ) polymerase 1 ( P09874 ) gene showed a better response rate to the paclitaxel regimen ( 45 . 8 % ) than to the gemcitabine regimen ( 10 . 5 % ; P for interaction = . 019 ) . CONCLUSION : Polymorphisms in the P04637 and P09874 genes are involved in inter - individual differences in the response to platinum - based doublet chemotherapy in patients with NSCLC .\",\n \"Molecular profiling in the treatment of colorectal cancer : focus on regorafenib . Metastatic colorectal cancer ( mCRC ) is a highly heterogeneous disease . Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies , including anti - P00533 antibodies , cetuximab and panitumumab , and P15692 inhibitors , bevacizumab , ramucirumab , and aflibercept . The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments , such as DB01367 mutation profiling for P00533 antibodies . DB08896 is a multikinase inhibitor currently used as late line therapy for mCRC . The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized . Here , we review currently available clinical evidence of mCRC molecular profiling , such as DB01367 , P15056 , and P22897 testing , and its role in targeted therapies with special focus on regorafenib treatment .\",\n \"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK69___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .\",\n \"___MASK45___ : a phenylamino - pyrimidine derivative with activity against P11274 - P00519 , P10721 and P09619 kinases . The P11274 - P00519 kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia ( CML ) . However , mutations within the P00519 kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib . Multiple distinct P11274 - P00519 kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported . ___MASK45___ is a tyrosine kinase inhibitor 30 - fold more potent than imatinib against P11274 - P00519 kinase . ___MASK45___ is active against a wide range of imatinib - resistant P11274 - P00519 mutant isoforms , except for T315I . Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting . Studies addressing the activity of nilotinib in newly - diagnosed patients with CML are underway . Furthermore , nilotinib is a potent inhibitor of P10721 and P09619 kinases . Here , we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by P10721 and / or P09619 mutant kinases , such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia .\",\n \"DB08896 for treatment of advanced gastrointestinal stromal tumors . INTRODUCTION : Gastrointestinal stromal tumors ( GISTs ) are abdominal sarcomas which are extremely refractory to chemotherapy treatment . The treatment of GISTs has been revolutionized by use of P10721 / platelet - derived growth factor receptor - α ( P16234 ) kinase inhibitors . Unfortunately , most tumors develop resistance to front - line ( imatinib ) or second - line ( sunitinib ) therapy . DB08896 , a P10721 / P16234 / vascular endothelial growth factor receptor ( VEGFR ) oral kinase inhibitor , has been shown to improve progression - free survival in the third - or fourth - line setting . AREAS COVERED : This review covers the preclinical and clinical studies of regorafenib for treatment of GIST . A literature search on regorafenib was carried out using the PubMed database up to October 2013 . EXPERT OPINION : Currently , imatinib and sunitinib represent the only proven first - and second - line therapies , respectively , for advanced GISTs . Based on the results of a Phase III study , regorafenib is now established as the only proven third - line therapy . DB08896 activity in this setting is believed to be due to its activity against oncogenic forms of P10721 / P16234 . Although side effects are common with this agent , they can be effectively managed with a combination of supportive care , dose interruptions / reductions . The toxicity profile is similar to other oral kinase inhibitors with anti - VEGFR activity . DB08896 is mainly metabolized by P08684 , and concomitant use of strong inducers / inhibitors of this enzyme should be avoided .\",\n \"Role of P15056 in thyroid oncogenesis . P15056 , a cytoplasmic serine - threonine protein kinase , plays a critical role in cell signaling as an activator within the mitogen - activated protein kinase ( MAPK ) pathway . The most common P15056 mutation is the V600E transversion , which causes constitutive kinase activity . This mutation has been found in a multitude of human cancers , including both papillary thyroid cancer ( PTC ) and papillary - derived anaplastic thyroid cancer ( ATC ) , in which it initiates follicular cell transformation . With such a high frequency of P15056 mutations in PTC ( 44 % ) and PTC - derived ATC ( 24 % ) , research in P15056 ( V600E ) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence . P15056 ( V600E ) in PTC has also provided valuable prognostic information , as its presence has been correlated with more aggressive and iodine - resistant phenotypes . Such findings have initiated research in targeting oncogenic P15056 in cancer therapeutics . Although multiple phase II clinical trials in patients with iodine - refractory metastatic PTC have shown significant efficacy for sorafenib , a first - generation P15056 inhibitor , the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib . Additionally , preclinical and clinical studies investigating combination therapy with agents such as selective ( PLX 4032 ) and potent ( DB08896 and ARQ 736 ) small - molecule P15056 inhibitors and Q96HU1 / extracellular signal - regulated kinase ( P29323 ) kinase inhibitors ( AZD6244 ) hold great promise in the treatment of P15056 ( V600E ) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC .\",\n \"Management of regorafenib - related toxicities : a review . DB08896 ( Stivarga , DB08896 ; Bayer Pharma AG , Berlin , Germany ) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 ( P35968 ) , P17948 , P35916 , fibroblast growth factor receptor 1 ( P11362 ) , RAF , P10721 , P07949 and P15056 . Its antiangiogenic effect is greater than that of its related drug , sorafenib . DB08896 has been approved by the US Food and Drug Administration ( FDA ) for the treatment of metastatic colorectal cancer ( mCRC ) in patients who have failed treatment with fluoropyrimidine , oxaliplatin and irinotecan based chemotherapy , an anti - P15692 therapy and , if P01116 wild type , an anti - P00533 therapy . The FDA based this approval on data from the CORRECT trial , which showed the efficacy of regorafenib compared with placebo . The most common grade 3 - 4 adverse reactions with the drug are hand foot skin reactions ( HFSR ) , diarrhea , hypertension and fatigue . This review discusses the efficacy data , and the incidence and management of regorafenib ' s toxicities .\",\n \"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK60___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .\",\n \"Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .\",\n \"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .\",\n \"AM251 induces apoptosis and G2 / M cell cycle arrest in A375 human melanoma cells . Human cutaneous melanoma is an aggressive and chemotherapy - resistant type of cancer . AM251 is a cannabinoid type 1 ( P21554 ) receptor antagonist / inverse agonist with off - target antitumor activity against pancreatic and colon cancer cells . The current study aimed to characterize the in - vitro antimelanoma activity of AM251 . The P15056 V600E mutant melanoma cell line , A375 , was used as an in - vitro model system . Characterization tools included a cell viability assay , nuclear morphology assessment , gene expression , western blot , flow cytometry with P08758 - FITC / 7 - AAD double staining , cell cycle analyses , and measurements of changes in intracellular DB02527 and calcium concentrations . AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability . AM251 , at a concentration that approximates the IC50 , downregulated genes encoding antiapoptotic proteins ( P10415 and survivin ) and increased transcription levels of proapoptotic Q07812 , induced alteration of P08758 reactivity , DNA fragmentation , chromatin condensation in the cell nuclei , and G2 / M phase arrest . AM251 also induced a 40 % increase in the basal DB02527 levels , but it did not affect intracellular calcium concentrations . The involvement of Q9Y2T6 , O75762 , and P35354 in the AM251 mechanism of action was excluded . The combination of AM251 with celecoxib produced a synergistic antitumor activity , although the mechanism underlying this effect remains to be elucidated . This study provides the first evidence of a proapoptotic effect and G2 / M cell cycle arrest of AM251 on A375 cells . This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma .\",\n \"Order of genes on human chromosome 5q with respect to 5q interstitial deletions . Using ( a ) somatic cell hybrids retaining partial chromosome 5 and ( b ) clinical samples from patients with acquired deletions of the long arm of chromosome 5 , combined with chromosome 5 - linked DNA probes , some of which exhibited RFLPs , we have determined the order of a series of genes on chromosome 5 . The order established is 5pter ---- MLVI - 2 ---- cen ---- P07686 ---- P00374 ---- Pi227 - --- cp12 . 6 ---- ( P05113 , P05112 ) ---- P08700 ---- P04141 ---- P05230 ---- ( P07333 , P09619 ) ---- ( treC , ADRBR ) ---- ( Q5SW96 - Q13585 , P09603 ) ---- qter . The suggested order and orientation for the closely linked P08700 / P04141 gene pair is cen ---- 5 ' P08700 3 ' ---- 5 ' P04141 3 ' ---- qter , on the basis of analysis of the P04141 rearrangement in HL60 DNA . The map position of the GRL locus , which was consistent with both somatic cell hybrid and 5q - analyses , was telomeric to P04141 and centromeric to P07333 / P09619 , near P05230 . Long - range restriction - enzyme analysis of 5q - DNAs did not detect rearrangements of 5q - linked probes except in HL60 DNA , but it did reveal putative long - range RFLPs of several loci . RFLPs for GRL , Pi227 , cp12 . 6 , P08700 , and P07333 can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions .\",\n \"G protein - coupled receptor kinase - 3 - deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses . Chemokine receptor interactions coordinate leukocyte migration in inflammation . Chemokine receptors are GPCRs that when activated , are phosphorylated by GRKs to turn off G protein - mediated signaling yet recruit additional signaling machinery . Recently , P35626 was identified as a negative regulator of P48061 / P61073 signaling that is defective in human WHIM syndrome . Here , we report that P35626 -/- mice exhibit numerous features of human WHIM , such as impaired P48061 - mediated desensitization , enhanced P61073 signaling to P29323 activation , altered granulocyte migration , and a mild myelokathexis . Moreover , P35626 -/- protects mice from two acute models of inflammatory arthritis ( K / BxN serum transfer and CAIA ) . In these granulocyte - dependent disease models , protection of P35626 -/- mice is mediated by retention of cells in the marrow , fewer circulating granulocytes in the peripheral blood , and reduced granulocytes in the joints during active inflammation . In contrast to WHIM , P35626 -/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia . Thus , we conclude that the loss of P35626 - mediated regulation of P48061 / P61073 signaling contributes to some , but not all , of the complete WHIM phenotype and that P35626 inhibition may be beneficial in the treatment of inflammatory arthritis .\",\n \"N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .\",\n \"Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .\",\n \"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK75___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .\",\n \"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .\",\n \"DB08896 ( DB08896 ) : a new oral multikinase inhibitor of angiogenic , stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Angiogenesis , a critical driver of tumor development , is controlled by interconnected signaling pathways . Vascular endothelial growth factor receptor ( VEGFR ) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature . DB08896 ( DB08896 ) , a novel oral multikinase inhibitor , potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays . Furthermore , regorafenib inhibits additional angiogenic kinases ( P17948 / 3 , platelet - derived growth factor receptor - β and fibroblast growth factor receptor 1 ) and the mutant oncogenic kinases P10721 , P07949 and B - RAF . The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast - enhanced magnetic resonance imaging . DB08896 administered once orally at 10 mg / kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts . In a daily ( qd )× 4 dosing study , the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition ( TGI ) . A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd × 5 dosing at 10 and 30 mg / kg . DB08896 exhibited potent dose - dependent TGI in various preclinical human xenograft models in mice , with tumor shrinkages observed in breast MDA - MB - 231 and renal 786 - O carcinoma models . Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki - 67 and phosphorylated extracellular regulated kinases 1 / 2 . These data demonstrate that regorafenib is a well - tolerated , orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies .\",\n \"Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .\",\n \"Biological and molecular effects of small molecule kinase inhibitors on low - passage human colorectal cancer cell lines . Low - passage cancer cell lines are versatile tools to study tumor cell biology . Here , we have employed four such cell lines , established from primary tumors of colorectal cancer ( CRC ) patients , to evaluate effects of the small molecule kinase inhibitors ( SMI ) vemurafenib , trametinib , perifosine , and regorafenib in an in vitro setting . The mutant P15056 ( V600E / V600K ) inhibitor vemurafenib , but also the Q02750 / 2 inhibitor trametinib efficiently inhibited DNA synthesis , signaling through P27361 / 2 and expression of genes downstream of P27361 / 2 in P15056 mutant cells only . In case of the AKT inhibitor perifosine , three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant . The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of P01116 , P15056 , P42336 , and P04637 mutations . DB08896 action was associated with broad - range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK / P29323 signaling . In vemurafenib - sensitive cells , the antiproliferative effect of vemurafenib was enhanced by the other SMI . Together , our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low - passage CRC cell lines as preclinical models .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK1___","___MASK36___","___MASK43___","___MASK45___","___MASK60___","___MASK69___","___MASK75___","___MASK82___","___MASK88___"],"string":"[\n \"___MASK1___\",\n \"___MASK36___\",\n \"___MASK43___\",\n \"___MASK45___\",\n \"___MASK60___\",\n \"___MASK69___\",\n \"___MASK75___\",\n \"___MASK82___\",\n \"___MASK88___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK88___"},"id":{"kind":"string","value":"MH_train_90"}}},{"rowIdx":91,"cells":{"query":{"kind":"string","value":"interacts_with DB01436?"},"supports":{"kind":"list like","value":["Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK95___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK75___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK36___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .","Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .","Impact of 27 - hydroxycholesterol on amyloid - beta peptide production and DB00171 - binding cassette transporter expression in primary human neurons . DB04540 is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid - beta protein precursor processing to form amyloid - beta peptides , which are a major constituent of cerebral amyloid plaques associated with Alzheimer ' s disease . 27 - Hydroxycholesterol ( 27OHC ) is synthesized from cholesterol via sterol 27 - hydroxylase ( Q02318 ) in the brain and , unlike cholesterol , can cross into the brain through the blood brain barrier from the circulation . Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid - beta peptide generation , however , this has not been investigated in primary human neurons . Here we show that 27OHC significantly reduced amyloid - beta peptide detected in cell culture supernatants from primary human neurons . We also show that 27OHC does not affect alpha - , beta - or gamma - secretase activity but does upregulate the liver X receptor ( LXR ) responsive genes O95477 , P45844 and P02649 . These data suggest that 27OHC - mediated reduction in extracellular amyloid - beta peptide levels is potentially due to its action as an LXR ligand .","Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK12___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .","DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .","Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism . Drugs and bile acids are taken up into hepatocytes by specialized transport proteins localized at the basolateral membrane , e . g . , organic anion transporting polypeptides . Following intracellular metabolism by cytochrome P450 ( CYP ) enzymes , drug metabolites are excreted into bile or urine via DB00171 - dependent multidrug resistance proteins ( P08183 and MRPs ) . Bile acids are excreted mainly via the bile salt export pump ( O95342 , O95342 ) . The genes coding for drug and bile acid transporters and CYP enzymes are regulated by a complex network of transcriptional cascades , notably by the ligand - activated nuclear receptors Q96RI1 , O75469 , and CAR and by the ligand - independent nuclear receptor HNF - 4alpha . The bile acid synthesizing enzymes P22680 , Q9UNU6 , and Q02318 are subject to negative feedback regulation by bile acids , which is partly mediated through the transcriptional repressor Q15466 . The role of transcriptional cofactors , such as Q15788 and P20142 - 1 , in mediating the gene - specific effects of individual nuclear receptors is becoming increasingly evident .","Purification and characterization of mouse O15528 overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL / ES . The expression of mouse O15528 in Escherichia coli has been dramatically enhanced by coexpression of GroEL / ES . To reveal the enzymatic properties of O15528 , we measured its hydroxylation activity toward vitamin D3 and DB01436 ( 1alpha ( OH ) D3 ) in addition to the physiological substrate DB00146 . Surprisingly , O15528 converted vitamin D3 to 1alpha , DB00146 . Both 1alpha - hydroxylation activity toward vitamin D3 , and 25 - hydroxylation activity toward 1alpha ( OH ) D3 were observed . The Km and Vmax values for 25 - hydroxylation activity toward 1alpha ( OH ) D3 were estimated to be 1 . 7 microM and 0 . 51 mol / min / mol P450 , respectively , while those for 1alpha - hydroxylation activity toward DB00146 were 0 . 050 microM and 2 . 73 mol / min / mol P450 , respectively . Note that the substrate must be fixed in the opposite direction in the substrate - binding pocket of O15528 between 1alpha - hydroxylation and 25 - hydroxylation . Based on these results and the fact that human Q02318 and Streptomyces CYP105A1 also convert vitamin D3 to 1alpha , DB00146 , 1alpha - hydroxylation , and 25 - hydroxylation of vitamin D3 appear to be closely linked together .","Preimplantation mouse blastocysts fail to express CYP genes required for estrogen biosynthesis . Implantation is initiated on day 4 in the mouse and on day 13 in the pig . The preimplantation pig blastocyst synthesizes steroid hormones , but whether preimplantation rodent embryos also have this ability has remained unresolved for the last two decades . In this study , the mRNAs encoding NADPH - cytochrome P450 reductase ( P450 - reductase ) , adrenodoxin , lanosterol 14 - demethylase P450 ( Q16850 ) , 17 alpha - hydroxylase P450 ( P05093 ) , cholesterol side - chain cleavage P450 ( P05108 ) , sterol 27 - hydroxylase P450 ( Q02318 ) , and aromatase P450 ( P11511 ) were examined in day 4 mouse blastocysts ( day 1 = vaginal plug ) and in day 13 and 16 pig blastocysts using reverse transcription - polymerase chain reaction ( RT - PCR ) . In mouse blastocysts , mRNAs of P450 - reductase , adrenodoxin , and Q16850 , but not P05093 , P05108 , Q02318 , and P11511 , were detected . In agreement with this finding , no aromatase protein could be detected by immunohistochemistry . By contrast , all these mRNAs were detected in the pig blastocyst . Furthermore , both the ovarian and placental types of aromatase ( P11511 ) mRNAs were detected in the pig blastocyst on days 13 and 16 of pregnancy , although the ovarian form was more abundant . Both forms of aromatase were much higher in day 13 than in day 16 pig blastocysts . The results provide definitive evidence that the preimplantation mouse blastocyst , as opposed to the pig blastocyst , has no ability to synthesize estrogen and no steroidogenic capacity . Maternal estrogen synthesis is essential for implantation of the mouse blastocyst .","___MASK65___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK65___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK65___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK65___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK65___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK65___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .","Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .","27 - hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol - loaded cells . The nuclear receptors liver X receptor alpha ( LXRalpha ) ( Q13133 ) and LXRbeta ( P55055 ) are important regulators of genes involved in lipid metabolism , including O95477 , P45844 , and sterol regulatory element - binding protein - 1c ( SREBP - 1c ) . Although it has been demonstrated that oxysterols are LXR ligands , little is known about the identity of the physiological activators of these receptors . Here we confirm earlier studies demonstrating a dose - dependent induction of O95477 and P45844 in human monocyte - derived macrophages by cholesterol loading . In addition , we show that formation of 27 - hydroxycholesterol and cholestenoic acid , products of Q02318 action on cholesterol , is dependent on the dose of cholesterol used to load the cells . Other proposed LXR ligands , including 20 ( S )- hydroxycholesterol , 22 ( R )- hydroxycholesterol , and 24 ( S ), 25 - epoxycholesterol , could not be detected under these conditions . A role for Q02318 in regulation of cholesterol - induced genes was demonstrated by the following findings . 1 ) Introduction of Q02318 into P29320 - 293 cells conferred an induction of P45844 and SREBP - 1c ; 2 ) upon cholesterol loading , Q02318 - expressing cells induce these genes to a greater extent than in control cells ; 3 ) in Q02318 - deficient human skin fibroblasts , the induction of O95477 in response to cholesterol loading was ablated ; and 4 ) in a coactivator association assay , 27 - hydroxycholesterol functionally activated LXR . We conclude that 27 - hydroxylation of cholesterol is an important pathway for LXR activation in response to cholesterol overload .","___MASK46___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK46___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .","Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Mitochondrial cholesterol transport : a possible target in the management of hyperlipidemia . Q02318 ( Q02318 ) may defend cells against accumulation of excess cholesterol , making this enzyme a possible target in the management of hyperlipidemia . The study objective was to analyze cholesterol homeostatic responses to increases in Q02318 activity in HepG2 cells and primary human hepatocytes . Increasing Q02318 activity by increasing enzyme expression led to significant increases in bile acid synthesis with compensatory increases in P04035 ( HMGR ) activity / protein , P01130 ( P01130 ) mRNA , and P01130 - mediated cholesterol uptake . Under these conditions , only a small increase in cellular 27 - hydroxycholesterol ( 27OH - Chol ) concentration was observed . No changes were detected in mature sterol regulatory element - binding proteins ( SREBP ) 1 or 2 . Increasing Q02318 activity by increasing mitochondrial cholesterol transport ( i . e . , substrate availability ) led to greater increases in bile acid synthesis with significant increases in cellular 27OH - Chol concentration . Mature SREBP 2 protein decreased significantly with compensatory decreases in HMGR protein . No change was detected in mature SREBP 1 protein . Despite increasing 27OH - Chol and lowering SREBP 2 protein concentrations , P01130 mRNA increased significantly , suggesting alternative mechanisms of P01130 transcriptional regulation . These findings suggest that regulation of liver mitochondrial cholesterol transport represents a potential therapeutic strategy in the treatment of hyperlipidemia and atherosclerosis .","Interleukins 1α and 1β as regulators of steroidogenesis in human NCI - H295R adrenocortical cells . Inflammatory cytokines interleukin - 1 ( IL - 1 ) and tumor necrosis factor - α ( P01375 - α ) regulate the activity of the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis at several levels . Although hypothalamic P06850 secretion may be the primary mechanism by which these cytokines activate the Q9Y251 axis , IL - 1 expression is increased within the adrenal glands in models for systemic inflammation , and IL - 1 may augment adrenal glucocorticoid production . Our aim was to investigate the direct effects of IL - 1α and IL - 1β on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI - H295R cell line as a model . mRNAs encoding receptors for IL - 1 , P01375 - α , and leukemia inhibitory factor ( P15018 ) were detectable in the cell line ( Affymetrix microarray analysis ) . Both IL - 1α and IL - 1β increased cortisol , androstenedione , dehydroepiandrosterone and DB05804 production , and the accumulation of mRNAs for steroidogenic acute regulatory protein ( STAR ) , 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and 3β - hydroxysteroid dehydrogenase 2 ( P26439 ) in these cells ( P < 0 . 05 for all ) . Both ILs augmented P01375 - α - and P15018 - induced STAR and P05093 mRNA accumulation , and P01375 - α - induced cortisol production ( P < 0 . 05 for all ) . Both ILs also increased the apoptotic index of the cells ( P < 0 . 05 ) , which was efficiently neutralized by their specific antibodies . The IL - induced changes in the STAR , P26439 , and P05093 protein levels were not as evident as those in the respective mRNA levels . In conclusion , the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production , and thus explain the observed discrepancy between the cortisol and ___MASK17___ concentrations sometimes seen in sepsis and chronic inflammatory states .","Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK68___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK68___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK68___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .","Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .","Elevated expression of the genes encoding P01375 and thromboxane synthase in leucocytes from patients with systemic sclerosis . OBJECTIVE : To determine the expression of molecular markers of prostanoid / fatty acid signalling in leucocytes of patients with systemic sclerosis ( SSc ) . METHODS : Gene expression in patient leucocytes was analysed using real - time fluorescence reverse transcriptase polymerase chain reaction for tumour necrosis factor alpha ( P01375 ) , thromboxane synthase ( TXAS , CYP5A ) , prostacyclin synthase ( CYP8A ) , monocyte chemoattractant protein - 1 ( P13500 ) , peroxisome proliferator - activated receptors ( Q07869 ) alpha , delta and gamma , low - density lipoprotein - associated lipoprotein lipase A ( 2 ) ( Q13093 ) , apolipoprotein E ( apoE ) and cholesterol 27 - hydroxylase ( Q02318 ) . RESULTS : Both P01375 and TXAS showed an increase in mean expression in the diseased group ( 6 . 3 - fold and 5 . 6 - fold respectively , P < 0 . 0001 ) . These two markers , along with Q02318 , PPARgamma and apoE , provided predictive markers for the development of carotid artery disease within the SSc patient population . CONCLUSION : The elevated levels of P01375 and thromboxane seen in SSc patient sera are paralleled by increases in the expression of the appropriate genes in leucocytes . This method will allow us to screen for a large number of candidate markers of disease in order to increase our understanding of the processes underlying the pathology of SSc .","Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK32___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK32___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK32___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK32___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK32___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK32___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK32___ .","Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation ."],"string":"[\n \"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK95___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK75___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK36___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .\",\n \"Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .\",\n \"Impact of 27 - hydroxycholesterol on amyloid - beta peptide production and DB00171 - binding cassette transporter expression in primary human neurons . DB04540 is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid - beta protein precursor processing to form amyloid - beta peptides , which are a major constituent of cerebral amyloid plaques associated with Alzheimer ' s disease . 27 - Hydroxycholesterol ( 27OHC ) is synthesized from cholesterol via sterol 27 - hydroxylase ( Q02318 ) in the brain and , unlike cholesterol , can cross into the brain through the blood brain barrier from the circulation . Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid - beta peptide generation , however , this has not been investigated in primary human neurons . Here we show that 27OHC significantly reduced amyloid - beta peptide detected in cell culture supernatants from primary human neurons . We also show that 27OHC does not affect alpha - , beta - or gamma - secretase activity but does upregulate the liver X receptor ( LXR ) responsive genes O95477 , P45844 and P02649 . These data suggest that 27OHC - mediated reduction in extracellular amyloid - beta peptide levels is potentially due to its action as an LXR ligand .\",\n \"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK12___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .\",\n \"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .\",\n \"Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism . Drugs and bile acids are taken up into hepatocytes by specialized transport proteins localized at the basolateral membrane , e . g . , organic anion transporting polypeptides . Following intracellular metabolism by cytochrome P450 ( CYP ) enzymes , drug metabolites are excreted into bile or urine via DB00171 - dependent multidrug resistance proteins ( P08183 and MRPs ) . Bile acids are excreted mainly via the bile salt export pump ( O95342 , O95342 ) . The genes coding for drug and bile acid transporters and CYP enzymes are regulated by a complex network of transcriptional cascades , notably by the ligand - activated nuclear receptors Q96RI1 , O75469 , and CAR and by the ligand - independent nuclear receptor HNF - 4alpha . The bile acid synthesizing enzymes P22680 , Q9UNU6 , and Q02318 are subject to negative feedback regulation by bile acids , which is partly mediated through the transcriptional repressor Q15466 . The role of transcriptional cofactors , such as Q15788 and P20142 - 1 , in mediating the gene - specific effects of individual nuclear receptors is becoming increasingly evident .\",\n \"Purification and characterization of mouse O15528 overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL / ES . The expression of mouse O15528 in Escherichia coli has been dramatically enhanced by coexpression of GroEL / ES . To reveal the enzymatic properties of O15528 , we measured its hydroxylation activity toward vitamin D3 and DB01436 ( 1alpha ( OH ) D3 ) in addition to the physiological substrate DB00146 . Surprisingly , O15528 converted vitamin D3 to 1alpha , DB00146 . Both 1alpha - hydroxylation activity toward vitamin D3 , and 25 - hydroxylation activity toward 1alpha ( OH ) D3 were observed . The Km and Vmax values for 25 - hydroxylation activity toward 1alpha ( OH ) D3 were estimated to be 1 . 7 microM and 0 . 51 mol / min / mol P450 , respectively , while those for 1alpha - hydroxylation activity toward DB00146 were 0 . 050 microM and 2 . 73 mol / min / mol P450 , respectively . Note that the substrate must be fixed in the opposite direction in the substrate - binding pocket of O15528 between 1alpha - hydroxylation and 25 - hydroxylation . Based on these results and the fact that human Q02318 and Streptomyces CYP105A1 also convert vitamin D3 to 1alpha , DB00146 , 1alpha - hydroxylation , and 25 - hydroxylation of vitamin D3 appear to be closely linked together .\",\n \"Preimplantation mouse blastocysts fail to express CYP genes required for estrogen biosynthesis . Implantation is initiated on day 4 in the mouse and on day 13 in the pig . The preimplantation pig blastocyst synthesizes steroid hormones , but whether preimplantation rodent embryos also have this ability has remained unresolved for the last two decades . In this study , the mRNAs encoding NADPH - cytochrome P450 reductase ( P450 - reductase ) , adrenodoxin , lanosterol 14 - demethylase P450 ( Q16850 ) , 17 alpha - hydroxylase P450 ( P05093 ) , cholesterol side - chain cleavage P450 ( P05108 ) , sterol 27 - hydroxylase P450 ( Q02318 ) , and aromatase P450 ( P11511 ) were examined in day 4 mouse blastocysts ( day 1 = vaginal plug ) and in day 13 and 16 pig blastocysts using reverse transcription - polymerase chain reaction ( RT - PCR ) . In mouse blastocysts , mRNAs of P450 - reductase , adrenodoxin , and Q16850 , but not P05093 , P05108 , Q02318 , and P11511 , were detected . In agreement with this finding , no aromatase protein could be detected by immunohistochemistry . By contrast , all these mRNAs were detected in the pig blastocyst . Furthermore , both the ovarian and placental types of aromatase ( P11511 ) mRNAs were detected in the pig blastocyst on days 13 and 16 of pregnancy , although the ovarian form was more abundant . Both forms of aromatase were much higher in day 13 than in day 16 pig blastocysts . The results provide definitive evidence that the preimplantation mouse blastocyst , as opposed to the pig blastocyst , has no ability to synthesize estrogen and no steroidogenic capacity . Maternal estrogen synthesis is essential for implantation of the mouse blastocyst .\",\n \"___MASK65___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK65___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK65___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK65___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK65___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK65___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .\",\n \"Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .\",\n \"27 - hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol - loaded cells . The nuclear receptors liver X receptor alpha ( LXRalpha ) ( Q13133 ) and LXRbeta ( P55055 ) are important regulators of genes involved in lipid metabolism , including O95477 , P45844 , and sterol regulatory element - binding protein - 1c ( SREBP - 1c ) . Although it has been demonstrated that oxysterols are LXR ligands , little is known about the identity of the physiological activators of these receptors . Here we confirm earlier studies demonstrating a dose - dependent induction of O95477 and P45844 in human monocyte - derived macrophages by cholesterol loading . In addition , we show that formation of 27 - hydroxycholesterol and cholestenoic acid , products of Q02318 action on cholesterol , is dependent on the dose of cholesterol used to load the cells . Other proposed LXR ligands , including 20 ( S )- hydroxycholesterol , 22 ( R )- hydroxycholesterol , and 24 ( S ), 25 - epoxycholesterol , could not be detected under these conditions . A role for Q02318 in regulation of cholesterol - induced genes was demonstrated by the following findings . 1 ) Introduction of Q02318 into P29320 - 293 cells conferred an induction of P45844 and SREBP - 1c ; 2 ) upon cholesterol loading , Q02318 - expressing cells induce these genes to a greater extent than in control cells ; 3 ) in Q02318 - deficient human skin fibroblasts , the induction of O95477 in response to cholesterol loading was ablated ; and 4 ) in a coactivator association assay , 27 - hydroxycholesterol functionally activated LXR . We conclude that 27 - hydroxylation of cholesterol is an important pathway for LXR activation in response to cholesterol overload .\",\n \"___MASK46___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK46___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .\",\n \"Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Mitochondrial cholesterol transport : a possible target in the management of hyperlipidemia . Q02318 ( Q02318 ) may defend cells against accumulation of excess cholesterol , making this enzyme a possible target in the management of hyperlipidemia . The study objective was to analyze cholesterol homeostatic responses to increases in Q02318 activity in HepG2 cells and primary human hepatocytes . Increasing Q02318 activity by increasing enzyme expression led to significant increases in bile acid synthesis with compensatory increases in P04035 ( HMGR ) activity / protein , P01130 ( P01130 ) mRNA , and P01130 - mediated cholesterol uptake . Under these conditions , only a small increase in cellular 27 - hydroxycholesterol ( 27OH - Chol ) concentration was observed . No changes were detected in mature sterol regulatory element - binding proteins ( SREBP ) 1 or 2 . Increasing Q02318 activity by increasing mitochondrial cholesterol transport ( i . e . , substrate availability ) led to greater increases in bile acid synthesis with significant increases in cellular 27OH - Chol concentration . Mature SREBP 2 protein decreased significantly with compensatory decreases in HMGR protein . No change was detected in mature SREBP 1 protein . Despite increasing 27OH - Chol and lowering SREBP 2 protein concentrations , P01130 mRNA increased significantly , suggesting alternative mechanisms of P01130 transcriptional regulation . These findings suggest that regulation of liver mitochondrial cholesterol transport represents a potential therapeutic strategy in the treatment of hyperlipidemia and atherosclerosis .\",\n \"Interleukins 1α and 1β as regulators of steroidogenesis in human NCI - H295R adrenocortical cells . Inflammatory cytokines interleukin - 1 ( IL - 1 ) and tumor necrosis factor - α ( P01375 - α ) regulate the activity of the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis at several levels . Although hypothalamic P06850 secretion may be the primary mechanism by which these cytokines activate the Q9Y251 axis , IL - 1 expression is increased within the adrenal glands in models for systemic inflammation , and IL - 1 may augment adrenal glucocorticoid production . Our aim was to investigate the direct effects of IL - 1α and IL - 1β on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI - H295R cell line as a model . mRNAs encoding receptors for IL - 1 , P01375 - α , and leukemia inhibitory factor ( P15018 ) were detectable in the cell line ( Affymetrix microarray analysis ) . Both IL - 1α and IL - 1β increased cortisol , androstenedione , dehydroepiandrosterone and DB05804 production , and the accumulation of mRNAs for steroidogenic acute regulatory protein ( STAR ) , 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and 3β - hydroxysteroid dehydrogenase 2 ( P26439 ) in these cells ( P < 0 . 05 for all ) . Both ILs augmented P01375 - α - and P15018 - induced STAR and P05093 mRNA accumulation , and P01375 - α - induced cortisol production ( P < 0 . 05 for all ) . Both ILs also increased the apoptotic index of the cells ( P < 0 . 05 ) , which was efficiently neutralized by their specific antibodies . The IL - induced changes in the STAR , P26439 , and P05093 protein levels were not as evident as those in the respective mRNA levels . In conclusion , the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production , and thus explain the observed discrepancy between the cortisol and ___MASK17___ concentrations sometimes seen in sepsis and chronic inflammatory states .\",\n \"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK68___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK68___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK68___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .\",\n \"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .\",\n \"Elevated expression of the genes encoding P01375 and thromboxane synthase in leucocytes from patients with systemic sclerosis . OBJECTIVE : To determine the expression of molecular markers of prostanoid / fatty acid signalling in leucocytes of patients with systemic sclerosis ( SSc ) . METHODS : Gene expression in patient leucocytes was analysed using real - time fluorescence reverse transcriptase polymerase chain reaction for tumour necrosis factor alpha ( P01375 ) , thromboxane synthase ( TXAS , CYP5A ) , prostacyclin synthase ( CYP8A ) , monocyte chemoattractant protein - 1 ( P13500 ) , peroxisome proliferator - activated receptors ( Q07869 ) alpha , delta and gamma , low - density lipoprotein - associated lipoprotein lipase A ( 2 ) ( Q13093 ) , apolipoprotein E ( apoE ) and cholesterol 27 - hydroxylase ( Q02318 ) . RESULTS : Both P01375 and TXAS showed an increase in mean expression in the diseased group ( 6 . 3 - fold and 5 . 6 - fold respectively , P < 0 . 0001 ) . These two markers , along with Q02318 , PPARgamma and apoE , provided predictive markers for the development of carotid artery disease within the SSc patient population . CONCLUSION : The elevated levels of P01375 and thromboxane seen in SSc patient sera are paralleled by increases in the expression of the appropriate genes in leucocytes . This method will allow us to screen for a large number of candidate markers of disease in order to increase our understanding of the processes underlying the pathology of SSc .\",\n \"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK32___ and its - in terms of P36551 - inhibition - \\\" inactive \\\" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK32___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK32___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK32___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK32___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK32___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK32___ .\",\n \"Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK12___","___MASK17___","___MASK32___","___MASK36___","___MASK46___","___MASK65___","___MASK68___","___MASK75___","___MASK95___"],"string":"[\n \"___MASK12___\",\n \"___MASK17___\",\n \"___MASK32___\",\n \"___MASK36___\",\n \"___MASK46___\",\n \"___MASK65___\",\n \"___MASK68___\",\n \"___MASK75___\",\n \"___MASK95___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK36___"},"id":{"kind":"string","value":"MH_train_91"}}},{"rowIdx":92,"cells":{"query":{"kind":"string","value":"interacts_with DB00216?"},"supports":{"kind":"list like","value":["Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .","Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK5___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .","Intramuscular gene transfer of P80511 inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta . P80511 is a well - known neuropeptide that has various protective effects on cardiovascular system . Our previous studies have shown that P80511 inhibits vascular smooth muscle cell ( VSMC ) proliferation in vitro . The present study aimed to explore the role of the P80511 in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism . Gene transfer of P80511 was performed with the use of intramuscular electroporation in a balloon - injured rat aorta model . Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase - mediated dUTP nick - end labeling assay . Overexpression of the P80511 gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer , as assessed by the intima - to - media ratio 14 days after balloon injury ( 29 . 2 +/- 3 . 7 % vs . 52 . 7 +/- 5 . 4 % ; n = 9 - 12 , P < 0 . 05 ) . In addition , P80511 gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury . Similarly , the addition of bioactive P80511 and the nitric oxide donor induced similar apoptosis in cultured VSMCs . The antagonist of the P80511 ( 1 ) receptor and inhibitors of DB02527 - PKA and nitric oxide blocked P80511 - mediated apoptosis . Furthermore , P80511 gene transfer increased inducible nitric oxide synthase and p53 but decreased P12004 and Bcl - 2 protein levels in balloon - injured rat aorta . Our data demonstrated that P80511 potently inhibited neointimal thickening in the rat aorta , at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro . Therefore , delivery of the P80511 gene may have therapeutic implications in limiting vascular restenosis .","P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK97___ ) in castrated male and female mice subjected to ___MASK97___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK97___ in mice CPs .","Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .","___MASK90___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK90___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK90___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .","Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .","Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .","P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK77___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK77___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK77___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK77___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .","Increased serum levels of P05109 / A9 and P80511 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus . OBJECTIVES : Patients with SLE have an increased morbidity and mortality from cardiovascular disease ( CVD ) . The reason for this is not entirely understood , but is believed to be partly related to the long - lasting inflammatory process seen in SLE . The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins P05109 / A9 and P80511 in SLE . METHODS : Serum levels of P05109 / A9 and P80511 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections , as well as in 100 healthy individuals . Cardiovascular manifestations were defined according to the SLICC / P10323 Damage Index ( SLICC / P10323 - DI ) . RESULTS : Serum levels of P05109 / A9 were elevated in our inactive SLE patients as compared with healthy individuals ( P < 0 . 0001 ) , which was not seen for P80511 ( P = 0 . 12 ) . SLE patients with a history of CVD had increased serum levels of both P05109 / A9 and P80511 compared with patients with no CVD or venous thromboembolism ( P = 0 . 003 and P = 0 . 006 , respectively ) . The presence of organ damage according to SLICC / P10323 - DI was associated with an increase in both P05109 / A9 and P80511 serum levels ( P = 0 . 001 and P = 0 . 006 , respectively ) . CONCLUSION : Elevated serum levels of P05109 / A9 and P80511 may be used as an indicator of severe disease and CVD in SLE , suggesting that SLE patients with elevated serum P05109 / A9 and P80511 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment .","Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .","Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK97___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK97___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .","The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and P28222 receptors . Age - related changes in circadian rhythms , including attenuation of photic phase shifts , are associated with changes in the central pacemaker in the suprachiasmatic nucleus ( SCN ) . Aging decreases expression of mRNA for vasoactive intestinal peptide ( P01282 ) , a key neuropeptide for rhythm generation and photic phase shifts , and increases expression of serotonin transporters and 5 - HT ( 1B ) receptors , whose activation inhibits these phase shifts . Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin - releasing peptide , which also modulates photic phase resetting . Because serotonin innervation trophically supports SCN P01282 mRNA expression , and serotonin transporters decrease extracellular serotonin , we predicted that chronic administration of the serotonin - selective reuptake inhibitor , fluoxetine , would attenuate the age - related changes in SCN P01282 mRNA expression and 5 - HT ( 1B ) receptors . In situ hybridization studies showed that fluoxetine treatment does not alter SCN P01282 mRNA expression , in either age group , at zeitgeber time ( ZT ) 6 or 13 ( ZT12 corresponds to lights off ) . However , receptor autoradiographic studies showed that fluoxetine prevents the age - related increase in SCN 5 - HT ( 1B ) receptors at ZT6 , and decreases SCN 5 - HT ( 1B ) receptors in both ages at ZT13 . Therefore , aging effects on SCN P01282 mRNA and SCN 5 - HT ( 1B ) receptors are differentially regulated ; the age - related increase in serotonin transporter sites mediates the latter but not the former . The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm , in contrast to previous reports of phase resetting by acute fluoxetine treatment .","Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK39___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .","The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe . Mek1 is a Chk2 / Rad53 / Cds1 - related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe . However , the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear . Here , we report that Mek1 is phosphorylated at serine - 12 ( P28222 ) , Q92748 and threonine - 15 ( T15 ) by Rad3 ( ATR ) and / or Tel1 ( Q13315 ) kinases that are activated by meiotic programmed double - strand breaks ( DSBs ) . Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates . Phosphorylation of these sites triggers autophosphorylation of Mek1 ; indeed , alanine replacement mutations of Mek1 - T318 and - T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates . Substrates of Mek1 include Mus81 - T275 , Rdh54 - Q8NHM4 and Rdh54 - T673 . Mus81 - T275 is known to regulate the Mus81 function in DNA cleavage , whereas Rdh54 - T6A / T673A mutant cells showed abnormal meiotic recombination . Taken together , we conclude that the phosphorylation of Mek1 by Rad3 or Tel1 , Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S . pombe .","Antidepressant effects on serotonin 1A / 1B receptors in the rat brain using a gene x environment model . A gene - environment ( GxE ) interaction is implicated in both the pathophysiology and treatment of major depressive disorder ( MDD ) . This study modeled the effects of genetic vulnerability by using the Flinders sensitive line ( FSL ) , a rat model of depression and its control counterpart - the Flinders resistant line ( FRL ) . The effects of environmental vulnerability ( e . g . , early - life stress ) were modeled by using maternal separation . Rats ( n = 105 ) were drawn from four groups reflecting experimental crossing of strain ( FSL vs . FRL ) and early - life stress ( high vs . low ) to assess the effects of two antidepressants ( escitalopram or nortriptyline ) compared to vehicle . Quantitative in vitro autoradiography was performed using [( 125 ) I ] MPPI ( P08908 ) and [( 125 ) I ] CYP ( P28222 ) in prefrontal cortex ( P27918 ) and hippocampus . Stringent , Bonferroni - corrected statistical analyses showed significant strain - by - rearing - by - treatment ( three - way ) interactions in P27918 P08908 and hippocampal P28222 receptors . Either vulnerability reduced serotonergic binding ; no additive effects were associated with the two vulnerabilities . Both antidepressants increased hippocampal P28222 receptor binding ; however , only nortriptyline selectively increased P27918 P08908 receptor binding . Taken together , our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a GxE interaction that depends on antidepressant class and brain region .","Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK80___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","___MASK28___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK28___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK28___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK28___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK28___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK28___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .","P10275 and calcitonin gene - related peptide in neurons of the genitofemoral nerve during testicular descent induced with human chorionic gonadotropin . BACKGROUND : Low levels of circulating testosterone during testis descent cause cryptorchidism in humans and rats . Treatment with human chorionic gonadotrophin ( hCG ) induces testis descent by stimulating production of testosterone ( T ) . Neurons of genitofemoral nerve ( GFN ) , which innervate testicular gubernaculum , may play a role in testis descent . METHODS : In the current study , putative correlations were made between T and GFN motor and sensory neuron activity during inguinoscrotal testis descent . Cryptorchidism was provoked in prepuberal rats with estradiol . Rats with testicular descent induced with hCG and cryptorchid controls were used . Cells of spinal cord and dorsal root ganglia were labeled by retrograde staining with fast - blue . Expression of androgen receptor ( AR ) and calcitonin gene - related peptide ( P80511 ) were detected with indirect immunofluorescence . RESULTS : Neurons labeled with fast - blue were found in the center of motor horn and dorsal root ganglia at levels Q9NUQ9 and Q401N2 . While number of motor neurons expressing AR was significantly higher in the group treated with hCG , number expressing P80511 was higher in controls . In dorsal root ganglion , number of cells immunostained with P80511 antibody was similar in both groups but AR was not detected . CONCLUSIONS : Present results support the hypothesis that motor nucleus of the GFN is a direct target of testosterone and that regulation of P80511 in sensory nucleus may be involved in testicular descent .","Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .","DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .","Identification of cellular pathways of \" type 1 , \" Th17 T cells , and P01375 - and inducible nitric oxide synthase - producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis . Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases . DB00091 A ( Q13216 ) is considered a \" gold standard \" therapy for moderate - to - severe psoriasis . We conducted a clinical trial with Q13216 and analyzed the treatment outcome in blood and skin of 11 responding patients . In the skin , as expected , Q13216 modulated genes from activated T cells and the \" type 1 \" pathway ( p40 , P01579 , and P35610 - 1 - regulated genes ) . However , Q13216 also modulated genes from the newly described Th17 pathway ( Q16552 , Q9GZX6 , and downstream genes P80511 , DEFB - 2 , IL - 1beta , SEPRINB3 , P80188 , and P78556 ) . Q13216 also affected dendritic cells , reducing P01375 and inducible NO synthase ( products of inflammatory P01375 - and inducible NO synthase - producing dendritic cells ) , Q01151 , and Q9NPF7 . We detected 220 early response genes ( day 14 posttreatment ) that were down - regulated by Q13216 . We classified > 95 % into proinflammatory or skin resident cells . More myeloid - derived than activated T cell genes were modulated by Q13216 ( 54 myeloid genes compared with 11 lymphocyte genes ) , supporting the hypothesis that myeloid derived genes contribute to pathogenic inflammation in psoriasis . In circulating mononuclear leukocytes , in stark contrast , no inflammatory gene activity was detected . Thus , we have constructed a genomic signature of successful treatment of psoriasis which may serve as a reference to guide development of other new therapies . In addition , these data also identify new gene targets for therapeutic modulation and may be applied to wide range of autoimmune diseases .","P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK77___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK77___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK77___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK77___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )","MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .","___MASK100___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK100___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .","___MASK100___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .","Neurochemical properties of aquaporin 1 - expressing sensory neurons from the ovine trigeminal ganglion . Aims of the present study were to investigate the distribution and morphology of aquaporin 1 - immunoreactive ( P29972 - IR ) neurons in the sensory ganglia of the sheep . Double immunohistochemical staining was applied to figure out whether DB05875 ( SP ) , calcitonin gene - related peptide ( P80511 ) and galanin are present in P29972 - bearing primary afferent neurons . The expression of P29972 was present only in trigeminal ganglion , whereas in nodose ganglion , jugular ganglion as well as C ( 1 ) - C ( 7 ) dorsal root ganglia no presence of P29972 was found . In trigeminal ganglion , 15 . 4 ± 2 . 3 % of Hu C / D - IR neurons ( pan - neuronal marker ) showed the presence of P29972 . The vast majority of P29972 - IR trigeminal sensory neurons ( approximately 69 . 6 ± 3 . 3 % , n = 5 ) were classified as middle in size , 28 . 6 ± 3 . 0 % of P29972 - IR neurons were small and only 1 . 8 ± 0 . 6 % of P29972 - positive neurons were large in size . Amongst the population of P29972 - IR trigeminal neurons as many as 58 . 5 ± 3 . 9 % were immunopositive to SP , 30 . 7 ± 2 . 3 % showed the presence of P80511 and 10 . 9 ± 0 . 2 % coexpressed galanin . In trigeminal ganglion , SP - IR as well as P80511 - IR ( but not galanin - IR ) nerve fibres were found in close neighbourhood of P29972 - IR neurons . It is concluded that P29972 is present in certain neuronal subsets of the ovine trigeminal ganglion ; however , the exact role of this water channel has to be elucidated .","[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK59___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK59___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .","Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .","Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings ."],"string":"[\n \"Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .\",\n \"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK5___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .\",\n \"Intramuscular gene transfer of P80511 inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta . P80511 is a well - known neuropeptide that has various protective effects on cardiovascular system . Our previous studies have shown that P80511 inhibits vascular smooth muscle cell ( VSMC ) proliferation in vitro . The present study aimed to explore the role of the P80511 in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism . Gene transfer of P80511 was performed with the use of intramuscular electroporation in a balloon - injured rat aorta model . Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase - mediated dUTP nick - end labeling assay . Overexpression of the P80511 gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer , as assessed by the intima - to - media ratio 14 days after balloon injury ( 29 . 2 +/- 3 . 7 % vs . 52 . 7 +/- 5 . 4 % ; n = 9 - 12 , P < 0 . 05 ) . In addition , P80511 gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury . Similarly , the addition of bioactive P80511 and the nitric oxide donor induced similar apoptosis in cultured VSMCs . The antagonist of the P80511 ( 1 ) receptor and inhibitors of DB02527 - PKA and nitric oxide blocked P80511 - mediated apoptosis . Furthermore , P80511 gene transfer increased inducible nitric oxide synthase and p53 but decreased P12004 and Bcl - 2 protein levels in balloon - injured rat aorta . Our data demonstrated that P80511 potently inhibited neointimal thickening in the rat aorta , at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro . Therefore , delivery of the P80511 gene may have therapeutic implications in limiting vascular restenosis .\",\n \"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK97___ ) in castrated male and female mice subjected to ___MASK97___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK97___ in mice CPs .\",\n \"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .\",\n \"___MASK90___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK90___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK90___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .\",\n \"Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .\",\n \"Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .\",\n \"P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK77___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK77___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK77___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK77___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .\",\n \"Increased serum levels of P05109 / A9 and P80511 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus . OBJECTIVES : Patients with SLE have an increased morbidity and mortality from cardiovascular disease ( CVD ) . The reason for this is not entirely understood , but is believed to be partly related to the long - lasting inflammatory process seen in SLE . The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins P05109 / A9 and P80511 in SLE . METHODS : Serum levels of P05109 / A9 and P80511 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections , as well as in 100 healthy individuals . Cardiovascular manifestations were defined according to the SLICC / P10323 Damage Index ( SLICC / P10323 - DI ) . RESULTS : Serum levels of P05109 / A9 were elevated in our inactive SLE patients as compared with healthy individuals ( P < 0 . 0001 ) , which was not seen for P80511 ( P = 0 . 12 ) . SLE patients with a history of CVD had increased serum levels of both P05109 / A9 and P80511 compared with patients with no CVD or venous thromboembolism ( P = 0 . 003 and P = 0 . 006 , respectively ) . The presence of organ damage according to SLICC / P10323 - DI was associated with an increase in both P05109 / A9 and P80511 serum levels ( P = 0 . 001 and P = 0 . 006 , respectively ) . CONCLUSION : Elevated serum levels of P05109 / A9 and P80511 may be used as an indicator of severe disease and CVD in SLE , suggesting that SLE patients with elevated serum P05109 / A9 and P80511 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment .\",\n \"Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .\",\n \"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK97___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK97___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .\",\n \"The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and P28222 receptors . Age - related changes in circadian rhythms , including attenuation of photic phase shifts , are associated with changes in the central pacemaker in the suprachiasmatic nucleus ( SCN ) . Aging decreases expression of mRNA for vasoactive intestinal peptide ( P01282 ) , a key neuropeptide for rhythm generation and photic phase shifts , and increases expression of serotonin transporters and 5 - HT ( 1B ) receptors , whose activation inhibits these phase shifts . Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin - releasing peptide , which also modulates photic phase resetting . Because serotonin innervation trophically supports SCN P01282 mRNA expression , and serotonin transporters decrease extracellular serotonin , we predicted that chronic administration of the serotonin - selective reuptake inhibitor , fluoxetine , would attenuate the age - related changes in SCN P01282 mRNA expression and 5 - HT ( 1B ) receptors . In situ hybridization studies showed that fluoxetine treatment does not alter SCN P01282 mRNA expression , in either age group , at zeitgeber time ( ZT ) 6 or 13 ( ZT12 corresponds to lights off ) . However , receptor autoradiographic studies showed that fluoxetine prevents the age - related increase in SCN 5 - HT ( 1B ) receptors at ZT6 , and decreases SCN 5 - HT ( 1B ) receptors in both ages at ZT13 . Therefore , aging effects on SCN P01282 mRNA and SCN 5 - HT ( 1B ) receptors are differentially regulated ; the age - related increase in serotonin transporter sites mediates the latter but not the former . The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm , in contrast to previous reports of phase resetting by acute fluoxetine treatment .\",\n \"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK39___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .\",\n \"The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe . Mek1 is a Chk2 / Rad53 / Cds1 - related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe . However , the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear . Here , we report that Mek1 is phosphorylated at serine - 12 ( P28222 ) , Q92748 and threonine - 15 ( T15 ) by Rad3 ( ATR ) and / or Tel1 ( Q13315 ) kinases that are activated by meiotic programmed double - strand breaks ( DSBs ) . Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates . Phosphorylation of these sites triggers autophosphorylation of Mek1 ; indeed , alanine replacement mutations of Mek1 - T318 and - T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates . Substrates of Mek1 include Mus81 - T275 , Rdh54 - Q8NHM4 and Rdh54 - T673 . Mus81 - T275 is known to regulate the Mus81 function in DNA cleavage , whereas Rdh54 - T6A / T673A mutant cells showed abnormal meiotic recombination . Taken together , we conclude that the phosphorylation of Mek1 by Rad3 or Tel1 , Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S . pombe .\",\n \"Antidepressant effects on serotonin 1A / 1B receptors in the rat brain using a gene x environment model . A gene - environment ( GxE ) interaction is implicated in both the pathophysiology and treatment of major depressive disorder ( MDD ) . This study modeled the effects of genetic vulnerability by using the Flinders sensitive line ( FSL ) , a rat model of depression and its control counterpart - the Flinders resistant line ( FRL ) . The effects of environmental vulnerability ( e . g . , early - life stress ) were modeled by using maternal separation . Rats ( n = 105 ) were drawn from four groups reflecting experimental crossing of strain ( FSL vs . FRL ) and early - life stress ( high vs . low ) to assess the effects of two antidepressants ( escitalopram or nortriptyline ) compared to vehicle . Quantitative in vitro autoradiography was performed using [( 125 ) I ] MPPI ( P08908 ) and [( 125 ) I ] CYP ( P28222 ) in prefrontal cortex ( P27918 ) and hippocampus . Stringent , Bonferroni - corrected statistical analyses showed significant strain - by - rearing - by - treatment ( three - way ) interactions in P27918 P08908 and hippocampal P28222 receptors . Either vulnerability reduced serotonergic binding ; no additive effects were associated with the two vulnerabilities . Both antidepressants increased hippocampal P28222 receptor binding ; however , only nortriptyline selectively increased P27918 P08908 receptor binding . Taken together , our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a GxE interaction that depends on antidepressant class and brain region .\",\n \"Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK80___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"___MASK28___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK28___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK28___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK28___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK28___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK28___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .\",\n \"P10275 and calcitonin gene - related peptide in neurons of the genitofemoral nerve during testicular descent induced with human chorionic gonadotropin . BACKGROUND : Low levels of circulating testosterone during testis descent cause cryptorchidism in humans and rats . Treatment with human chorionic gonadotrophin ( hCG ) induces testis descent by stimulating production of testosterone ( T ) . Neurons of genitofemoral nerve ( GFN ) , which innervate testicular gubernaculum , may play a role in testis descent . METHODS : In the current study , putative correlations were made between T and GFN motor and sensory neuron activity during inguinoscrotal testis descent . Cryptorchidism was provoked in prepuberal rats with estradiol . Rats with testicular descent induced with hCG and cryptorchid controls were used . Cells of spinal cord and dorsal root ganglia were labeled by retrograde staining with fast - blue . Expression of androgen receptor ( AR ) and calcitonin gene - related peptide ( P80511 ) were detected with indirect immunofluorescence . RESULTS : Neurons labeled with fast - blue were found in the center of motor horn and dorsal root ganglia at levels Q9NUQ9 and Q401N2 . While number of motor neurons expressing AR was significantly higher in the group treated with hCG , number expressing P80511 was higher in controls . In dorsal root ganglion , number of cells immunostained with P80511 antibody was similar in both groups but AR was not detected . CONCLUSIONS : Present results support the hypothesis that motor nucleus of the GFN is a direct target of testosterone and that regulation of P80511 in sensory nucleus may be involved in testicular descent .\",\n \"Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .\",\n \"DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .\",\n \"Identification of cellular pathways of \\\" type 1 , \\\" Th17 T cells , and P01375 - and inducible nitric oxide synthase - producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis . Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases . DB00091 A ( Q13216 ) is considered a \\\" gold standard \\\" therapy for moderate - to - severe psoriasis . We conducted a clinical trial with Q13216 and analyzed the treatment outcome in blood and skin of 11 responding patients . In the skin , as expected , Q13216 modulated genes from activated T cells and the \\\" type 1 \\\" pathway ( p40 , P01579 , and P35610 - 1 - regulated genes ) . However , Q13216 also modulated genes from the newly described Th17 pathway ( Q16552 , Q9GZX6 , and downstream genes P80511 , DEFB - 2 , IL - 1beta , SEPRINB3 , P80188 , and P78556 ) . Q13216 also affected dendritic cells , reducing P01375 and inducible NO synthase ( products of inflammatory P01375 - and inducible NO synthase - producing dendritic cells ) , Q01151 , and Q9NPF7 . We detected 220 early response genes ( day 14 posttreatment ) that were down - regulated by Q13216 . We classified > 95 % into proinflammatory or skin resident cells . More myeloid - derived than activated T cell genes were modulated by Q13216 ( 54 myeloid genes compared with 11 lymphocyte genes ) , supporting the hypothesis that myeloid derived genes contribute to pathogenic inflammation in psoriasis . In circulating mononuclear leukocytes , in stark contrast , no inflammatory gene activity was detected . Thus , we have constructed a genomic signature of successful treatment of psoriasis which may serve as a reference to guide development of other new therapies . In addition , these data also identify new gene targets for therapeutic modulation and may be applied to wide range of autoimmune diseases .\",\n \"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK77___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK77___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK77___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK77___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .\",\n \"___MASK100___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK100___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .\",\n \"___MASK100___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .\",\n \"Neurochemical properties of aquaporin 1 - expressing sensory neurons from the ovine trigeminal ganglion . Aims of the present study were to investigate the distribution and morphology of aquaporin 1 - immunoreactive ( P29972 - IR ) neurons in the sensory ganglia of the sheep . Double immunohistochemical staining was applied to figure out whether DB05875 ( SP ) , calcitonin gene - related peptide ( P80511 ) and galanin are present in P29972 - bearing primary afferent neurons . The expression of P29972 was present only in trigeminal ganglion , whereas in nodose ganglion , jugular ganglion as well as C ( 1 ) - C ( 7 ) dorsal root ganglia no presence of P29972 was found . In trigeminal ganglion , 15 . 4 ± 2 . 3 % of Hu C / D - IR neurons ( pan - neuronal marker ) showed the presence of P29972 . The vast majority of P29972 - IR trigeminal sensory neurons ( approximately 69 . 6 ± 3 . 3 % , n = 5 ) were classified as middle in size , 28 . 6 ± 3 . 0 % of P29972 - IR neurons were small and only 1 . 8 ± 0 . 6 % of P29972 - positive neurons were large in size . Amongst the population of P29972 - IR trigeminal neurons as many as 58 . 5 ± 3 . 9 % were immunopositive to SP , 30 . 7 ± 2 . 3 % showed the presence of P80511 and 10 . 9 ± 0 . 2 % coexpressed galanin . In trigeminal ganglion , SP - IR as well as P80511 - IR ( but not galanin - IR ) nerve fibres were found in close neighbourhood of P29972 - IR neurons . It is concluded that P29972 is present in certain neuronal subsets of the ovine trigeminal ganglion ; however , the exact role of this water channel has to be elucidated .\",\n \"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK59___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK59___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .\",\n \"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .\",\n \"Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK100___","___MASK28___","___MASK39___","___MASK59___","___MASK5___","___MASK77___","___MASK80___","___MASK90___","___MASK97___"],"string":"[\n \"___MASK100___\",\n \"___MASK28___\",\n \"___MASK39___\",\n \"___MASK59___\",\n \"___MASK5___\",\n \"___MASK77___\",\n \"___MASK80___\",\n \"___MASK90___\",\n \"___MASK97___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK59___"},"id":{"kind":"string","value":"MH_train_92"}}},{"rowIdx":93,"cells":{"query":{"kind":"string","value":"interacts_with DB00973?"},"supports":{"kind":"list like","value":["Pathophysiological factors affecting CAR gene expression . The body defends itself against potentially harmful compounds , such as drugs and toxic endogenous compounds and their metabolites , by inducing the expression of enzymes and transporters involved in their metabolism and elimination . The orphan nuclear receptor CAR ( Q14994 controls phase I ( CYP2B , CYP2C , CYP3A ) , phase II ( P22309 ) , and transporter ( Q9Y6L6 , Q92887 ) genes involved in drug metabolism and bilirubin clearance . Q14994 ( CAR ) is activated by xenobiotics , such as phenobarbital , but also by toxic endogenous compounds such as bilirubin metabolite ( s ) . To better understand the inter - and intravariability in drug detoxification , we studied the molecular mechanisms involved in CAR gene expression in human hepatocytes . We clearly identified CAR as a glucocorticoid receptor ( GR ) target gene , and we proposed the hypothesis of a signal transduction where the activation of GR plays a critical function in CAR - mediated cellular response . According to our model , chemicals or pathophysiological factors that affect GR function should decrease CAR function . To test this hypothesis , we recently investigated the effect of microtubule disrupting agents ( MIAs ) or proinflammatory cytokines . These compounds are well - known inhibitors of GR transactivation property . MIAs activate c - Jun N - terminal kinase ( JNK ) , which phosphorylates and inactivates GR , whereas proinflammatory cytokines , such as P05231 or IL1beta , induce AP - 1 or NF - kB activation , respectively , leading to GR inhibition . As expected , we observed that these molecules inhibit both CAR gene expression and phenobarbital - mediated CYP gene expression in human hepatocytes .","Nardosinone protects H9c2 cardiac cells from angiotensin II - induced hypertrophy . Pathological cardiac hypertrophy induced by angiotensin II ( AngII ) can subsequently give rise to heart failure , a leading cause of mortality . Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis , a well - known traditional Chinese medicine . In order to investigate the effects of nardosinone on AngII - induced cardiac cell hypertrophy and the related mechanisms , the myoblast cell line H9c2 , derived from embryonic rat heart , was treated with nardosinone ( 25 , 50 , 100 , and 200 μmol / L ) or AngII ( 1 μmol / L ) . Then cell surface area and mRNA expression of classical markers of hypertrophy were detected . The related protein levels in PI3K / Akt / P42345 and MEK / P29323 signaling pathways were examined by Western blotting . It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII . The mRNA expression of P01160 , DB04899 and β - MHC was obviously elevated in AngII - treated H9c2 cells , which could be effectively blocked by nardosinone at the concentration of 100 μmol / L . Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K / Akt and MEK / P29323 signaling pathways . It was suggested that the inhibitory effect of nardosinone on Ang II - induced hypertrophy in H9c2 cells might be mediated by targeting PI3K / Akt and MEK / P29323 signaling pathways .","[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F - VII , F - X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non - diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F - VII , F - X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance .","Genetics of familial forms of thrombocytopenia . The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias , as well as the availability of new methods for studying megakaryopoiesis , has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology , pathogenesis and clinical aspects . In particular , new diseases have been described , as deriving from mutations in the genes P21333 , Q9H4B7 , P17301 / P05106 , Q9UPS8 , P99999 , and Q9H222 or Q9H221 . Moreover , forms previously considered separate entities were found to be different clinical aspects of a single disease . For instance , identification of P35579 as the gene whose mutations cause the May - Hegglin anomaly led to the recognition that Sebastian platelet syndrome , Epstein syndrome , and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders . Despite these advances , knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described . In this review , we provide a systematic description of hereditary thrombocytopenias as we know them today , giving special attention to genetic aspects .","Inhibition of phosphatidylinositol 3 - kinase - and P29323 MAPK - regulated protein synthesis reveals the pro - apoptotic properties of P25942 ligation in carcinoma cells . P25942 , a member of the tumor necrosis factor receptor superfamily , is frequently expressed in carcinomas where its stimulation results in induction of apoptosis when de novo protein synthesis is inhibited . The requirement of protein synthesis inhibition for efficient killing suggests that P25942 transduces potent survival signals capable of suppressing its pro - apoptotic effects . We have found that inhibition of P25942 signaling on the phosphatidylinositol 3 - kinase ( PI3K ) and P29323 MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma cells to P25942 - mediated cell death . The P25942 - mediated PI3K and P29323 activities were found to converge on the regulation of protein synthesis in carcinoma cells via a pathway involving the activation of p90 ribosomal S6 kinase ( p90Rsk ) and p70S6 kinases , upstream of the translation elongation factor eEF2 . In addition , P25942 ligation was found to mediate a PI3K - and mammalian target of rapamycin ( P42345 ) - dependent phosphorylation of Q13541 and its subsequent dissociation from the P06730 P06730 as well as an P29323 - dependent phosphorylation of P06730 , thus promoting translation initiation . Concomitantly , the antiapoptotic protein cFLIP was found to be induced in P29965 - stimulated carcinoma cells in a PI3K - , P29323 - , and mammalian target of rapamycin ( P42345 ) - dependent manner and down - regulation of cFLIPS expression sensitized to P25942 - mediated carcinoma cell death . These data underline the significance of the PI3K and P29323 pathways in controlling the balance between P25942 - mediated survival and death signals through the regulation of the protein synthesis machinery . Pharmacological agents that target this machinery or its upstream kinases could , therefore , be exploited for P25942 - based tumor therapy .","[ The effect of type II diabetes and the metabolic syndrome on cardiac second window preconditioning ] . Preconditioning is the most powerful endogenous mechanism , to protect the heart against ischemic damage . Conflicting data are published whether preconditioning can be induced in case of diabetes and the metabolic syndrome , which are clinically very relevant conditions . If preconditioning could be induced consistently and chronically in this population , an important reduction of surgical morbidity and mortality could be reached . In this project we induced hypoxic preconditioning in mice and used cardiac pressure - conductance catheterisation and infarct size as outcome parameters . In the first part , we found that hypoxic preconditioning was capable to reduce infarct size with 40 % and preserve the load - independent parameters with 33 % after coronary occlusion . A DKO ( double knock - out : ob / ob ; P01130 -/- ) model for the metabolic syndrome developed a larger infarct size and had a reduced contractility . No preconditioning could be induced in this model . To detect the determing factor of the resistance to preconditioning , we used single knock - out models . A comparable preconditioning effect of wild type mice could be induced in the lipoprotein receptor deficient ( P01130 -/- ) model for dyslipidemia . The leptin deficient ( ob / ob ) model , characterized by insulin resistance and abdominal obesity had , identically to the DKO model , a larger infarct size . A second window of preconditioning could be induced , although it was less pronounced than the wild type and P01130 -/- model . P01308 resistance and abdominal obesity could be identified as the major factor in the resistance to preconditioning .","[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .","DB00973 as a potential treatment for non - alcoholic fatty liver disease : is the intestine a modulator of hepatic insulin sensitivity and hepatic fat accumulation ? Non - alcoholic fatty liver disease ( NAFLD ) is the hepatic component of the metabolic syndrome and is known to be associated with marked insulin resistance and increased risk of cardiovascular disease . DB00973 , an inhibitor of intestinal cholesterol absorption , inhibits Niemann - Pick C1 - like 1 ( Q9UHC9 ) . Interestingly , Q9UHC9 is abundantly expressed in human liver , as well as in the intestine . Recent reports suggest a potential benefit of ezetimibe in improving hepatic insulin sensitivity and decreasing hepatic inflammation and lipid accumulation . P01308 resistance and excess hepatic fat accumulation are regarded as key factors in the pathogenesis of NAFLD . We suggest , therefore , that urgent studies are needed to assess the potential therapeutic benefit of ezetimibe in treating NAFLD .","Nuclear hormone receptors and cholesterol trafficking : the orphans find a new home . There are many homeostatic mechanisms that contribute to the regulation of cellular and serum cholesterol levels in humans . Much of our understanding of this regulation arose from studies of the cellular pathways controlling cholesterol synthesis and the uptake and degradation of low - density lipoproteins . The physiology governing cholesterol disposition in whole animals , including the molecular mechanisms responsible for dietary uptake of cholesterol and its subsequent catabolism to bile acids , are only now being uncovered . This review summarizes recent studies that have used modern genetic techniques , as well as cell biological methods , to begin to elucidate the pathways responsible for cholesterol trafficking in vivo . This work has led to the realization that networks of nuclear hormone receptors , including the LXR , Q96RI1 , Q07869 , and RXR proteins , play critical roles in lipid metabolism by virtue of their transcriptional regulation of the genes that control sterol metabolic pathways . Some of the major downstream targets of these regulatory networks involve members of the ABC transporter family , including O95477 , P45844 , Q9H222 , Q9H221 , P21439 / Mdr2 , and SPGP / O95342 . These transporters contribute to the movement of sterols and biliary lipids across cellular membranes via mechanisms that have yet to be elucidated . The potential for manipulating these cholesterol trafficking pathways via drugs targeted to the nuclear hormone receptors has generated great interest in their biology and will undoubtedly lead to new therapeutic approaches to human disorders in the coming years .","Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .","Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .","Apolipoprotein B100 danger - associated signal 1 ( ApoBDS - 1 ) triggers platelet activation and boosts platelet - leukocyte proinflammatory responses . Low - density lipoproteins ( LDL ) , occurring in vivo in both their native and oxidative form , modulate platelet function and thereby contribute to atherothrombosis . We recently identified and demonstrated that ' ApoB100 danger - associated signal 1 ' ( ApoBDS - 1 ) , a native peptide derived from P04114 ( ApoB100 ) of LDL , induces inflammatory responses in innate immune cells . Platelets are critically involved in the development as well as in the lethal consequences of atherothrombotic diseases , but whether ApoBDS - 1 has also an impact on platelet function is unknown . In this study we examined the effect of ApoBDS - 1 on human platelet function and platelet - leukocyte interactions in vitro . Stimulation with ApoBDS - 1 induced platelet activation , degranulation , adhesion and release of proinflammatory cytokines . ApoBDS - 1 - stimulated platelets triggered innate immune responses by augmenting leukocyte activation , adhesion and transmigration to / through activated HUVEC monolayers , under flow conditions . These platelet - activating effects were sequence - specific , and stimulation of platelets with ApoBDS - 1 activated intracellular signalling pathways , including Ca2 + , PI3K / Akt , P98160 , and p38 - and P29323 - MAPK . Moreover , our data indicates that ApoBDS - 1 - induced platelet activation is partially dependent of positive feedback from ADP on P47900 and Q9H244 , and TxA2 . In conclusion , we demonstrate that ApoBDS - 1 is an effective platelet agonist , boosting platelet - leukocyte ' s proinflammatory responses , and potentially contributing to the multifaceted inflammatory - promoting effects of LDL in the pathogenesis of atherothrombosis .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK39___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","P42892 and β - arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein - coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β - arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK293 cells and non - transformed human colonocytes , we observed that G protein - coupled receptor kinase 2 and β P49407 / 2 terminate plasma membrane Ca ( 2 +) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca ( 2 +) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF - κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP - dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation .","The transcriptional coactivator DRIP / mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) / mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 / MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1 / Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and / or glioma - associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium - induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation .","Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype . BACKGROUND : Epidemiological studies have shown that low plasma levels of high - density lipoprotein ( HDL ) cholesterol are associated with increased risk of cardiovascular disease , but the mechanisms for the possible atheroprotective effects of HDL cholesterol have still not been fully clarified , in particular in relation to clinical studies . OBJECTIVE : To examine the inflammatory , anti - oxidative and metabolic phenotype of subjects with low plasma HDL cholesterol levels . METHODS AND RESULTS : Fifteen subjects with low HDL cholesterol levels ( eleven males and four females ) and 19 subjects with high HDL ( three males and 16 females ) were recruited . Low HDL cholesterol was defined as ≤ 10th age / sex specific percentile and high HDL - C was defined as ≥ 90 age / sex specific percentile . Inflammatory markers in circulation and PBMC gene expression of cholesterol efflux mediators were measured . Our main findings were : ( i ) subjects with low plasma HDL cholesterol levels were characterized by increased plasma levels of CRP , P14780 , neopterin , Q9H2A7 and P05362 as well as low plasma levels of adiponectin , suggesting an inflammatory phenotype ; ( ii ) these individuals also had reduced paraoxonase ( P27169 ) 1 activity in plasma and Q15165 gene expression in peripheral blood mononuclear cells ( PBMC ) accompanied by increased plasma levels of oxidized LDL suggesting decreased anti - oxidative capacity ; and ( iii ) PBMC from low HDL subjects also had decreased mRNA levels of O95477 and P45844 , suggesting impaired reverse cholesterol transport . CONCLUSION : Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype that could contribute to the increased risk of atherosclerotic disorders in these subjects with low HDL levels .","___MASK8___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .","Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .","Leptin promotes neointima formation and smooth muscle cell proliferation via NADPH oxidase activation and signalling in caveolin - rich microdomains . AIMS : P02649 ( apoE ) may act as a vasculoprotective factor by promoting plasma lipid clearance and cholesterol efflux . Moreover , apoE accumulates at sites of vascular injury and modulates the effect of growth factors on smooth muscle cells ( SMCs ) . Experimental data suggested that hypothalamic apoE expression is reduced in obesity and associated with leptin resistance . In this study , we examined the role of apoE in mediating the effects of leptin on vascular lesion formation . METHODS AND RESULTS : Leptin was administered to apoE knockout ( apoE -/- ) mice via osmotic pumps to increase its circulating levels . Morphometric analysis revealed that leptin did not alter neointima formation and failed to increase α - actin - or P12004 - immunopositive SMCs after vascular injury . Similar findings were obtained after analysis of atherosclerotic lesions . Comparison of apoE -/- , wild - type , or P01130 -/- mice and functional analyses in aortic SMCs from WT or apoE -/- mice or human arterial SMCs after treatment with small interfering ( si ) RNA or heparinase revealed that leptin requires the presence of apoE , expressed , secreted and bound to the cell surface , to fully activate leptin receptor signalling and to promote SMC proliferation and neointima formation . Mechanistically , leptin induced the phosphorylation and membrane translocation of caveolin ( cav )- 1 , and apoE down - regulation or caveolae disruption inhibited the leptin - induced p47phox activation , ROS formation and SMC proliferation . Finally , leptin failed to increase neointima formation in mice lacking cav - 1 . CONCLUSION : Our findings suggest that apoE mediates the effects of leptin on vascular lesion formation by stabilizing cav - 1 - enriched cell membrane microdomains in SMCs , thus allowing NADPH oxidase assembly and ROS - mediated mitogenic signalling .","Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK42___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK42___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK42___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .","Oxysterol binding protein induces upregulation of SREBP - 1c and enhances hepatic lipogenesis . BACKGROUND : Oxysterol binding protein ( P22059 ) has previously been implicated as a sterol sensor that regulates sphingomyelin synthesis and the activity of extracellular signal - regulated kinases ( P29323 ) . METHODS AND RESULTS : We determined the effects of adenovirus - mediated hepatic overexpression of P22059 and its homologues ORP1L and Q9H4L5 on mouse serum lipids . Whereas ORP1L and Q9H4L5 had no effect on serum lipids , P22059 induced a marked increase of VLDL triglycerides ( TG ) . Also , the liver tissue TG were elevated in the AdOSBP - injected mice , and their TG secretion rate was increased by 70 % . The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator , SREBP - 1c , as well as the Insig - 1 mRNA , were upregulated two - fold in the P22059 - expressing livers . No change occurred in the messages of liver X receptor target genes O95477 , Q9H222 , and P22680 , and the Insig - 2a mRNA was reduced . The phosphorylation of P29323 was decreased in AdOSBP - infected liver and cultured hepatocytes . Importantly , silencing of P22059 in hepatocytes suppressed the induction of P36956 - c by insulin and resulted in a reduction of TG synthesis . CONCLUSION : Our results demonstrate that P22059 regulates hepatic TG metabolism and suggest the involvement of P22059 in the insulin signaling pathways that control hepatic lipogenesis .","Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .","Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .","Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK4___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .","Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia . Sitosterolemia is a rare , autosomal recessive disease caused by mutations in the adenosine triphosphate - binding cassette transporter genes Q9H222 or Q9H221 that result in accumulation of xenosterols in the body . Clinical manifestations include tendon xanthomas , premature coronary artery disease , hemolytic anemia , macrothrombocytopenia , and bleeding . Although the effect of sterol accumulation on the predisposition for atherosclerosis is evident , how xenosterol accumulation leads to defects in platelet physiology is unknown . Sitosterolemia induced in Abcg5 - and Abcg8 - deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes , leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its αIIbβ3 integrin receptor , internalization of the αIIbβ3 complex , generation of platelet - derived microparticles , and changes in the quantity and subcellular localization of filamin . The latter was associated with macrothrombocytopenia , shedding of GPIbα , impaired platelet adhesion to P04275 , and inability to form stable thrombi . Plasma levels of soluble GPIbα were strongly correlated with plasma sitosterol levels in samples from human sitosterolemic patients , implicating a similar mechanism of sterol - induced platelet passivation in the human disease . Intercalation of plant sterols into the plasma membrane therefore results in dysregulation of multiple platelet activation pathways , leading to macrothrombocytopenia and bleeding .","P32189 deficiency alters expression of genes involved in lipid metabolism , carbohydrate metabolism , and insulin signaling . P32189 ( GK ) is at the interface of fat and carbohydrate metabolism and has been implicated in insulin resistance and type 2 diabetes mellitus . To define GK ' s role in insulin resistance , we examined gene expression in brown adipose tissue in a glycerol kinase knockout ( KO ) mouse model using microarray analysis . Global gene expression profiles of KO mice were distinct from wild type with 668 differentially expressed genes . These include genes involved in lipid metabolism , carbohydrate metabolism , insulin signaling , and insulin resistance . Real - time polymerase chain reaction analysis confirmed the differential expression of selected genes involved in lipid and carbohydrate metabolism . PathwayAssist analysis confirmed direct and indirect connections between glycerol kinase and genes in lipid metabolism , carbohydrate metabolism , insulin signaling , and insulin resistance . Network component analysis ( P40199 ) showed that the transcription factors ( TFs ) P37231 , P36956 , Q12772 , P40763 , P42229 , SP1 , CEBPalpha , CREB , GR and Q07869 have altered activity in the KO mice . P40199 also revealed the individual contribution of these TFs on the expression of genes altered in the microarray data . This study elucidates the complex network of glycerol kinase and further confirms a possible role for glycerol kinase deficiency , a simple Mendelian disorder , in insulin resistance , and type 2 diabetes mellitus , a common complex genetic disorder .","DB04540 - lowering effect of ezetimibe in uridine diphosphate glucuronosyltransferase 1A - deficient ( Gunn ) rats . DB00973 ( EZE ) selectively blocks intestinal cholesterol absorption by interacting with Niemann - Pick C1 Like 1 ( Q9UHC9 ) . After administration , EZE is extensively metabolized in liver and intestine to its phenolic glucuronide form ( EZE - G ) by uridine diphosphate glucuronosyltransferases ( UGTs ) , among which P22309 and 1A3 exhibit highest activity . EZE - G is excreted into bile and undergoes extensive enterohepatic recirculation . Considering the pharmacokinetic properties of EZE and an in vitro binding study showing the high affinity binding of EZE - G to Q9UHC9 , glucuronidation by UGTs has been believed to be essential for the pharmacological efficacy of EZE . To study the role of glucuronidation by UGTs for the cholesterol - lowering effect of EZE , in vitro and in vivo studies were performed using Gunn rats , which hereditarily lack the expression of P22309 enzymes . The biliary excreted amount of EZE - G was reduced by 73 % up to 3 h after administration of EZE ( 0 . 3 mg / kg ) in Gunn rats , which is consistent with the reduction of in vitro EZE glucuronidation activity found in liver and intestinal microsome from Gunn rats . These results indicate that the formation of EZE - G in Gunn rats is much lower than that in Wistar rats . However , in vivo study showed that 0 . 3 mg / kg EZE , which is the clinically relevant dose , reduced cholesterol absorption in both Wistar and Gunn rats to nearly the same degree and the dose dependence was not significantly different between Wistar and Gunn rats at the range 0 . 001 approximately 0 . 3 mg / kg . These results indicate that a deficiency of P22309 activity does not necessarily alter the cholesterol - lowering effect of EZE in rats at therapeutic doses .","The Q9H222 Q9H221 sterol transporter and phytosterols : implications for cardiometabolic disease . PURPOSE OF REVIEW : This review summarizes recent developments in the activity , regulation , and physiology of the Q9H222 Q9H221 ( G5G8 ) transporter and the use of its xenobiotic substrates , phytosterols , as cholesterol lowering agents in the treatment of cardiovascular disease . Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome . RECENT FINDINGS : Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction . The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility . Finally , the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction , suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit . SUMMARY : P01308 resistance elevates G5G8 and increases susceptibility to cholesterol gallstones . However , this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine . Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease .","[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .","HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing P16671 - dependent cholesteryl ester accumulation in macrophages . Protease inhibitors decrease the viral load in HIV patients , however the patients develop hypertriglyceridemia , hypercholesterolemia , and atherosclerosis . It has been assumed that protease inhibitor - dependent increases in atherosclerosis are secondary to the dyslipidemia . Incubation of THP - 1 cells or human PBMCs with protease inhibitors caused upregulation of P16671 and the accumulation of cholesteryl esters . The use of P16671 - blocking antibodies , a P16671 morpholino , and monocytes isolated from P16671 null mice demonstrated that protease inhibitor - induced increases in cholesteryl esters were dependent on P16671 upregulation . These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating P16671 and cholesteryl ester accumulation independent of dyslipidemia . Studies with P01130 null mice demonstrated that low doses of protease inhibitors induce an increase in the level of P16671 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids . Furthermore , the lack of P16671 protected the animals from protease inhibitor - induced atherosclerosis . Finally , ritonavir increased P37231 and P16671 mRNA levels in a PKC - and P37231 - dependent manner . We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of P16671 and the subsequent accumulation of sterol in macrophages .","Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK71___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .","Current therapy for patients with sitosterolemia -- effect of ezetimibe on plant sterol metabolism . Sitosterolemia is a rare , autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations , caused by mutations in the adenosine triphosphate - bind - ing cassette ( DB01048 ) transporter Q9H222 or Q9H221 genes . Markedly increased serum concentration of plant sterols . such as sitosterol and campesterol , cause premature atherosclerosis and massive xanthomas . Hitherto known treatments for sitosterolemia , including a low - sterol diet , bile - salt binding resins , ileal bypass surgery and low density lipoprotein ( LDL ) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels , subsequently developing premature atherosclerotic cardiovascular diseases . DB00973 , an inhibitor of intestinal cholesterol absorption through its binding to Niemann - Pick C1 - like 1 ( Q9UHC9 ) , has been widely used for decreasing serum LDL - cholesterol levels in patients with hypercholesterolemia . DB00973 also reduces the gastrointestinal absorption of plant sterols , thereby also lowering the serum concentrations of plant sterols . This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia . In the current review , we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease , one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis . DB00973 administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51 . 3 % and 48 . 9 % , respectively , in the two patients , demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy .","LXR driven induction of HDL - cholesterol is independent of intestinal cholesterol absorption and O95477 protein expression . We investigated whether : ( 1 ) liver X receptor ( LXR ) - driven induction of high - density lipoprotein cholesterol ( HDL - C ) and other LXR - mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption ; and ( 2 ) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis . Mice were fed 0 . 2 % cholesterol and treated with GW3965 + ezetimibe , GW3965 or ezetimibe . GW3965 + ezetimibe treatment elevated serum HDL - C and Apolipoprotein ( Apo ) AI , effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols . No changes in intestinal DB00171 - binding cassette ( DB01048 ) A1 or Q9H222 protein expression were observed , despite increased mRNA expression , while hepatic O95477 was slightly reduced . The combined treatment caused a pronounced down - regulation of intestinal Niemann - Pick C1 - like 1 ( Q9UHC9 ) and reduced hepatic and intestinal cholesterol levels . GW3965 did not affect the intestinal cholesterol absorption , but increased serum HDL - C and ApoAI levels . GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1 - 6 cells . DB00973 reduced the intestinal cholesterol absorption , O95477 and Q9H222 , but did not affect the serum HDL - C or ApoAI levels . Thus , the LXR - driven induction of HDL - C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic O95477 was not required . Inhibited influx of cholesterol via Q9UHC9 and / or low levels of intracellular cholesterol prevented post - transcriptional expression of intestinal O95477 and Q9H222 , despite increased mRNA levels . Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol .","P35568 regulation in health and disease . The global incidence of diabetes is increasing at epidemic rates . Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years . Type 2 diabetes accounts for 95 % of all cases and is characterized in part by impaired sensitivity to insulin or ' insulin resistance ' . Defects in the insulin signalling pathways underpin this resistance . In the current article we discuss the regulation of P01308 Receptor Substrate - 1 ( P35568 ) , a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance . Coordination of P35568 function is multi - faceted , involving phosphorylation of P35568 at multiple serine / threonine residues . This controls many aspects of P35568 , including its interaction with the insulin receptor and subsequent tyrosine phosphorylation , as well as its subcellular distribution and targeting for degradation by the proteasome . Such tight control ensures appropriate transduction and attenuation of the insulin signal , thereby regulating insulin action in healthy individuals . Emerging evidence indicates that ' diabetogenic factors ' associated with insulin resistance , such as TNFalpha and elevated circulating fatty acids , impact on insulin signalling at the level of P35568 serine / threonine phosphorylation . The expression and / or activity of several kinases , such as O15111 beta ( IKKbeta ) and salt - induced kinase 2 ( Q9H0K1 ) , and the phosphorylation of P35568 at key sites , such as Ser307 and Ser789 , are increased in states of insulin resistance . Identifying the pathways by which such factors activate these and other kinases , and defining the precise roles of specific serine / threonine phosphorylation events in P35568 regulation , represent important goals which may eventually provide a rationale for therapeutic intervention .","Q07869 and P37231 activators induce cholesterol removal from human macrophage foam cells through stimulation of the O95477 pathway . Peroxisome proliferator - activated receptors ( PPARs ) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation . Q07869 and P37231 are both expressed in human macrophages where they exert anti - inflammatory effects . The activation of Q07869 may promote foam - cell formation by inducing expression of the macrophage scavenger receptor P16671 . This prompted us to investigate the influence of different Q07869 - activators on cholesterol metabolism and foam - cell formation of human primary and THP - 1 macrophages . Here we show that Q07869 and P37231 activators do not influence acetylated low density lipoprotein - induced foam - cell formation of human macrophages . In contrast , Q07869 and P37231 activators induce the expression of the gene encoding O95477 , a transporter that controls apoAI - mediated cholesterol efflux from macrophages . These effects are likely due to enhanced expression of liver - x - receptor alpha , an oxysterol - activated nuclear receptor which induces O95477 - promoter transcription . Moreover , Q07869 and P37231 activators increase apoAI - induced cholesterol efflux from normal macrophages . In contrast , Q07869 or P37231 activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease , which is due to a genetic defect in O95477 . Here we identify a regulatory role for Q07869 and P37231 in the first steps of the reverse - cholesterol - transport pathway through the activation of O95477 - mediated cholesterol efflux in human macrophages .","Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK3___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .","The molecular mechanisms underlying the reduction of LDL apoB - 100 by ezetimibe plus simvastatin . The combination of ezetimibe , an inhibitor of Niemann - Pick C1 - like 1 protein ( Q9UHC9 ) , and an P04035 inhibitor decreases cholesterol absorption and synthesis . In clinical trials , ezetimibe plus simvastatin produces greater LDL - cholesterol reductions than does monotherapy . The molecular mechanism for this enhanced efficacy has not been defined . P04114 ( apoB - 100 ) kinetics were determined in miniature pigs treated with ezetimibe ( 0 . 1 mg / kg / day ) , ezetimibe plus simvastatin ( 10 mg / kg / day ) , or placebo ( n = 7 / group ) . DB00973 decreased cholesterol absorption ( - 79 % ) and plasma phytosterols ( - 91 % ) , which were not affected further by simvastatin . DB00973 increased plasma lathosterol ( + 65 % ) , which was prevented by addition of simvastatin . The combination decreased total cholesterol ( - 35 % ) and LDL - cholesterol ( - 47 % ) . VLDL apoB pool size decreased 26 % , due to a 35 % decrease in VLDL apoB production . LDL apoB pool size decreased 34 % due to an 81 % increase in the fractional catabolic rate , both of which were significantly greater than monotherapy . Combination treatment decreased hepatic microsomal cholesterol ( - 29 % ) and cholesteryl ester ( - 65 % ) and increased P01130 ( P01130 ) expression by 240 % . The combination increased Q9UHC9 expression in liver and intestine , consistent with increased Q12772 expression . DB00973 plus simvastatin decreases VLDL and LDL apoB - 100 concentrations through reduced VLDL production and upregulation of P01130 - mediated LDL clearance .","Inhibition of Niemann - Pick - type C1 - like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1 - antitrypsin Z deposition . Autophagy can degrade aggregate - prone proteins , but excessive autophagy can have adverse effects . It would be beneficial if autophagy could be enhanced in a cell type - specific manner , but this has been difficult because the basic mechanism of autophagy is common . In the present study we found that inhibition of Niemann - Pick - type C1 - like 1 ( Q9UHC9 ) by ezetimibe activates autophagy only in hepatocytes and small intestinal epithelia , but not in other cells . DB00973 induced accumulation of free cholesterol in the late endosome / lysosome and increased partitioning of a Ragulator component , Q6IAA8 , in rafts . The latter change led to down - regulation of mammalian target of rapamycin ( P42345 ) C1 activity by decreasing P42345 recruitment to the late endosome / lysosome and activated autophagy . A primary effect of ezetimibe was found to be a decrease of free cholesterol in the plasma membrane , because all the results caused by ezetimibe were suppressed by supplementation of cholesterol as a methyl - β - cyclodextrin complex . By enhancing autophagy in human primary hepatocytes with ezetimibe , insoluble mutant α1 - antitrypsin Z was reduced significantly . CONCLUSION : Inhibition of Q9UHC9 by ezetimibe activates autophagy in human hepatocytes by modulating cholesterol homeostasis . DB00973 may be used to ameliorate liver degeneration in α1 - antitrypsin deficiency .","Genetic demonstration of intestinal Q9UHC9 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels . OBJECTIVE : The correlation between intestinal cholesterol absorption values and plasma low - density lipoprotein - cholesterol ( LDL - C ) levels remains controversial . Niemann - Pick - C1 - Like 1 ( Q9UHC9 ) is essential for intestinal cholesterol absorption , and is the target of ezetimibe , a cholesterol absorption inhibitor . However , studies with Q9UHC9 knockout mice or ezetimibe can not definitively clarify this correlation because Q9UHC9 expression is not restricted to intestine in humans and mice . In this study we sought to genetically address this issue . METHODS AND RESULTS : We developed a mouse model that lacks endogenous ( Q9UHC9 ) and P01130 ( P01130 ) ( DKO ) , but transgenically expresses human Q9UHC9 in gastrointestinal tract only ( DKO / Q9NUQ9 ( IntOnly ) mice ) . Our novel model eliminated potential effects of non - intestinal Q9UHC9 on cholesterol homeostasis . We found that human Q9UHC9 was localized at the intestinal brush border membrane of DKO / Q9NUQ9 ( IntOnly ) mice . DB04540 feeding induced formation of Q9UHC9 - positive vesicles beneath this membrane in an ezetimibe - sensitive manner . Compared to DKO mice , DKO / Q9NUQ9 ( IntOnly ) mice showed significant increases in cholesterol absorption and blood / hepatic / biliary cholesterol . Increased blood cholesterol was restricted to very low - density lipoprotein ( VLDL ) and LDL fractions , which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48 . Additionally , DKO / Q9NUQ9 ( IntOnly ) mice displayed decreased fecal cholesterol excretion and hepatic / intestinal expression of cholesterologenic genes . DB00973 treatment virtually reversed all of the transgene - related phenotypes in DKO / Q9NUQ9 ( IntOnly ) mice . CONCLUSION : Our findings from DKO / Q9NUQ9 ( IntOnly ) mice clearly demonstrate that Q9UHC9 - mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B - containing atherogenic lipoproteins , at least in mice .","Inhibition of NF - kappaB activation in macrophages increases atherosclerosis in P01130 - deficient mice . Atherosclerosis is now generally accepted as a chronic inflammatory condition . The transcription factor NF - kappaB is a key regulator of inflammation , immune responses , cell survival , and cell proliferation . To investigate the role of NF - kappaB activation in macrophages during atherogenesis , we used P01130 - deficient mice with a macrophage - restricted deletion of O15111 2 ( O14920 ) , which is essential for NF - kappaB activation by proinflammatory signals . These mice showed increased atherosclerosis as quantified by lesion area measurements . In addition , the lesions were more advanced and showed more necrosis and increased cell number in early lesions . Southern blotting revealed that deletion of O14920 was approximately 65 % in macrophages , coinciding with a reduction of 50 % in NF - kappaB activation , as compared with controls . In both groups , the expression of differentiation markers , uptake of bacteria , and endocytosis of modified LDL was similar . Upon stimulation with LPS , production of P01375 was reduced by approximately 50 % in O14920 - deleted macrophages . Interestingly , we also found a major reduction in the anti - inflammatory cytokine P22301 . Our data show that inhibition of the NF - kappaB pathway in macrophages leads to more severe atherosclerosis in mice , possibly by affecting the pro - and anti - inflammatory balance that controls the development of atherosclerosis .","___MASK8___ yields consistent dose - dependent inhibition of ADP - induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in Q9H244 , P47900 , and P05106 . The platelet P2Y ( 12 ) receptor is the target of clopidogrel therapy , which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect . This receptor is also a target for ticagrelor ( AZD6140 ) , the first reversibly binding oral P2Y ( 12 ) receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy . Single nucleotide polymorphisms ( SNPs ) have been described in the gene for this receptor ( Q9H244 ) , some of which have been associated with variability in platelet reactivity . SNPs in P47900 and P05106 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate ( ADP ) . We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study ( stable atherosclerotic disease ) and the DISPERSE2 study ( non - ST - segment elevation acute coronary syndromes ) . Platelet aggregation data ( at baseline and 4 weeks ) and DNA samples from clopidogrel - naive Caucasian patients treated with ticagrelor were available for 151 patients . Seventy four SNPs within three genes were genotyped . After adjustment for multiple comparisons , none of these SNPs were found to significantly influence inhibition of ADP - induced platelet aggregation by ticagrelor .","TNFalpha induces O95477 through NF - kappaB in macrophages and in phagocytes ingesting apoptotic cells . Recent evidence suggests that tumor necrosis factor alpha ( TNFalpha ) signaling in vascular cells can have antiatherogenic consequences , but the mechanisms are poorly understood . TNFalpha is released by free cholesterol - loaded apoptotic macrophages , and the clearance of these cells by phagocytic macrophages may help to limit plaque development . Macrophage cholesterol uptake induces DB00171 - binding cassette ( DB01048 ) transporter O95477 promoting cholesterol efflux to apolipoprotein A - I and reducing atherosclerosis . We show that TNFalpha induces O95477 mRNA and protein in control and cholesterol - loaded macrophages and enhances cholesterol efflux to apolipoprotein A - I . The induction of O95477 by TNFalpha is reduced by 65 % in O15111 beta - deficient macrophages and by 30 % in p38alpha - deficient macrophages , but not in jun kinase 1 ( P45983 ) - or P45984 - deficient macrophages . To evaluate the potential pathophysiological significance of these observations , we fed TNFalpha - secreting free cholesterol - loaded apoptotic macrophages to a healthy macrophage monolayer ( phagocytes ) . O95477 mRNA and protein were markedly induced in the phagocytes , a response that was mediated both by TNFalpha signaling and by liver X receptor activation . Thus , TNFalpha signals primarily through NF - kappaB to induce O95477 expression in macrophages . In atherosclerotic plaques , this process may help phagocytic macrophages to efflux excess lipids derived from the ingestion of cholesterol - rich apoptotic corpses .","17 ___MASK52___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .","aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK60___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .","miR - 200c inhibits melanoma progression and drug resistance through down - regulation of BMI - 1 . MicroRNAs ( miRNAs ) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression . Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents . The role of miRNAs in melanoma progression and drug resistance has not been well studied . Herein , we demonstrate that miR - 200c is down - regulated in melanomas ( primary and metastatic ) compared with melanocytic nevi . Overexpression of miR - 200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance . miR - 200c overexpression resulted in significant down - regulation of BMI - 1 , Q9UNQ0 , Q9H222 , and P08183 expression and in a concomitant increase in P12830 levels . Knockdown of BMI - 1 showed similar effects as miR - 200c overexpression in melanoma cells . In addition , miR - 200c overexpression significantly inhibited melanoma xenograft growth and metastasis in vivo , and this correlated with diminished expression of BMI - 1 and reduced levels of P12830 in these tumors . The effects of miR - 200c on melanoma cell proliferation and migratory capacity and on self - renewal were rescued by overexpression of Bmi - 1 , and the reversal of these phenotypes correlated with a reduction in P12830 expression and increased levels of Q9UNQ0 , Q9H222 , and P08183 . Taken together , these findings demonstrate a key role for miR - 200c in melanoma progression and drug resistance . These results suggest that miR - 200c may represent a critical target for increasing melanoma sensitivity to clinical therapies .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","DB00877 effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties . Neointima formation , the leading cause of restenosis , is caused by proliferation of coronary artery smooth muscle cells ( CASMCs ) and is associated with infiltration by monocytes . DB00877 inhibits neointima formation after stent implantation in humans . It reduces proliferation by its effects on mammalian target of rapamycin ( P42345 ) kinase . In this study , we investigated the expression of P42345 in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype . In neointimal CASMCs , P42345 exhibited increased phosphorylation and was translocated to the nucleus compared with control . Comparative gene expression analysis of CASMCs treated with rapamycin ( 100 ng / ml ) revealed down - regulation of the transcription factor Q01094 , a key regulator of G ( 1 )/ S - phase entry , and of various retinoblastoma protein / Q01094 - regulated genes . In addition , we found changes in the expression of genes associated with replication , apoptosis , and extracellular matrix formation . Furthermore , rapamycin decreased the gene expression of endothelial monocyte - activating polypeptide - II ( EMAP - II ) . This decrease of EMAP - II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells . Addition of EMAP - II counteracted the antiadhesive effect of rapamycin . Therefore , EMAP - II may comprise a mechanism of rapamycin - mediated reduction of the proinflammatory activation of CASMCs . The effects reported here of rapamycin on the down - regulation of genes involved in cell cycle progression , apoptosis , proliferation , and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation . In addition , rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC , a mechanism suggested to be mediated by the production and release of EMAP II .","[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK8___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .","___MASK4___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK4___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .","Selective regulation of P22309 and SREBP - 1c mRNA expression by docosahexaenoic , eicosapentaenoic , and arachidonic acids . We evaluated , in human cell line HepG2 , the action of individual dietary polyunsaturated fatty acids ( PUFAs ) on the expression of several lipid metabolism genes . The effects of docosahexaenoic acid , 22 : 6 , n - 3 ( DB01708 ) , eicosapentaenoic acid , 20 : 5 , n - 3 ( EPA ) , and arachidonic acid , 20 : 4 , n - 6 ( AA ) were studied alone and with vitamin E ( Vit . E ) . DB01708 , EPA , and AA down - regulated mRNAs and encoded proteins of stearoyl - DB01992 desaturase ( O00767 ) and sterol regulatory element binding protein ( SREBP - 1c ) , two major factors involved in unsaturated fatty acids synthesis . DB01708 affected SREBP - 1c mRNA less markedly than EPA and AA . Vit . E did not affect these products , both when individually added or together with fatty acids . The expression of UDP - glucuronosyl transferase 1A1 ( P22309 ) mRNA , an enzyme of phase II drug metabolism with relevant actions within lipid metabolism , resulted also differentially regulated . DB01708 did not essentially reduce P22309 mRNA expression while EPA and AA produced a considerable decrease . Nevertheless , when these PUFAs were combined with Vit . E , which by itself did not produce any effect , the result was a reduction of P22309 mRNA with DB01708 , an increase reverting to basal level with EPA and no variation with AA . Observed regulations did not result to be mediated by peroxisome proliferator - activated receptor ( Q07869 ) . Our data indicate that major dietary PUFAs and Vit . E are differentially and selectively able to affect the expression of genes involved in lipid metabolism . The different actions of these slightly different molecules could be associated with their physiological role as relevant nutrient molecules .","Q9Y5Q5 mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting . [ Corrected ] . Q9Y5Q5 is a membrane - bound serine protease that acts as the atrial natriuretic peptide ( P01160 ) convertase in the heart . Recent studies show that corin also activates P01160 in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy - induced hypertension . Two Q9Y5Q5 gene mutations , K317E and S472G , were identified in preeclamptic patients and shown to have reduced activity in vitro . In this study , we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function . By molecular modeling , the mutation K317E was predicted to alter corin P01130 - 2 module conformation . Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation . In contrast , the mutation S472G was predicted to abolish a β - sheet critical for corin frizzled - 2 module structure . In Western blot analysis and flow cytometry , S472G mutant was not detected on the cell surface in transfected HEK293 cells . By immunostaining , the S472G mutant was found in the ER , indicating that the mutation S472G disrupted the β - sheet , causing corin misfolding and ER retention . Thus , these results show that mutations in the Q9Y5Q5 gene may impair corin function by entirely different mechanisms . Together , our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients .","DB04540 and plant sterol absorption : recent insights . The recent discovery of transporters in the intestinal mucosa and the canalicular membrane has given new insights into the regulation of intestinal absorption as well as the biliary output of cholesterol and plant sterols . The 2 adenosine triphosphate ( DB00171 ) - binding cassette ( DB01048 ) half - transporters Q9H222 and Q9H221 are expressed in the mucosa cells and the canalicular membrane , and they resecrete sterols , especially absorbed plant sterols , back into the intestinal lumen and from the liver into bile . Defects of either of these cotransporters lead to the rare inherited disease of phytosterolemia , which is clinically defined by hyperabsorption and diminished biliary excretion of plant sterols . Furthermore , it has been recently demonstrated that the Niemann - Pick C1 - Like 1 ( Q9UHC9 ) transporter is most likely responsible for the transport of cholesterol and plant sterols from the brush border membrane into the intestinal mucosa . DB00973 interferes with Q9UHC9 , reducing the intestinal uptake of cholesterol and plant sterols . These new findings contribute to our understanding of cholesterol and plant sterol concentrations in serum , and the effect of dietary and drug intervention to reduce serum concentrations of sterols .","___MASK35___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .","Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .","DB02342 causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non - Smad signaling pathways in immortalized uterine fibroid cells . OBJECTIVE : To investigate the effects and the mechanism of action of 2 - methoxyestradiol ( 2ME ( 2 ) ) on transforming growth factor ( TGF ) β3 - induced profibrotic response in immortalized human uterine fibroid smooth muscle ( huLM ) cells . DESIGN : Laboratory study . SETTING : University research laboratory . PATIENTS ( S ) : Not applicable . INTERVENTIONS ( S ) : Not applicable . MAIN OUTCOME MEASURE ( S ) : huLM cells were treated with TGF - β3 ( 5 ηg / mL ) in the presence or absence of specific P84022 inhibitor SIS3 ( 1 μmol / L ) , inhibitor of the PI3K / Akt ( LY294002 , 10 μmol / L ) , or 2ME ( 2 ) ( 0 . 5 μmol / L ) , and the expression of collagen ( Col ) type I ( αI ) , Col III ( αI ) , plasminogen activator inhibitor ( P05121 ) 1 , connective tissue growth factor ( P29279 ) , and α - smooth muscle actin ( α - SMA ) were determined by real - time reverse - transcription polymerase chain reaction and immunoblotting . The effect of 2ME ( 2 ) on Smad - microtubule binding was evaluated by coimmunoprecipitation . RESULT ( S ) : Our data revealed that TGF - β3 - induced fibrogenic response in huLM is mediated by both Smad - dependent and Smad - independent PI3K / Akt / P42345 signaling pathways . 2ME ( 2 ) abrogates TGF - β3 - induced expression of Col I ( αI ) , Col III ( αI ) , P05121 , P29279 , and α - SMA . Molecularly , 2ME ( 2 ) ameliorates TGF - β3 - induced Q15796 / 3 phosphorylation and nuclear translocation . In addition , 2ME ( 2 ) inhibits TGF - β3 - induced activation of the PI3K / Akt / P42345 pathway . CONCLUSION ( S ) : TGF - β3 - induced profibrotic response in fibroid cells is mediated by Smad - dependent and Smad - independent PI3K / Akt / P42345 pathways . 2ME ( 2 ) inhibits TGF - β3 profibrotic effects in huLM cells by ameliorating both Smad - dependent and Smad - independent signaling pathways .","Relative expression of cholesterol transport - related proteins and inflammation markers through the induction of 7 - ketosterol - mediated stress in Caco - 2 cells . Human diets contain sterol oxidation products that can induce cytotoxic effects , mainly caused by cholesterol oxides . However , phytosterol oxides effects have been less extensively investigated . This study evaluates the production of inflammatory biomarkers ( IL - 1β , P10145 , P22301 , TNFα ) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism ( Q9UHC9 , Q9H222 / 8 , HMGCoA , ACAT ) produced by 7 - ketosterols ( stigmasterol / cholesterol ) in Caco - 2 cells . These effects were linked to intracellular signaling pathways by using several inhibitors . Results showed 7 - ketostigmasterol to have a greater proinflammatory potential than 7 - ketocholesterol . In non - pre - treated cells , only efflux transporters were down - regulated by 7 - ketosterols , showing a greater influence upon Q9H222 expression . Cell - pre - incubation with bradykinin induced changes in ABCG expression levels after 7 - ketostigmasterol - incubation ; however , the energetic metabolism inhibition reduced Q9UHC9 expression only in 7 - ketocholesterol - incubated cells . In non - pre - treated cells , HMG - DB01992 was up - regulated by both 7 - ketosterols . However , exposure to inhibitors down - regulated the expression levels , mainly in 7 - ketocholesterol - incubated cells . While ACAT expression values in non - pre - treated cells were unchanged , exposure to inhibitors caused down - regulation of mRNA levels . These results suggest that internalization and excretion of 7 - ketostigmasterol is probably influenced by [ Ca ] i , which also could mediate HMGCoA activity in POPs metabolism . However , energetic metabolism and reducing equivalents exert different influences upon the 7 - ketosterol internalization .","An absolute role of the PKC - dependent NF - kappaB activation for induction of P14780 in hepatocellular carcinoma cells . Matrix metalloproteinases ( MMPs ) play an important role in inflammation , tumor cell invasion , and metastasis . We found that phorbol - 12 - myristate - 13 - acetate ( PMA ) - stimulated invasion of the hepatocellular carcinoma ( HCC ) SNU - 387 and SNU - 398 cells and that PMA induced the secretion of P14780 in the cells , but did not induce the secretion of P08253 . The PMA - induced P14780 secretion was abolished by treatment of a pan - protein kinase C ( PKC ) inhibitor , GF109203X , and an inhibitor of NF - kappaB activation , sulfasalazine , and partly inhibited by treatment of inhibitors of P29323 pathway , PD98059 and U0126 . In addition , the PMA - stimulated activation of the P14780 promoter was completely inhibited by a mutation of the NF - kappaB site within the P14780 promoter , but not completely by mutations of two AP - 1 sites . Moreover , the P14780 induction by P14210 and P01375 was also completely inhibited by GF109203X and sulfasalazine , but not by PD98059 and U0126 . These data demonstrate that the PKC - dependent NF - kappaB activation is absolute for P14780 induction and that the PKC - dependent P29323 activation devotes to increase the expression level of P14780 , in HCC cells .","DB04540 metabolite , 5 - cholesten - 3β - 25 - diol - 3 - sulfate , promotes hepatic proliferation in mice . Oxysterols are well known as physiological ligands of liver X receptors ( LXRs ) . Oxysterols , 25 - hydroxycholesterol ( 25HC ) and 27 - hydroxycholesterol as endogenous ligands of LXRs , suppress cell proliferation via LXRs signaling pathway . Recent reports have shown that sulfated oxysterol , 5 - cholesten - 3β - 25 - diol - 3 - sulfate ( 25HC3S ) as LXRs antagonist , plays an opposite direction to oxysterols in lipid biosynthesis . The present report was to explore the effect and mechanism of 25HC3S on hepatic proliferation in vivo . Following administration , 25HC3S had a 48 h half life in the circulation and widely distributed in mouse tissues . Profiler ™ PCR array and RTqPCR analysis showed that either exogenous or endogenous 25HC3S generated by overexpression of oxysterol sulfotransferase ( SULT2B1b ) plus administration of 25HC significantly up - regulated the proliferation gene expression of Wt1 , Pcna , cMyc , cyclin A , FoxM1b , and CDC25b in a dose - dependent manner in liver while substantially down - regulating the expression of cell cycle arrest gene Chek2 and apoptotic gene Apaf1 . Either exogenous or endogenous administration of 25HC3S significantly induced hepatic DNA replication as measured by immunostaining of the P12004 labeling index and was associated with reduction in expression of LXR response genes , such as O95477 and SREBP - 1c . Synthetic LXR agonist T0901317 effectively blocked 25HC3S - induced hepatic proliferation . CONCLUSIONS : 25HC3S may be a potent regulator of hepatocyte proliferation and oxysterol sulfation may represent a novel regulatory pathway in liver proliferation via inactivating LXR signaling ."],"string":"[\n \"Pathophysiological factors affecting CAR gene expression . The body defends itself against potentially harmful compounds , such as drugs and toxic endogenous compounds and their metabolites , by inducing the expression of enzymes and transporters involved in their metabolism and elimination . The orphan nuclear receptor CAR ( Q14994 controls phase I ( CYP2B , CYP2C , CYP3A ) , phase II ( P22309 ) , and transporter ( Q9Y6L6 , Q92887 ) genes involved in drug metabolism and bilirubin clearance . Q14994 ( CAR ) is activated by xenobiotics , such as phenobarbital , but also by toxic endogenous compounds such as bilirubin metabolite ( s ) . To better understand the inter - and intravariability in drug detoxification , we studied the molecular mechanisms involved in CAR gene expression in human hepatocytes . We clearly identified CAR as a glucocorticoid receptor ( GR ) target gene , and we proposed the hypothesis of a signal transduction where the activation of GR plays a critical function in CAR - mediated cellular response . According to our model , chemicals or pathophysiological factors that affect GR function should decrease CAR function . To test this hypothesis , we recently investigated the effect of microtubule disrupting agents ( MIAs ) or proinflammatory cytokines . These compounds are well - known inhibitors of GR transactivation property . MIAs activate c - Jun N - terminal kinase ( JNK ) , which phosphorylates and inactivates GR , whereas proinflammatory cytokines , such as P05231 or IL1beta , induce AP - 1 or NF - kB activation , respectively , leading to GR inhibition . As expected , we observed that these molecules inhibit both CAR gene expression and phenobarbital - mediated CYP gene expression in human hepatocytes .\",\n \"Nardosinone protects H9c2 cardiac cells from angiotensin II - induced hypertrophy . Pathological cardiac hypertrophy induced by angiotensin II ( AngII ) can subsequently give rise to heart failure , a leading cause of mortality . Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis , a well - known traditional Chinese medicine . In order to investigate the effects of nardosinone on AngII - induced cardiac cell hypertrophy and the related mechanisms , the myoblast cell line H9c2 , derived from embryonic rat heart , was treated with nardosinone ( 25 , 50 , 100 , and 200 μmol / L ) or AngII ( 1 μmol / L ) . Then cell surface area and mRNA expression of classical markers of hypertrophy were detected . The related protein levels in PI3K / Akt / P42345 and MEK / P29323 signaling pathways were examined by Western blotting . It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII . The mRNA expression of P01160 , DB04899 and β - MHC was obviously elevated in AngII - treated H9c2 cells , which could be effectively blocked by nardosinone at the concentration of 100 μmol / L . Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K / Akt and MEK / P29323 signaling pathways . It was suggested that the inhibitory effect of nardosinone on Ang II - induced hypertrophy in H9c2 cells might be mediated by targeting PI3K / Akt and MEK / P29323 signaling pathways .\",\n \"[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F - VII , F - X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non - diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F - VII , F - X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance .\",\n \"Genetics of familial forms of thrombocytopenia . The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias , as well as the availability of new methods for studying megakaryopoiesis , has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology , pathogenesis and clinical aspects . In particular , new diseases have been described , as deriving from mutations in the genes P21333 , Q9H4B7 , P17301 / P05106 , Q9UPS8 , P99999 , and Q9H222 or Q9H221 . Moreover , forms previously considered separate entities were found to be different clinical aspects of a single disease . For instance , identification of P35579 as the gene whose mutations cause the May - Hegglin anomaly led to the recognition that Sebastian platelet syndrome , Epstein syndrome , and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders . Despite these advances , knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described . In this review , we provide a systematic description of hereditary thrombocytopenias as we know them today , giving special attention to genetic aspects .\",\n \"Inhibition of phosphatidylinositol 3 - kinase - and P29323 MAPK - regulated protein synthesis reveals the pro - apoptotic properties of P25942 ligation in carcinoma cells . P25942 , a member of the tumor necrosis factor receptor superfamily , is frequently expressed in carcinomas where its stimulation results in induction of apoptosis when de novo protein synthesis is inhibited . The requirement of protein synthesis inhibition for efficient killing suggests that P25942 transduces potent survival signals capable of suppressing its pro - apoptotic effects . We have found that inhibition of P25942 signaling on the phosphatidylinositol 3 - kinase ( PI3K ) and P29323 MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma cells to P25942 - mediated cell death . The P25942 - mediated PI3K and P29323 activities were found to converge on the regulation of protein synthesis in carcinoma cells via a pathway involving the activation of p90 ribosomal S6 kinase ( p90Rsk ) and p70S6 kinases , upstream of the translation elongation factor eEF2 . In addition , P25942 ligation was found to mediate a PI3K - and mammalian target of rapamycin ( P42345 ) - dependent phosphorylation of Q13541 and its subsequent dissociation from the P06730 P06730 as well as an P29323 - dependent phosphorylation of P06730 , thus promoting translation initiation . Concomitantly , the antiapoptotic protein cFLIP was found to be induced in P29965 - stimulated carcinoma cells in a PI3K - , P29323 - , and mammalian target of rapamycin ( P42345 ) - dependent manner and down - regulation of cFLIPS expression sensitized to P25942 - mediated carcinoma cell death . These data underline the significance of the PI3K and P29323 pathways in controlling the balance between P25942 - mediated survival and death signals through the regulation of the protein synthesis machinery . Pharmacological agents that target this machinery or its upstream kinases could , therefore , be exploited for P25942 - based tumor therapy .\",\n \"[ The effect of type II diabetes and the metabolic syndrome on cardiac second window preconditioning ] . Preconditioning is the most powerful endogenous mechanism , to protect the heart against ischemic damage . Conflicting data are published whether preconditioning can be induced in case of diabetes and the metabolic syndrome , which are clinically very relevant conditions . If preconditioning could be induced consistently and chronically in this population , an important reduction of surgical morbidity and mortality could be reached . In this project we induced hypoxic preconditioning in mice and used cardiac pressure - conductance catheterisation and infarct size as outcome parameters . In the first part , we found that hypoxic preconditioning was capable to reduce infarct size with 40 % and preserve the load - independent parameters with 33 % after coronary occlusion . A DKO ( double knock - out : ob / ob ; P01130 -/- ) model for the metabolic syndrome developed a larger infarct size and had a reduced contractility . No preconditioning could be induced in this model . To detect the determing factor of the resistance to preconditioning , we used single knock - out models . A comparable preconditioning effect of wild type mice could be induced in the lipoprotein receptor deficient ( P01130 -/- ) model for dyslipidemia . The leptin deficient ( ob / ob ) model , characterized by insulin resistance and abdominal obesity had , identically to the DKO model , a larger infarct size . A second window of preconditioning could be induced , although it was less pronounced than the wild type and P01130 -/- model . P01308 resistance and abdominal obesity could be identified as the major factor in the resistance to preconditioning .\",\n \"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .\",\n \"DB00973 as a potential treatment for non - alcoholic fatty liver disease : is the intestine a modulator of hepatic insulin sensitivity and hepatic fat accumulation ? Non - alcoholic fatty liver disease ( NAFLD ) is the hepatic component of the metabolic syndrome and is known to be associated with marked insulin resistance and increased risk of cardiovascular disease . DB00973 , an inhibitor of intestinal cholesterol absorption , inhibits Niemann - Pick C1 - like 1 ( Q9UHC9 ) . Interestingly , Q9UHC9 is abundantly expressed in human liver , as well as in the intestine . Recent reports suggest a potential benefit of ezetimibe in improving hepatic insulin sensitivity and decreasing hepatic inflammation and lipid accumulation . P01308 resistance and excess hepatic fat accumulation are regarded as key factors in the pathogenesis of NAFLD . We suggest , therefore , that urgent studies are needed to assess the potential therapeutic benefit of ezetimibe in treating NAFLD .\",\n \"Nuclear hormone receptors and cholesterol trafficking : the orphans find a new home . There are many homeostatic mechanisms that contribute to the regulation of cellular and serum cholesterol levels in humans . Much of our understanding of this regulation arose from studies of the cellular pathways controlling cholesterol synthesis and the uptake and degradation of low - density lipoproteins . The physiology governing cholesterol disposition in whole animals , including the molecular mechanisms responsible for dietary uptake of cholesterol and its subsequent catabolism to bile acids , are only now being uncovered . This review summarizes recent studies that have used modern genetic techniques , as well as cell biological methods , to begin to elucidate the pathways responsible for cholesterol trafficking in vivo . This work has led to the realization that networks of nuclear hormone receptors , including the LXR , Q96RI1 , Q07869 , and RXR proteins , play critical roles in lipid metabolism by virtue of their transcriptional regulation of the genes that control sterol metabolic pathways . Some of the major downstream targets of these regulatory networks involve members of the ABC transporter family , including O95477 , P45844 , Q9H222 , Q9H221 , P21439 / Mdr2 , and SPGP / O95342 . These transporters contribute to the movement of sterols and biliary lipids across cellular membranes via mechanisms that have yet to be elucidated . The potential for manipulating these cholesterol trafficking pathways via drugs targeted to the nuclear hormone receptors has generated great interest in their biology and will undoubtedly lead to new therapeutic approaches to human disorders in the coming years .\",\n \"Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .\",\n \"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .\",\n \"Apolipoprotein B100 danger - associated signal 1 ( ApoBDS - 1 ) triggers platelet activation and boosts platelet - leukocyte proinflammatory responses . Low - density lipoproteins ( LDL ) , occurring in vivo in both their native and oxidative form , modulate platelet function and thereby contribute to atherothrombosis . We recently identified and demonstrated that ' ApoB100 danger - associated signal 1 ' ( ApoBDS - 1 ) , a native peptide derived from P04114 ( ApoB100 ) of LDL , induces inflammatory responses in innate immune cells . Platelets are critically involved in the development as well as in the lethal consequences of atherothrombotic diseases , but whether ApoBDS - 1 has also an impact on platelet function is unknown . In this study we examined the effect of ApoBDS - 1 on human platelet function and platelet - leukocyte interactions in vitro . Stimulation with ApoBDS - 1 induced platelet activation , degranulation , adhesion and release of proinflammatory cytokines . ApoBDS - 1 - stimulated platelets triggered innate immune responses by augmenting leukocyte activation , adhesion and transmigration to / through activated HUVEC monolayers , under flow conditions . These platelet - activating effects were sequence - specific , and stimulation of platelets with ApoBDS - 1 activated intracellular signalling pathways , including Ca2 + , PI3K / Akt , P98160 , and p38 - and P29323 - MAPK . Moreover , our data indicates that ApoBDS - 1 - induced platelet activation is partially dependent of positive feedback from ADP on P47900 and Q9H244 , and TxA2 . In conclusion , we demonstrate that ApoBDS - 1 is an effective platelet agonist , boosting platelet - leukocyte ' s proinflammatory responses , and potentially contributing to the multifaceted inflammatory - promoting effects of LDL in the pathogenesis of atherothrombosis .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK39___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"P42892 and β - arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein - coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β - arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK293 cells and non - transformed human colonocytes , we observed that G protein - coupled receptor kinase 2 and β P49407 / 2 terminate plasma membrane Ca ( 2 +) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca ( 2 +) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF - κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP - dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation .\",\n \"The transcriptional coactivator DRIP / mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) / mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 / MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1 / Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and / or glioma - associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium - induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation .\",\n \"Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype . BACKGROUND : Epidemiological studies have shown that low plasma levels of high - density lipoprotein ( HDL ) cholesterol are associated with increased risk of cardiovascular disease , but the mechanisms for the possible atheroprotective effects of HDL cholesterol have still not been fully clarified , in particular in relation to clinical studies . OBJECTIVE : To examine the inflammatory , anti - oxidative and metabolic phenotype of subjects with low plasma HDL cholesterol levels . METHODS AND RESULTS : Fifteen subjects with low HDL cholesterol levels ( eleven males and four females ) and 19 subjects with high HDL ( three males and 16 females ) were recruited . Low HDL cholesterol was defined as ≤ 10th age / sex specific percentile and high HDL - C was defined as ≥ 90 age / sex specific percentile . Inflammatory markers in circulation and PBMC gene expression of cholesterol efflux mediators were measured . Our main findings were : ( i ) subjects with low plasma HDL cholesterol levels were characterized by increased plasma levels of CRP , P14780 , neopterin , Q9H2A7 and P05362 as well as low plasma levels of adiponectin , suggesting an inflammatory phenotype ; ( ii ) these individuals also had reduced paraoxonase ( P27169 ) 1 activity in plasma and Q15165 gene expression in peripheral blood mononuclear cells ( PBMC ) accompanied by increased plasma levels of oxidized LDL suggesting decreased anti - oxidative capacity ; and ( iii ) PBMC from low HDL subjects also had decreased mRNA levels of O95477 and P45844 , suggesting impaired reverse cholesterol transport . CONCLUSION : Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype that could contribute to the increased risk of atherosclerotic disorders in these subjects with low HDL levels .\",\n \"___MASK8___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .\",\n \"Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .\",\n \"Leptin promotes neointima formation and smooth muscle cell proliferation via NADPH oxidase activation and signalling in caveolin - rich microdomains . AIMS : P02649 ( apoE ) may act as a vasculoprotective factor by promoting plasma lipid clearance and cholesterol efflux . Moreover , apoE accumulates at sites of vascular injury and modulates the effect of growth factors on smooth muscle cells ( SMCs ) . Experimental data suggested that hypothalamic apoE expression is reduced in obesity and associated with leptin resistance . In this study , we examined the role of apoE in mediating the effects of leptin on vascular lesion formation . METHODS AND RESULTS : Leptin was administered to apoE knockout ( apoE -/- ) mice via osmotic pumps to increase its circulating levels . Morphometric analysis revealed that leptin did not alter neointima formation and failed to increase α - actin - or P12004 - immunopositive SMCs after vascular injury . Similar findings were obtained after analysis of atherosclerotic lesions . Comparison of apoE -/- , wild - type , or P01130 -/- mice and functional analyses in aortic SMCs from WT or apoE -/- mice or human arterial SMCs after treatment with small interfering ( si ) RNA or heparinase revealed that leptin requires the presence of apoE , expressed , secreted and bound to the cell surface , to fully activate leptin receptor signalling and to promote SMC proliferation and neointima formation . Mechanistically , leptin induced the phosphorylation and membrane translocation of caveolin ( cav )- 1 , and apoE down - regulation or caveolae disruption inhibited the leptin - induced p47phox activation , ROS formation and SMC proliferation . Finally , leptin failed to increase neointima formation in mice lacking cav - 1 . CONCLUSION : Our findings suggest that apoE mediates the effects of leptin on vascular lesion formation by stabilizing cav - 1 - enriched cell membrane microdomains in SMCs , thus allowing NADPH oxidase assembly and ROS - mediated mitogenic signalling .\",\n \"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK42___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK42___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK42___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .\",\n \"Oxysterol binding protein induces upregulation of SREBP - 1c and enhances hepatic lipogenesis . BACKGROUND : Oxysterol binding protein ( P22059 ) has previously been implicated as a sterol sensor that regulates sphingomyelin synthesis and the activity of extracellular signal - regulated kinases ( P29323 ) . METHODS AND RESULTS : We determined the effects of adenovirus - mediated hepatic overexpression of P22059 and its homologues ORP1L and Q9H4L5 on mouse serum lipids . Whereas ORP1L and Q9H4L5 had no effect on serum lipids , P22059 induced a marked increase of VLDL triglycerides ( TG ) . Also , the liver tissue TG were elevated in the AdOSBP - injected mice , and their TG secretion rate was increased by 70 % . The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator , SREBP - 1c , as well as the Insig - 1 mRNA , were upregulated two - fold in the P22059 - expressing livers . No change occurred in the messages of liver X receptor target genes O95477 , Q9H222 , and P22680 , and the Insig - 2a mRNA was reduced . The phosphorylation of P29323 was decreased in AdOSBP - infected liver and cultured hepatocytes . Importantly , silencing of P22059 in hepatocytes suppressed the induction of P36956 - c by insulin and resulted in a reduction of TG synthesis . CONCLUSION : Our results demonstrate that P22059 regulates hepatic TG metabolism and suggest the involvement of P22059 in the insulin signaling pathways that control hepatic lipogenesis .\",\n \"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .\",\n \"Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .\",\n \"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK4___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .\",\n \"Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia . Sitosterolemia is a rare , autosomal recessive disease caused by mutations in the adenosine triphosphate - binding cassette transporter genes Q9H222 or Q9H221 that result in accumulation of xenosterols in the body . Clinical manifestations include tendon xanthomas , premature coronary artery disease , hemolytic anemia , macrothrombocytopenia , and bleeding . Although the effect of sterol accumulation on the predisposition for atherosclerosis is evident , how xenosterol accumulation leads to defects in platelet physiology is unknown . Sitosterolemia induced in Abcg5 - and Abcg8 - deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes , leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its αIIbβ3 integrin receptor , internalization of the αIIbβ3 complex , generation of platelet - derived microparticles , and changes in the quantity and subcellular localization of filamin . The latter was associated with macrothrombocytopenia , shedding of GPIbα , impaired platelet adhesion to P04275 , and inability to form stable thrombi . Plasma levels of soluble GPIbα were strongly correlated with plasma sitosterol levels in samples from human sitosterolemic patients , implicating a similar mechanism of sterol - induced platelet passivation in the human disease . Intercalation of plant sterols into the plasma membrane therefore results in dysregulation of multiple platelet activation pathways , leading to macrothrombocytopenia and bleeding .\",\n \"P32189 deficiency alters expression of genes involved in lipid metabolism , carbohydrate metabolism , and insulin signaling . P32189 ( GK ) is at the interface of fat and carbohydrate metabolism and has been implicated in insulin resistance and type 2 diabetes mellitus . To define GK ' s role in insulin resistance , we examined gene expression in brown adipose tissue in a glycerol kinase knockout ( KO ) mouse model using microarray analysis . Global gene expression profiles of KO mice were distinct from wild type with 668 differentially expressed genes . These include genes involved in lipid metabolism , carbohydrate metabolism , insulin signaling , and insulin resistance . Real - time polymerase chain reaction analysis confirmed the differential expression of selected genes involved in lipid and carbohydrate metabolism . PathwayAssist analysis confirmed direct and indirect connections between glycerol kinase and genes in lipid metabolism , carbohydrate metabolism , insulin signaling , and insulin resistance . Network component analysis ( P40199 ) showed that the transcription factors ( TFs ) P37231 , P36956 , Q12772 , P40763 , P42229 , SP1 , CEBPalpha , CREB , GR and Q07869 have altered activity in the KO mice . P40199 also revealed the individual contribution of these TFs on the expression of genes altered in the microarray data . This study elucidates the complex network of glycerol kinase and further confirms a possible role for glycerol kinase deficiency , a simple Mendelian disorder , in insulin resistance , and type 2 diabetes mellitus , a common complex genetic disorder .\",\n \"DB04540 - lowering effect of ezetimibe in uridine diphosphate glucuronosyltransferase 1A - deficient ( Gunn ) rats . DB00973 ( EZE ) selectively blocks intestinal cholesterol absorption by interacting with Niemann - Pick C1 Like 1 ( Q9UHC9 ) . After administration , EZE is extensively metabolized in liver and intestine to its phenolic glucuronide form ( EZE - G ) by uridine diphosphate glucuronosyltransferases ( UGTs ) , among which P22309 and 1A3 exhibit highest activity . EZE - G is excreted into bile and undergoes extensive enterohepatic recirculation . Considering the pharmacokinetic properties of EZE and an in vitro binding study showing the high affinity binding of EZE - G to Q9UHC9 , glucuronidation by UGTs has been believed to be essential for the pharmacological efficacy of EZE . To study the role of glucuronidation by UGTs for the cholesterol - lowering effect of EZE , in vitro and in vivo studies were performed using Gunn rats , which hereditarily lack the expression of P22309 enzymes . The biliary excreted amount of EZE - G was reduced by 73 % up to 3 h after administration of EZE ( 0 . 3 mg / kg ) in Gunn rats , which is consistent with the reduction of in vitro EZE glucuronidation activity found in liver and intestinal microsome from Gunn rats . These results indicate that the formation of EZE - G in Gunn rats is much lower than that in Wistar rats . However , in vivo study showed that 0 . 3 mg / kg EZE , which is the clinically relevant dose , reduced cholesterol absorption in both Wistar and Gunn rats to nearly the same degree and the dose dependence was not significantly different between Wistar and Gunn rats at the range 0 . 001 approximately 0 . 3 mg / kg . These results indicate that a deficiency of P22309 activity does not necessarily alter the cholesterol - lowering effect of EZE in rats at therapeutic doses .\",\n \"The Q9H222 Q9H221 sterol transporter and phytosterols : implications for cardiometabolic disease . PURPOSE OF REVIEW : This review summarizes recent developments in the activity , regulation , and physiology of the Q9H222 Q9H221 ( G5G8 ) transporter and the use of its xenobiotic substrates , phytosterols , as cholesterol lowering agents in the treatment of cardiovascular disease . Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome . RECENT FINDINGS : Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction . The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility . Finally , the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction , suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit . SUMMARY : P01308 resistance elevates G5G8 and increases susceptibility to cholesterol gallstones . However , this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine . Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease .\",\n \"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .\",\n \"HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing P16671 - dependent cholesteryl ester accumulation in macrophages . Protease inhibitors decrease the viral load in HIV patients , however the patients develop hypertriglyceridemia , hypercholesterolemia , and atherosclerosis . It has been assumed that protease inhibitor - dependent increases in atherosclerosis are secondary to the dyslipidemia . Incubation of THP - 1 cells or human PBMCs with protease inhibitors caused upregulation of P16671 and the accumulation of cholesteryl esters . The use of P16671 - blocking antibodies , a P16671 morpholino , and monocytes isolated from P16671 null mice demonstrated that protease inhibitor - induced increases in cholesteryl esters were dependent on P16671 upregulation . These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating P16671 and cholesteryl ester accumulation independent of dyslipidemia . Studies with P01130 null mice demonstrated that low doses of protease inhibitors induce an increase in the level of P16671 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids . Furthermore , the lack of P16671 protected the animals from protease inhibitor - induced atherosclerosis . Finally , ritonavir increased P37231 and P16671 mRNA levels in a PKC - and P37231 - dependent manner . We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of P16671 and the subsequent accumulation of sterol in macrophages .\",\n \"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK71___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .\",\n \"Current therapy for patients with sitosterolemia -- effect of ezetimibe on plant sterol metabolism . Sitosterolemia is a rare , autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations , caused by mutations in the adenosine triphosphate - bind - ing cassette ( DB01048 ) transporter Q9H222 or Q9H221 genes . Markedly increased serum concentration of plant sterols . such as sitosterol and campesterol , cause premature atherosclerosis and massive xanthomas . Hitherto known treatments for sitosterolemia , including a low - sterol diet , bile - salt binding resins , ileal bypass surgery and low density lipoprotein ( LDL ) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels , subsequently developing premature atherosclerotic cardiovascular diseases . DB00973 , an inhibitor of intestinal cholesterol absorption through its binding to Niemann - Pick C1 - like 1 ( Q9UHC9 ) , has been widely used for decreasing serum LDL - cholesterol levels in patients with hypercholesterolemia . DB00973 also reduces the gastrointestinal absorption of plant sterols , thereby also lowering the serum concentrations of plant sterols . This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia . In the current review , we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease , one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis . DB00973 administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51 . 3 % and 48 . 9 % , respectively , in the two patients , demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy .\",\n \"LXR driven induction of HDL - cholesterol is independent of intestinal cholesterol absorption and O95477 protein expression . We investigated whether : ( 1 ) liver X receptor ( LXR ) - driven induction of high - density lipoprotein cholesterol ( HDL - C ) and other LXR - mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption ; and ( 2 ) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis . Mice were fed 0 . 2 % cholesterol and treated with GW3965 + ezetimibe , GW3965 or ezetimibe . GW3965 + ezetimibe treatment elevated serum HDL - C and Apolipoprotein ( Apo ) AI , effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols . No changes in intestinal DB00171 - binding cassette ( DB01048 ) A1 or Q9H222 protein expression were observed , despite increased mRNA expression , while hepatic O95477 was slightly reduced . The combined treatment caused a pronounced down - regulation of intestinal Niemann - Pick C1 - like 1 ( Q9UHC9 ) and reduced hepatic and intestinal cholesterol levels . GW3965 did not affect the intestinal cholesterol absorption , but increased serum HDL - C and ApoAI levels . GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1 - 6 cells . DB00973 reduced the intestinal cholesterol absorption , O95477 and Q9H222 , but did not affect the serum HDL - C or ApoAI levels . Thus , the LXR - driven induction of HDL - C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic O95477 was not required . Inhibited influx of cholesterol via Q9UHC9 and / or low levels of intracellular cholesterol prevented post - transcriptional expression of intestinal O95477 and Q9H222 , despite increased mRNA levels . Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol .\",\n \"P35568 regulation in health and disease . The global incidence of diabetes is increasing at epidemic rates . Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years . Type 2 diabetes accounts for 95 % of all cases and is characterized in part by impaired sensitivity to insulin or ' insulin resistance ' . Defects in the insulin signalling pathways underpin this resistance . In the current article we discuss the regulation of P01308 Receptor Substrate - 1 ( P35568 ) , a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance . Coordination of P35568 function is multi - faceted , involving phosphorylation of P35568 at multiple serine / threonine residues . This controls many aspects of P35568 , including its interaction with the insulin receptor and subsequent tyrosine phosphorylation , as well as its subcellular distribution and targeting for degradation by the proteasome . Such tight control ensures appropriate transduction and attenuation of the insulin signal , thereby regulating insulin action in healthy individuals . Emerging evidence indicates that ' diabetogenic factors ' associated with insulin resistance , such as TNFalpha and elevated circulating fatty acids , impact on insulin signalling at the level of P35568 serine / threonine phosphorylation . The expression and / or activity of several kinases , such as O15111 beta ( IKKbeta ) and salt - induced kinase 2 ( Q9H0K1 ) , and the phosphorylation of P35568 at key sites , such as Ser307 and Ser789 , are increased in states of insulin resistance . Identifying the pathways by which such factors activate these and other kinases , and defining the precise roles of specific serine / threonine phosphorylation events in P35568 regulation , represent important goals which may eventually provide a rationale for therapeutic intervention .\",\n \"Q07869 and P37231 activators induce cholesterol removal from human macrophage foam cells through stimulation of the O95477 pathway . Peroxisome proliferator - activated receptors ( PPARs ) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation . Q07869 and P37231 are both expressed in human macrophages where they exert anti - inflammatory effects . The activation of Q07869 may promote foam - cell formation by inducing expression of the macrophage scavenger receptor P16671 . This prompted us to investigate the influence of different Q07869 - activators on cholesterol metabolism and foam - cell formation of human primary and THP - 1 macrophages . Here we show that Q07869 and P37231 activators do not influence acetylated low density lipoprotein - induced foam - cell formation of human macrophages . In contrast , Q07869 and P37231 activators induce the expression of the gene encoding O95477 , a transporter that controls apoAI - mediated cholesterol efflux from macrophages . These effects are likely due to enhanced expression of liver - x - receptor alpha , an oxysterol - activated nuclear receptor which induces O95477 - promoter transcription . Moreover , Q07869 and P37231 activators increase apoAI - induced cholesterol efflux from normal macrophages . In contrast , Q07869 or P37231 activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease , which is due to a genetic defect in O95477 . Here we identify a regulatory role for Q07869 and P37231 in the first steps of the reverse - cholesterol - transport pathway through the activation of O95477 - mediated cholesterol efflux in human macrophages .\",\n \"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK3___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .\",\n \"The molecular mechanisms underlying the reduction of LDL apoB - 100 by ezetimibe plus simvastatin . The combination of ezetimibe , an inhibitor of Niemann - Pick C1 - like 1 protein ( Q9UHC9 ) , and an P04035 inhibitor decreases cholesterol absorption and synthesis . In clinical trials , ezetimibe plus simvastatin produces greater LDL - cholesterol reductions than does monotherapy . The molecular mechanism for this enhanced efficacy has not been defined . P04114 ( apoB - 100 ) kinetics were determined in miniature pigs treated with ezetimibe ( 0 . 1 mg / kg / day ) , ezetimibe plus simvastatin ( 10 mg / kg / day ) , or placebo ( n = 7 / group ) . DB00973 decreased cholesterol absorption ( - 79 % ) and plasma phytosterols ( - 91 % ) , which were not affected further by simvastatin . DB00973 increased plasma lathosterol ( + 65 % ) , which was prevented by addition of simvastatin . The combination decreased total cholesterol ( - 35 % ) and LDL - cholesterol ( - 47 % ) . VLDL apoB pool size decreased 26 % , due to a 35 % decrease in VLDL apoB production . LDL apoB pool size decreased 34 % due to an 81 % increase in the fractional catabolic rate , both of which were significantly greater than monotherapy . Combination treatment decreased hepatic microsomal cholesterol ( - 29 % ) and cholesteryl ester ( - 65 % ) and increased P01130 ( P01130 ) expression by 240 % . The combination increased Q9UHC9 expression in liver and intestine , consistent with increased Q12772 expression . DB00973 plus simvastatin decreases VLDL and LDL apoB - 100 concentrations through reduced VLDL production and upregulation of P01130 - mediated LDL clearance .\",\n \"Inhibition of Niemann - Pick - type C1 - like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1 - antitrypsin Z deposition . Autophagy can degrade aggregate - prone proteins , but excessive autophagy can have adverse effects . It would be beneficial if autophagy could be enhanced in a cell type - specific manner , but this has been difficult because the basic mechanism of autophagy is common . In the present study we found that inhibition of Niemann - Pick - type C1 - like 1 ( Q9UHC9 ) by ezetimibe activates autophagy only in hepatocytes and small intestinal epithelia , but not in other cells . DB00973 induced accumulation of free cholesterol in the late endosome / lysosome and increased partitioning of a Ragulator component , Q6IAA8 , in rafts . The latter change led to down - regulation of mammalian target of rapamycin ( P42345 ) C1 activity by decreasing P42345 recruitment to the late endosome / lysosome and activated autophagy . A primary effect of ezetimibe was found to be a decrease of free cholesterol in the plasma membrane , because all the results caused by ezetimibe were suppressed by supplementation of cholesterol as a methyl - β - cyclodextrin complex . By enhancing autophagy in human primary hepatocytes with ezetimibe , insoluble mutant α1 - antitrypsin Z was reduced significantly . CONCLUSION : Inhibition of Q9UHC9 by ezetimibe activates autophagy in human hepatocytes by modulating cholesterol homeostasis . DB00973 may be used to ameliorate liver degeneration in α1 - antitrypsin deficiency .\",\n \"Genetic demonstration of intestinal Q9UHC9 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels . OBJECTIVE : The correlation between intestinal cholesterol absorption values and plasma low - density lipoprotein - cholesterol ( LDL - C ) levels remains controversial . Niemann - Pick - C1 - Like 1 ( Q9UHC9 ) is essential for intestinal cholesterol absorption , and is the target of ezetimibe , a cholesterol absorption inhibitor . However , studies with Q9UHC9 knockout mice or ezetimibe can not definitively clarify this correlation because Q9UHC9 expression is not restricted to intestine in humans and mice . In this study we sought to genetically address this issue . METHODS AND RESULTS : We developed a mouse model that lacks endogenous ( Q9UHC9 ) and P01130 ( P01130 ) ( DKO ) , but transgenically expresses human Q9UHC9 in gastrointestinal tract only ( DKO / Q9NUQ9 ( IntOnly ) mice ) . Our novel model eliminated potential effects of non - intestinal Q9UHC9 on cholesterol homeostasis . We found that human Q9UHC9 was localized at the intestinal brush border membrane of DKO / Q9NUQ9 ( IntOnly ) mice . DB04540 feeding induced formation of Q9UHC9 - positive vesicles beneath this membrane in an ezetimibe - sensitive manner . Compared to DKO mice , DKO / Q9NUQ9 ( IntOnly ) mice showed significant increases in cholesterol absorption and blood / hepatic / biliary cholesterol . Increased blood cholesterol was restricted to very low - density lipoprotein ( VLDL ) and LDL fractions , which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48 . Additionally , DKO / Q9NUQ9 ( IntOnly ) mice displayed decreased fecal cholesterol excretion and hepatic / intestinal expression of cholesterologenic genes . DB00973 treatment virtually reversed all of the transgene - related phenotypes in DKO / Q9NUQ9 ( IntOnly ) mice . CONCLUSION : Our findings from DKO / Q9NUQ9 ( IntOnly ) mice clearly demonstrate that Q9UHC9 - mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B - containing atherogenic lipoproteins , at least in mice .\",\n \"Inhibition of NF - kappaB activation in macrophages increases atherosclerosis in P01130 - deficient mice . Atherosclerosis is now generally accepted as a chronic inflammatory condition . The transcription factor NF - kappaB is a key regulator of inflammation , immune responses , cell survival , and cell proliferation . To investigate the role of NF - kappaB activation in macrophages during atherogenesis , we used P01130 - deficient mice with a macrophage - restricted deletion of O15111 2 ( O14920 ) , which is essential for NF - kappaB activation by proinflammatory signals . These mice showed increased atherosclerosis as quantified by lesion area measurements . In addition , the lesions were more advanced and showed more necrosis and increased cell number in early lesions . Southern blotting revealed that deletion of O14920 was approximately 65 % in macrophages , coinciding with a reduction of 50 % in NF - kappaB activation , as compared with controls . In both groups , the expression of differentiation markers , uptake of bacteria , and endocytosis of modified LDL was similar . Upon stimulation with LPS , production of P01375 was reduced by approximately 50 % in O14920 - deleted macrophages . Interestingly , we also found a major reduction in the anti - inflammatory cytokine P22301 . Our data show that inhibition of the NF - kappaB pathway in macrophages leads to more severe atherosclerosis in mice , possibly by affecting the pro - and anti - inflammatory balance that controls the development of atherosclerosis .\",\n \"___MASK8___ yields consistent dose - dependent inhibition of ADP - induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in Q9H244 , P47900 , and P05106 . The platelet P2Y ( 12 ) receptor is the target of clopidogrel therapy , which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect . This receptor is also a target for ticagrelor ( AZD6140 ) , the first reversibly binding oral P2Y ( 12 ) receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy . Single nucleotide polymorphisms ( SNPs ) have been described in the gene for this receptor ( Q9H244 ) , some of which have been associated with variability in platelet reactivity . SNPs in P47900 and P05106 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate ( ADP ) . We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study ( stable atherosclerotic disease ) and the DISPERSE2 study ( non - ST - segment elevation acute coronary syndromes ) . Platelet aggregation data ( at baseline and 4 weeks ) and DNA samples from clopidogrel - naive Caucasian patients treated with ticagrelor were available for 151 patients . Seventy four SNPs within three genes were genotyped . After adjustment for multiple comparisons , none of these SNPs were found to significantly influence inhibition of ADP - induced platelet aggregation by ticagrelor .\",\n \"TNFalpha induces O95477 through NF - kappaB in macrophages and in phagocytes ingesting apoptotic cells . Recent evidence suggests that tumor necrosis factor alpha ( TNFalpha ) signaling in vascular cells can have antiatherogenic consequences , but the mechanisms are poorly understood . TNFalpha is released by free cholesterol - loaded apoptotic macrophages , and the clearance of these cells by phagocytic macrophages may help to limit plaque development . Macrophage cholesterol uptake induces DB00171 - binding cassette ( DB01048 ) transporter O95477 promoting cholesterol efflux to apolipoprotein A - I and reducing atherosclerosis . We show that TNFalpha induces O95477 mRNA and protein in control and cholesterol - loaded macrophages and enhances cholesterol efflux to apolipoprotein A - I . The induction of O95477 by TNFalpha is reduced by 65 % in O15111 beta - deficient macrophages and by 30 % in p38alpha - deficient macrophages , but not in jun kinase 1 ( P45983 ) - or P45984 - deficient macrophages . To evaluate the potential pathophysiological significance of these observations , we fed TNFalpha - secreting free cholesterol - loaded apoptotic macrophages to a healthy macrophage monolayer ( phagocytes ) . O95477 mRNA and protein were markedly induced in the phagocytes , a response that was mediated both by TNFalpha signaling and by liver X receptor activation . Thus , TNFalpha signals primarily through NF - kappaB to induce O95477 expression in macrophages . In atherosclerotic plaques , this process may help phagocytic macrophages to efflux excess lipids derived from the ingestion of cholesterol - rich apoptotic corpses .\",\n \"17 ___MASK52___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .\",\n \"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK60___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .\",\n \"miR - 200c inhibits melanoma progression and drug resistance through down - regulation of BMI - 1 . MicroRNAs ( miRNAs ) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression . Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents . The role of miRNAs in melanoma progression and drug resistance has not been well studied . Herein , we demonstrate that miR - 200c is down - regulated in melanomas ( primary and metastatic ) compared with melanocytic nevi . Overexpression of miR - 200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance . miR - 200c overexpression resulted in significant down - regulation of BMI - 1 , Q9UNQ0 , Q9H222 , and P08183 expression and in a concomitant increase in P12830 levels . Knockdown of BMI - 1 showed similar effects as miR - 200c overexpression in melanoma cells . In addition , miR - 200c overexpression significantly inhibited melanoma xenograft growth and metastasis in vivo , and this correlated with diminished expression of BMI - 1 and reduced levels of P12830 in these tumors . The effects of miR - 200c on melanoma cell proliferation and migratory capacity and on self - renewal were rescued by overexpression of Bmi - 1 , and the reversal of these phenotypes correlated with a reduction in P12830 expression and increased levels of Q9UNQ0 , Q9H222 , and P08183 . Taken together , these findings demonstrate a key role for miR - 200c in melanoma progression and drug resistance . These results suggest that miR - 200c may represent a critical target for increasing melanoma sensitivity to clinical therapies .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"DB00877 effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties . Neointima formation , the leading cause of restenosis , is caused by proliferation of coronary artery smooth muscle cells ( CASMCs ) and is associated with infiltration by monocytes . DB00877 inhibits neointima formation after stent implantation in humans . It reduces proliferation by its effects on mammalian target of rapamycin ( P42345 ) kinase . In this study , we investigated the expression of P42345 in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype . In neointimal CASMCs , P42345 exhibited increased phosphorylation and was translocated to the nucleus compared with control . Comparative gene expression analysis of CASMCs treated with rapamycin ( 100 ng / ml ) revealed down - regulation of the transcription factor Q01094 , a key regulator of G ( 1 )/ S - phase entry , and of various retinoblastoma protein / Q01094 - regulated genes . In addition , we found changes in the expression of genes associated with replication , apoptosis , and extracellular matrix formation . Furthermore , rapamycin decreased the gene expression of endothelial monocyte - activating polypeptide - II ( EMAP - II ) . This decrease of EMAP - II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells . Addition of EMAP - II counteracted the antiadhesive effect of rapamycin . Therefore , EMAP - II may comprise a mechanism of rapamycin - mediated reduction of the proinflammatory activation of CASMCs . The effects reported here of rapamycin on the down - regulation of genes involved in cell cycle progression , apoptosis , proliferation , and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation . In addition , rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC , a mechanism suggested to be mediated by the production and release of EMAP II .\",\n \"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK8___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .\",\n \"___MASK4___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK4___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .\",\n \"Selective regulation of P22309 and SREBP - 1c mRNA expression by docosahexaenoic , eicosapentaenoic , and arachidonic acids . We evaluated , in human cell line HepG2 , the action of individual dietary polyunsaturated fatty acids ( PUFAs ) on the expression of several lipid metabolism genes . The effects of docosahexaenoic acid , 22 : 6 , n - 3 ( DB01708 ) , eicosapentaenoic acid , 20 : 5 , n - 3 ( EPA ) , and arachidonic acid , 20 : 4 , n - 6 ( AA ) were studied alone and with vitamin E ( Vit . E ) . DB01708 , EPA , and AA down - regulated mRNAs and encoded proteins of stearoyl - DB01992 desaturase ( O00767 ) and sterol regulatory element binding protein ( SREBP - 1c ) , two major factors involved in unsaturated fatty acids synthesis . DB01708 affected SREBP - 1c mRNA less markedly than EPA and AA . Vit . E did not affect these products , both when individually added or together with fatty acids . The expression of UDP - glucuronosyl transferase 1A1 ( P22309 ) mRNA , an enzyme of phase II drug metabolism with relevant actions within lipid metabolism , resulted also differentially regulated . DB01708 did not essentially reduce P22309 mRNA expression while EPA and AA produced a considerable decrease . Nevertheless , when these PUFAs were combined with Vit . E , which by itself did not produce any effect , the result was a reduction of P22309 mRNA with DB01708 , an increase reverting to basal level with EPA and no variation with AA . Observed regulations did not result to be mediated by peroxisome proliferator - activated receptor ( Q07869 ) . Our data indicate that major dietary PUFAs and Vit . E are differentially and selectively able to affect the expression of genes involved in lipid metabolism . The different actions of these slightly different molecules could be associated with their physiological role as relevant nutrient molecules .\",\n \"Q9Y5Q5 mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting . [ Corrected ] . Q9Y5Q5 is a membrane - bound serine protease that acts as the atrial natriuretic peptide ( P01160 ) convertase in the heart . Recent studies show that corin also activates P01160 in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy - induced hypertension . Two Q9Y5Q5 gene mutations , K317E and S472G , were identified in preeclamptic patients and shown to have reduced activity in vitro . In this study , we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function . By molecular modeling , the mutation K317E was predicted to alter corin P01130 - 2 module conformation . Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation . In contrast , the mutation S472G was predicted to abolish a β - sheet critical for corin frizzled - 2 module structure . In Western blot analysis and flow cytometry , S472G mutant was not detected on the cell surface in transfected HEK293 cells . By immunostaining , the S472G mutant was found in the ER , indicating that the mutation S472G disrupted the β - sheet , causing corin misfolding and ER retention . Thus , these results show that mutations in the Q9Y5Q5 gene may impair corin function by entirely different mechanisms . Together , our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients .\",\n \"DB04540 and plant sterol absorption : recent insights . The recent discovery of transporters in the intestinal mucosa and the canalicular membrane has given new insights into the regulation of intestinal absorption as well as the biliary output of cholesterol and plant sterols . The 2 adenosine triphosphate ( DB00171 ) - binding cassette ( DB01048 ) half - transporters Q9H222 and Q9H221 are expressed in the mucosa cells and the canalicular membrane , and they resecrete sterols , especially absorbed plant sterols , back into the intestinal lumen and from the liver into bile . Defects of either of these cotransporters lead to the rare inherited disease of phytosterolemia , which is clinically defined by hyperabsorption and diminished biliary excretion of plant sterols . Furthermore , it has been recently demonstrated that the Niemann - Pick C1 - Like 1 ( Q9UHC9 ) transporter is most likely responsible for the transport of cholesterol and plant sterols from the brush border membrane into the intestinal mucosa . DB00973 interferes with Q9UHC9 , reducing the intestinal uptake of cholesterol and plant sterols . These new findings contribute to our understanding of cholesterol and plant sterol concentrations in serum , and the effect of dietary and drug intervention to reduce serum concentrations of sterols .\",\n \"___MASK35___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .\",\n \"Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .\",\n \"DB02342 causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non - Smad signaling pathways in immortalized uterine fibroid cells . OBJECTIVE : To investigate the effects and the mechanism of action of 2 - methoxyestradiol ( 2ME ( 2 ) ) on transforming growth factor ( TGF ) β3 - induced profibrotic response in immortalized human uterine fibroid smooth muscle ( huLM ) cells . DESIGN : Laboratory study . SETTING : University research laboratory . PATIENTS ( S ) : Not applicable . INTERVENTIONS ( S ) : Not applicable . MAIN OUTCOME MEASURE ( S ) : huLM cells were treated with TGF - β3 ( 5 ηg / mL ) in the presence or absence of specific P84022 inhibitor SIS3 ( 1 μmol / L ) , inhibitor of the PI3K / Akt ( LY294002 , 10 μmol / L ) , or 2ME ( 2 ) ( 0 . 5 μmol / L ) , and the expression of collagen ( Col ) type I ( αI ) , Col III ( αI ) , plasminogen activator inhibitor ( P05121 ) 1 , connective tissue growth factor ( P29279 ) , and α - smooth muscle actin ( α - SMA ) were determined by real - time reverse - transcription polymerase chain reaction and immunoblotting . The effect of 2ME ( 2 ) on Smad - microtubule binding was evaluated by coimmunoprecipitation . RESULT ( S ) : Our data revealed that TGF - β3 - induced fibrogenic response in huLM is mediated by both Smad - dependent and Smad - independent PI3K / Akt / P42345 signaling pathways . 2ME ( 2 ) abrogates TGF - β3 - induced expression of Col I ( αI ) , Col III ( αI ) , P05121 , P29279 , and α - SMA . Molecularly , 2ME ( 2 ) ameliorates TGF - β3 - induced Q15796 / 3 phosphorylation and nuclear translocation . In addition , 2ME ( 2 ) inhibits TGF - β3 - induced activation of the PI3K / Akt / P42345 pathway . CONCLUSION ( S ) : TGF - β3 - induced profibrotic response in fibroid cells is mediated by Smad - dependent and Smad - independent PI3K / Akt / P42345 pathways . 2ME ( 2 ) inhibits TGF - β3 profibrotic effects in huLM cells by ameliorating both Smad - dependent and Smad - independent signaling pathways .\",\n \"Relative expression of cholesterol transport - related proteins and inflammation markers through the induction of 7 - ketosterol - mediated stress in Caco - 2 cells . Human diets contain sterol oxidation products that can induce cytotoxic effects , mainly caused by cholesterol oxides . However , phytosterol oxides effects have been less extensively investigated . This study evaluates the production of inflammatory biomarkers ( IL - 1β , P10145 , P22301 , TNFα ) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism ( Q9UHC9 , Q9H222 / 8 , HMGCoA , ACAT ) produced by 7 - ketosterols ( stigmasterol / cholesterol ) in Caco - 2 cells . These effects were linked to intracellular signaling pathways by using several inhibitors . Results showed 7 - ketostigmasterol to have a greater proinflammatory potential than 7 - ketocholesterol . In non - pre - treated cells , only efflux transporters were down - regulated by 7 - ketosterols , showing a greater influence upon Q9H222 expression . Cell - pre - incubation with bradykinin induced changes in ABCG expression levels after 7 - ketostigmasterol - incubation ; however , the energetic metabolism inhibition reduced Q9UHC9 expression only in 7 - ketocholesterol - incubated cells . In non - pre - treated cells , HMG - DB01992 was up - regulated by both 7 - ketosterols . However , exposure to inhibitors down - regulated the expression levels , mainly in 7 - ketocholesterol - incubated cells . While ACAT expression values in non - pre - treated cells were unchanged , exposure to inhibitors caused down - regulation of mRNA levels . These results suggest that internalization and excretion of 7 - ketostigmasterol is probably influenced by [ Ca ] i , which also could mediate HMGCoA activity in POPs metabolism . However , energetic metabolism and reducing equivalents exert different influences upon the 7 - ketosterol internalization .\",\n \"An absolute role of the PKC - dependent NF - kappaB activation for induction of P14780 in hepatocellular carcinoma cells . Matrix metalloproteinases ( MMPs ) play an important role in inflammation , tumor cell invasion , and metastasis . We found that phorbol - 12 - myristate - 13 - acetate ( PMA ) - stimulated invasion of the hepatocellular carcinoma ( HCC ) SNU - 387 and SNU - 398 cells and that PMA induced the secretion of P14780 in the cells , but did not induce the secretion of P08253 . The PMA - induced P14780 secretion was abolished by treatment of a pan - protein kinase C ( PKC ) inhibitor , GF109203X , and an inhibitor of NF - kappaB activation , sulfasalazine , and partly inhibited by treatment of inhibitors of P29323 pathway , PD98059 and U0126 . In addition , the PMA - stimulated activation of the P14780 promoter was completely inhibited by a mutation of the NF - kappaB site within the P14780 promoter , but not completely by mutations of two AP - 1 sites . Moreover , the P14780 induction by P14210 and P01375 was also completely inhibited by GF109203X and sulfasalazine , but not by PD98059 and U0126 . These data demonstrate that the PKC - dependent NF - kappaB activation is absolute for P14780 induction and that the PKC - dependent P29323 activation devotes to increase the expression level of P14780 , in HCC cells .\",\n \"DB04540 metabolite , 5 - cholesten - 3β - 25 - diol - 3 - sulfate , promotes hepatic proliferation in mice . Oxysterols are well known as physiological ligands of liver X receptors ( LXRs ) . Oxysterols , 25 - hydroxycholesterol ( 25HC ) and 27 - hydroxycholesterol as endogenous ligands of LXRs , suppress cell proliferation via LXRs signaling pathway . Recent reports have shown that sulfated oxysterol , 5 - cholesten - 3β - 25 - diol - 3 - sulfate ( 25HC3S ) as LXRs antagonist , plays an opposite direction to oxysterols in lipid biosynthesis . The present report was to explore the effect and mechanism of 25HC3S on hepatic proliferation in vivo . Following administration , 25HC3S had a 48 h half life in the circulation and widely distributed in mouse tissues . Profiler ™ PCR array and RTqPCR analysis showed that either exogenous or endogenous 25HC3S generated by overexpression of oxysterol sulfotransferase ( SULT2B1b ) plus administration of 25HC significantly up - regulated the proliferation gene expression of Wt1 , Pcna , cMyc , cyclin A , FoxM1b , and CDC25b in a dose - dependent manner in liver while substantially down - regulating the expression of cell cycle arrest gene Chek2 and apoptotic gene Apaf1 . Either exogenous or endogenous administration of 25HC3S significantly induced hepatic DNA replication as measured by immunostaining of the P12004 labeling index and was associated with reduction in expression of LXR response genes , such as O95477 and SREBP - 1c . Synthetic LXR agonist T0901317 effectively blocked 25HC3S - induced hepatic proliferation . CONCLUSIONS : 25HC3S may be a potent regulator of hepatocyte proliferation and oxysterol sulfation may represent a novel regulatory pathway in liver proliferation via inactivating LXR signaling .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK35___","___MASK39___","___MASK3___","___MASK42___","___MASK4___","___MASK52___","___MASK60___","___MASK71___","___MASK8___"],"string":"[\n \"___MASK35___\",\n \"___MASK39___\",\n \"___MASK3___\",\n \"___MASK42___\",\n \"___MASK4___\",\n \"___MASK52___\",\n \"___MASK60___\",\n \"___MASK71___\",\n \"___MASK8___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK4___"},"id":{"kind":"string","value":"MH_train_93"}}},{"rowIdx":94,"cells":{"query":{"kind":"string","value":"interacts_with DB06441?"},"supports":{"kind":"list like","value":["Activation of Gi - coupled receptors releases a tonic state of inhibited platelet aggregation . Single - receptor pharmacology does not satisfactorily explain the physiology of the ADP - induced platelet aggregation response . It has been shown that , in addition to Gq - coupled receptor activation , one Gi - coupled receptor , either the ADP P2T or the alpha2 - adrenoceptor , is required for elicitation of aggregation . The underlying mechanism of this action , however , has not been elucidated . By systematically assaying the entire time course of the aggregation and its fade using two methods of aggregometry , we have investigated the role of graded activation of these two Gi - coupled receptors . We demonstrate that constant activation of either of two Gq - coupled receptors , the ADP P47900 or the 5 - Q13049 , and incremental activation of either of the two Gi - coupled receptors , tightly regulates the aggregation response in vitro , through the apparent release of a tonic inhibition of platelet aggregation . This tightly regulated release of inhibition , which appears analogous to the phenomena of disinhibition observed in the central nervous system , may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions .","Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK10___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","[ Recent advances on the studies of the platelet ' s inhibition and aggregation . State of the art of new Q9H244 antagonists ] . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : i ) it is a pro - drug that needs to be metabolized to its active metabolite ; ii ) it has a delayed onset and offset of action ; iii ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG ( Coronary Artery Bypass Grafting ) related bleeding complications . Two direct and reversible Q9H244 antagonists , cangrelor and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but was , like prasugrel , was associated with higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery was necessary in ticagrelor - treated patients compared to clopidogrel - treated patients to limit the severity of post - surgical bleeding .","New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . DB08816 is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .","( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .","( Pro ) renin promotes fibrosis gene expression in P29320 cells through a Nox4 - dependent mechanism . The ( pro ) renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this study , we report that human embryonic kidney cells ( P29320 ) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin - converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence ( lucigenin ) and electron spin resonance spectroscopy ( hydroxylamine radical transition ) . Also , both renin and prorenin increased Nox4 expression while Nox2 , p47 ( phox ) , and p67 ( phox ) remained unchanged . In an investigation of the effects of renin and prorenin on fibrosis genes , it appeared that both proteins stimulated transforming growth factor - β ( TGF - β ) , fibronectin , and plasminogen activator inhibitor type 1 ( P05121 ) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells . When the cells were transfected with a siRNA targeting the PRR , Nox4 expression was efficiently prevented as well as the increase in superoxide production , TGF - β , fibronectin , and P05121 . Finally , we demonstrated that transfection of the cells with a Nox4 - specific small interfering ( si ) RNA also prevented fibrosis gene expression following treatment with renin or prorenin . The results demonstrate that renin and prorenin , through their specific membrane receptor and independently of angiotensin II , promote fibrosis gene expression via a Nox4 - dependent mechanism .","Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . DB08816 is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .","Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .","Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .","DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .","DB06441 : a review on pharmacology and clinical trial development . Dual antiplatelet therapy with aspirin and an oral ADP Q9H244 receptor antagonist is the standard - of - care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention ( P05154 ) . However , currently available ADP Q9H244 receptor antagonists have several limitations , such as interindividual response variability , drug - drug interactions , slow onset / offset and only oral availability . DB06441 is a reversible , potent , intravenous , competitive inhibitor of the ADP Q9H244 receptor that rapidly achieves near complete and predictable platelet inhibition . Along with reversible binding to the receptor cangrelor also has a very short half - life ( 3 - 5 min ) , which in turn results in a rapid offset of action . These properties make cangrelor a promising drug for clinical use in patients undergoing P05154 or patients waiting for major surgery but still require antiplatelet protection . This manuscript provides an update of the current status of knowledge on cangrelor , focusing on its pharmacologic properties and clinical trial development , including the BRIDGE and CHAMPION - PHOENIX trials .","B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .","State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .","Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK88___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK88___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .","Genetics in gestational diabetes mellitus : association with incidence , severity , pregnancy outcome and response to treatment . Constant advances in gene mapping technology have allowed research to focus from rare monogenic disorders on common complex diseases involving multiple susceptibility genes - environment interactions . Gestational diabetes mellitus ( GDM ) is a heterogeneous pathogenic condition affecting 2 - 5 % of all pregnant women during pregnancy . GDM is considered to result when genetic predisposition is triggered by increased insulin resistance during pregnancy leading to what seems to be one of the primary characteristics of GDM , the pancreatic b - cell impairment . Genetic predisposition to GDM has been suggested given the occurrence of the disease within family members . Furthermore , GDM is reported to be often present in women with maturity onset diabetes of the young ( MODY ) gene mutations . In addition , candidate susceptibility gene variants have been suggested to increase the risk of GDM . These genes include glucokinase ( GCK ) , HLA antigens , insulin receptor ( P06213 ) , insulin - like growth factor - 2 ( P01344 ) , P41235 , insulin gene ( P01308 - VNTR ) , plasminogen activator inhibitor 1 ( P05121 ) , potassium inwardly rectifying channel subfamily J , member 11 ( Q14654 ) , hepatocyte nuclear factor - 4a ( P41235 ) . Identification of the possible underlying genetic factors of GDM would eventually enrich our knowledge on the pathophysiologic mechanism of the disease and contribute to the individualization of both prevention and treatment of complications for the mother and fetus . However , so far , little is known about the genetic basis of GDM and its potential clinical significance . This review focuses on possible gestational diabetes mellitus susceptibility genes and their association with the disease incidence and severity as well as the pregnancy outcome and the response to treatment .","DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK74___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .","Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .","DB06441 in percutaneous coronary intervention . DB06441 is a novel , intravenous Q9H244 receptor antagonist in development for use in percutaneous coronary intervention . Currently in Phase III testing , the reversible platelet inhibitor provides several inherent advantages over other Q9H244 receptor antagonists in this setting for the prevention of adverse cardiac events . Unlike the class of thienopyridines ( ticlopidine , clopidogrel and potentially soon to be available , prasugrel ) , cangrelor has nearly immediate onset after a bolus dose and a short half - life , and achieves maximal inhibition of ADP - mediated platelet function . DB06441 ' s distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism . These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention .","DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .","Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .","Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK72___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .","The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .","Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .","A critical appraisal of the functional evolution of Q9H244 antagonists as antiplatelet drugs . Q9H244 receptor mediated inhibition of platelet aggregation is one of the most explored and exploited pathways in antiplatelet drug therapy to prevent ischemic events in patients undergoing percutaneous coronary intervention ( P05154 ) for the treatment of the acute coronary syndrome ( ACS ) . DB00208 , DB00758 , Prasugrel , DB08816 , DB06441 and Elinogrel are the Q9H244 inhibitors that act as antiplatelet drugs . In this review , the features of these drugs and the factors reported to be responsible for drug resistance or drug ineffectiveness were described . The features like drug metabolism , reversible or irreversible binding of drugs to their target protein and the mode of administration were observed to evolve along with the antiplatelet drugs . These features also include the drug - drug interactions , the pharmacogenetics and pharmacodynamics of Q9H244 inhibitors . We attempted to critically analyze how the desirable features were met by the Q9H244 inhibitors in the course of time . This review provides an overview of the evolution of Q9H244 inhibitors and may guide the researchers to develop better antiplatelet drugs in the future .","Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .","Oxidized DB00171 ( oATP ) attenuates proinflammatory signaling via P2 receptor - independent mechanisms . Periodate - oxidized DB00171 ( oATP ) , which covalently modifies nucleotide - binding proteins , can significantly attenuate proinflammatory signaling . Although the Q99572 nucleotide receptor ( P2X7R ) is irreversibly antagonized by oATP , it is unclear whether anti - inflammatory actions of oATP are predominantly mediated via its actions on P2X7R . Here , we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X7R : human umbilical vein endothelial cells ( HUVEC ) , HEK293 cells , and 1321N1 astrocytes . oATP decreased by 40 - 70 % the secretion of interleukin ( IL ) - 8 stimulated by tumor necrosis factor - alpha ( P01375 ) in all three cell types , by IL - 1beta in HUVEC and 1321N1 cells , and by endotoxin in HUVEC . Attenuation of P01375 - stimulated P10145 secretion by oATP was similar in wild - type P29320 cells or P29320 cells stably expressing recombinant P2X7R . oATP also attenuated cytokine - stimulated expression of nuclear factor - kappaB - luciferase reporter genes expressed in P29320 or 1321N1 cells , but did not affect the rapid downregulation of IkappaB . oATP had no effect on uridine triphosphate - induced activation of native P41231 receptors in P29320 cells , but reduced the potency and efficacy of ADP as an agonist of native P47900 receptors . However , inhibition of P47900 receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on P01375 - stimulated P10145 secretion . Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes , oATP markedly inhibited ecto - ATPase activity in these cells , resulting in a significant accumulation of extracellular DB00171 . In summary , oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes .","Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK6___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK6___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .","Transitioning patients from cangrelor to clopidogrel : pharmacodynamic evidence of a competitive effect . BACKGROUND : DB06441 is a direct , parenteral , and reversible inhibitor of the platelet Q9H244 receptor currently undergoing Phase III testing . As many individuals treated acutely with cangrelor will often be treated long - term with a thienopyridine , it is important to determine the effects of concurrent cangrelor and clopidogrel administration . METHODS AND RESULTS : Ten healthy volunteers received a 600 mg oral loading dose of clopidogrel and then underwent serial platelet function monitoring for 6 h . Two weeks later these same individuals received a 600 mg clopidogrel loading dose simultaneously with a cangrelor IV bolus ( 30 microg / kg ) and a 2 - hour infusion ( 4 microg / kg / min ) . A separate group of ten volunteers received a 600 mg clopidogrel loading dose after administration of a cangrelor bolus and a 1 - hour infusion . The effects on ADP - induced platelet activation and aggregation were evaluated by flow cytometry , whole - blood electrical impedance , and light - transmittance aggregometry . DB06441 and clopidogrel alone achieved the expected levels of platelet inhibition . However , the sustained platelet inhibition anticipated for clopidogrel treatment did not occur when cangrelor was initiated simultaneously . No such effect was found when clopidogrel was started upon completion of the cangrelor infusion . CONCLUSION : To achieve sustained platelet Q9H244 inhibition in patients treated with cangrelor , clopidogrel administration should be started when the cangrelor infusion is terminated .","A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .","Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .","Spin trapping agent phenyl - N - tert - butylnitrone prevents diisopropylphosphorofluoridate - induced excitotoxicity in skeletal muscle of the rat . Indirect evidence suggests that reactive oxygen species ( ROS ) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate ( ___MASK91___ ) . Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase ( P22303 ) activity was reduced to less than 30 % of control . The spin trapping agent phenyl - N - tert - butylnitrone ( PBN ) was used in vivo to directly assess the formation of ROS during ___MASK91___ ( 1 . 75 mg / kg , s . c . ) induced muscle hyperactivity . Pretreatment with PBN ( 300 mg / kg , i . p . ) , the concentration necessary for in vivo spin trapping , prevented muscle hyperactivity as well as necrosis and attenuated the ___MASK91___ induced P22303 inhibition otherwise seen in ___MASK91___ only treated rats . PBN had no effect when given after fasciculations were established . Muscle extracts from PBN and ___MASK91___ treated rats subjected to electron spin resonance ( P03372 ) spectroscopy tested negative for ROS . While the role of PBN as an antioxidant is well established , its prophylactic effect against excitotoxity induced by an P22303 inhibitor are due to its protection of P22303 , an unexpected non - antioxidant action .","The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK98___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","DB06441 for treatment of coronary thrombosis . OBJECTIVE : To review and assess available literature on the chemistry , pharmacology , pharmacodynamics , pharmacokinetics , clinical studies , adverse events , drug interactions , special populations , and dosing and administration for cangrelor , a product in late stage Phase II clinical trials . DATA SOURCES : A literature search of MEDLINE ( 1966 - March 2006 ) , International Pharmaceutical Abstracts ( 1970 - February 2006 ) , and Cochrane database ( first quarter 2006 ) was conducted using key terms of cangrelor , AR - C69931MX , and Q9H244 receptor antagonist . Bibliographies of relevant articles were reviewed for additional references . The Medicines Company Web site was reviewed , and a company representative was contacted . STUDY SELECTION AND DATA EXTRACTION : Available English - language literature , including abstracts , preclinical studies , clinical trials , and review articles , was reviewed . DATA SYNTHESIS : DB06441 is a Q9H244 antagonist under development for treatment of acute coronary syndrome . DB06441 has been studied as an intravenous infusion in doses of 2 or 4 microg / kg / min . It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity . Published Phase II trials have demonstrated safety and inhibition of platelet aggregation . CONCLUSIONS : DB06441 is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events . Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel . Phase III trials will provide more definitive information on clinical efficacy and safety . Until then , the role of cangrelor is uncertain .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK32___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","Nerve agent exposure elicits site - specific changes in protein phosphorylation in mouse brain . Organophosphorus ( OP ) compounds cause toxic symptoms , including convulsions , coma , and death , as the result of irreversible inhibition of acetylcholinesterase ( P22303 ) . The development of effective treatments to block these effects and attenuate long - term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions . We employed a candidate method ( called CNSProfile ) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound , diisopropyl fluorophosphate ( ___MASK91___ ) . Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of ___MASK91___ - treated mice ; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho - specific antibodies . ___MASK91___ exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL / 6 and FVB mice . ___MASK91___ treatment significantly altered phosphorylation at regulatory residues on glutamate receptors , including Serine897 ( S897 ) of the Q9UHB4 DB01221 receptor . Q9UHB4 phosphorylation was bi - directionally regulated after ___MASK91___ in striatum versus hippocampus . Q9UHB4 phosphorylation was reduced in striatum , but elevated in hippocampus , compared with controls . Q9UD71 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate , Threonine75 ( T75 ) . Phencynonate hydrochloride , a muscarinic cholinergic antagonist , prevented seizure - like behaviors and the observed changes in phosphorylation induced by ___MASK91___ . The data reveal region - specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure - like behavior and which are reversed by the muscarinic receptor blockade . This approach identifies specific targets for nerve agents , including substrates for Cdk5 kinase , which may be the basis for new anti - convulsant therapies .","Endothelial Q09428 - 8 acts in an P29323 - independent pathway during atrioventricular cushion development . Q09428 - 8 , a conserved leucine - rich repeats protein , was first identified as a positive regulator of Ras pathway in Caenorhabditis elegans . Biochemical studies indicated that Q09428 - 8 interacts with Ras and Raf , leading to the elevated P29323 activity . However , the physiological role of Q09428 - 8 during mammalian development remains unclear . Here we found that germline deletion of Q09428 - 8 in mice resulted in early embryonic lethality . Inactivated Q09428 - 8 specifically in mouse endothelial cells ( ECs ) revealed that Q09428 - 8 is essential for embryonic heart development . Q09428 - 8 deficiency in ECs resulted in late embryonic lethality , and the mutant mice displayed multiple cardiac defects . The reduced endothelial - mesenchymal transformation ( EMT ) and the reduced mesenchyme proliferation phase were observed in the atrioventricular canal ( AVC ) within the mutant hearts , leading to the formation of hypoplastic endocardial cushions . However , P29323 activation did not appear to be affected in mutant ECs , suggesting that Q09428 - 8 may act in an P29323 - independent pathway to regulate AVC development .","Autocrine regulation of γ - irradiation - induced DNA damage response via extracellular nucleotides - mediated activation of Q15077 and Q9H244 receptors . A key component of the response to DNA damage caused by ionizing radiation is DNA repair . Release of extracellular nucleotides , such as DB00171 , from cells plays a role in signaling via P2 receptors . We show here that release of DB00171 , followed by activation of P2Y receptors , is involved in the response to γ - irradiation - induced DNA damage . Formation of phosphorylated histone variant P16104 ( γ P16104 ) foci , which are induced in nuclei by DNA damage and contribute to accumulation of DNA - repair factors , was increased at 1 - 3h after γ - ray irradiation ( 2 . 0Gy ) of human lung cancer A549 cells . Focus formation was suppressed by pre - treatment with the ecto - nucleotidase apyrase . Pre - treatment with ecto - nucleotidase inhibitor ARL67156 or post - treatment with DB00171 or UTP facilitated induction of γ P16104 , indicating that extracellular nucleotides play a role in induction of γ P16104 foci . Next , we examined the effect of P2 receptor inhibitors on activation of ataxia telangiectasia mutated ( Q13315 ; a protein kinase ) and accumulation of Q12888 ( a DNA repair factor ) , both of which are important for DNA repair , at DNA damage sites . Q15077 receptor antagonist MRS2578 , Q9H244 receptor antagonist clopidogrel , and Q99572 receptor antagonists A438079 and oxATP significantly inhibited these processes . Release of DB00171 was detected within 2 . 5min after irradiation , but was blocked by A438079 . Activation of Q13315 and accumulation of Q12888 were decreased in Q15077 or Q9H244 receptor - knockdown cells . We conclude that autocrine / paracrine signaling through Q99572 - dependent DB00171 release and activation of Q15077 and Q9H244 receptors serves to amplify the cellular response to DNA damage caused by γ - irradiation .","Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK88___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .","Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .","P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 is in clinical development as an orally active agent .","Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK98___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .","Q9H244 inhibitors : pharmacologic mechanism and clinical relevance . Platelets play a critical role in the pathogenesis of atherothrombotic processes and inhibition of platelet aggregation by antiplatelet therapy is essential and really important in the acute coronary syndromes or in the setting of percutaneous coronary intervention . The first family of adenosine diphosphate Q9H244 receptors inhibiting drug is represented by thienopyridines and among these ticlopidine was the first approved by Food and Drug Administration ; actually its use is discouraged because of its potential side effects ( neutropenia , anemia , gastrointestinal distress and thrombotic thrombocytopenic purpura ) . The second generation of thienopyridines is represented by clopidogrel that has replaced ticlopidine in the clinical practice ; clopidogrel has the largest clinical experience . Prasugrel represents the third generation . It inhibits platelet aggregation by irreversibly blocking the adenosine diphosphate Q9H244 receptor . DB08816 , DB06441 and Enilogrel represent the last generation of thienopyridines . This review is focused on the effects of adenosine diphosphate Q9H244 inhibitors .","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK99___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","New frontiers in the management of acute coronary syndromes : cangrelor and elinogrel . The activation and aggregation of platelets at sites of vascular injury or near to implanted stent are pivotal in the development of thrombotic events during and after an acute coronary syndrome ( ACS ) or a percutaneous coronary intervention ( P05154 ) . For that reason , an exclusively oral dual antiplatelet treatment regimen with platelet Q9H244 receptor antagonists in addition to the cyclooxygenase inhibitor aspirin has become the cornerstone of treatment in that contest . However , every trial underlines the same problem : if maximizing antiplatelet therapy significantly attenuates ischemic events in patients with coronary artery disease , on the other side it may also increase bleeding phenomena . These limitations have prompted a search for novel antiplatelet agents with a more favorable risk - benefit ratio . Moreover , an early onset of action is desirable during P05154 and an early offset after bleeding events . Two novel antiplatelet agents , DB06441 and Elinogrel , are available in intravenous form ( Elinogrel also in oral form ) and expand this context . Recent trials have tested them against DB00758 regarding efficacy and safety outcomes . This review aimed at providing an overview on intravenous emerging compounds and recent patents in the setting of ACS and P05154 .","Alteration of synaptic activity - regulating genes underlying functional improvement by long - term exposure to an enriched environment in the adult brain . BACKGROUND : Housing animals in an enriched environment ( EE ) enhances behavioral function . However , the mechanism underlying this EE - mediated functional improvement and the resultant changes in gene expression have yet to be elucidated . OBJECTIVES : We attempted to investigate the underlying mechanisms associated with long - term exposure to an EE by evaluating gene expression patterns . METHODS : We housed 6 - week - old CD - 1 ( ICR ) mice in standard cages or an EE comprising a running wheel , novel objects , and social interaction for 2 months . Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test , and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis ( GSEA ) . RESULTS : In behavioral assessment , an EE significantly enhanced rotarod performance and short - term working memory . Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE . GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated , whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated . In particular , both microarray and GSEA demonstrated that EE exposure increased opioid signaling , acetylcholine release cycle , and postsynaptic neurotransmitter receptors but decreased Na + / Cl - - dependent neurotransmitter transporters , including dopamine transporter Slc6a3 in the brain . Western blotting confirmed that Q01959 , Q9UD71 ( Q9UD71 ) , and Q9H244 were largely altered in a region - specific manner . CONCLUSION : An EE enhanced motor and cognitive function through the alteration of synaptic activity - regulating genes , improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters .","Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .","Efficacy and safety of cangrelor for patients with coronary artery disease : a meta - analysis of four randomized trials . BACKGROUND : The efficacy and safety of new intravenous Q9H244 inhibitor ( cangrelor ) for patients with coronary artery disease ( CAD ) remain unclear . METHODS AND RESULTS : Trials were identified in PubMed , Web of Science , Embase , and Cochrane Database searches . We included four randomized , placebo - controlled reports in the meta - analysis . The database consisted of 36 , 081 patients on cangrelor compared with clopidogrel or placebo . Major adverse cardiac events ( MACE ) were defined as the primary efficacy endpoint and major or severe bleeding at 48 hours was defined as the primary safety endpoint . DB06441 significantly decreased risk of MACE ( OR : 0 . 87 , P = 0 . 002 ) and stent thrombosis ( OR : 0 . 53 , P < 0 . 001 ) . However , at the same time , an increase in TIMI minor bleeding ( OR : 1 . 49 , P = 0 . 04 ) and in GUSTO moderate bleeding ( OR : 1 . 43 , P = 0 . 04 ) were observed by cangrelor . CONCLUSIONS : Intravenous administration of cangrelor is benefit to reduce risk of MACE and stent thrombosis in patients with CAD excepting for increased minor bleeding events .","The ' allosteric modulator ' P35240 - 202676 disrupts G protein - coupled receptor function via sulphydryl - sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 - 202676 ( N -( 2 , 3 - diphenyl - 1 , 2 , 4 - thiadiazol - 5 -( 2H )- ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein - coupled receptors ( GPCRs ) . It was postulated that P35240 - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi - family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 - 202676 ( 10 (- 7 )- 10 (- 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS - based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor - mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol - based mechanism of action . 4 . In routine incubations containing DTT , P35240 - 202676 had no effect on receptor - driven G protein activity , as assessed for adenosine A1 , alpha2 - adrenergic , cannabinoid P21554 , lysophosphatidic acid Q92633 , muscarinic M2 / M4 , purinergic Q9H244 or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .","Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .","DB06441 AstraZeneca . AstraZeneca is developing the P2T ( P2YADP ) purinoceptor antagonist and platelet aggregation inhibitor , cangrelor , for the potential treatment of unstable angina and as an ultrafast - acting intravenous antithrombotic agent . It is in phase IIb clinical trials [ 315723 ] . NDA and MAA applications are planned for after 2003 [ 275466 ] , [ 314472 ] . It superseded the earlier compound , ARL - 67085 , which also reached phase II trials [ 328760 ] . In ex vivo samples of angina patients ' blood , cangrelor inhibits platelet / monocyte conjugate development , which indicate the drug has some degree of disease - modifying activity [ 377418 ] . AstraZeneca is also developing derivatives of cangrelor . Removal of the triphosphate side chain , modification of the ribose to a carbocycle and the purine to a triazolopyridine resulted in a potent ( IC50 = 4 nM ) orally - active P2T / Q9H244 receptor antagonist . A lead compound was scheduled to enter trials as an antithrombotic agent in July 2000 [ 377666 ] . In March 1999 , Lehman Brothers predicted a 30 % probability that the drug would reach world markets and would be launched in 2002 [ 336599 ] .","Electrocardiographic safety of cangrelor , a new intravenous antiplatelet agent : a randomized , double - blind , placebo - and moxifloxacin - controlled thorough QT study . DB06441 is an intravenous Q9H244 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes . To determine the electrophysiologic safety of parenteral cangrelor , cardiac repolarization effects were measured in 67 healthy volunteers ( aged 18 - 45 years ) in a randomized crossover design , including 4 treatment sequences of therapeutic cangrelor , supratherapeutic cangrelor , placebo , and moxifloxacin ( positive control ) . Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1 . For both cangrelor and moxifloxacin , time - matched , placebo - adjusted change in QT from baseline was evaluated using an individual ( QTcI ) heart rate correction . After cangrelor dosing , change in QTcI was < 5 ms at all times points and all corresponding upper 2 - sided 90 % confidence intervals ( CIs ) were < 10 ms . Although moxifloxacin failed to show a lower CI > 5 ms , expected time trends and lower CI > 4 . 0 ms demonstrate assay sensitivity . QTcI was not affected by plasma concentrations of cangrelor metabolites , and cangrelor had no other adverse effects on electrocardiographic parameters . Clinically , cangrelor exposure was well tolerated . Thus , this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers ( clinicaltrials . gov ; identifier NCT00699504 ) .","___MASK6___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK6___ , in the USA in 2003 .","DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .","Pharmacodynamic effects during the transition between cangrelor and ticagrelor . OBJECTIVES : This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor . BACKGROUND : DB06441 is an intravenous antagonist of Q9H244 and its use will require transition to and from oral agents . METHODS : Patients ( n = 12 ) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited . On study day 1 , they received a bolus plus 2 - h infusion of cangrelor plus a 180 - mg dose of ticagrelor at either 0 . 5 h ( n = 6 ) or 1 . 25 h ( n = 6 ) . Pharmacodynamic effects ( light transmission platelet aggregation in response to 20 and 5 μmol / l adenosine diphosphate , VerifyNow , Q9H244 assay ( Accumetrics , San Diego , California ) , vasodilator - stimulated phosphoprotein index , and flow cytometry ) were assessed during and after the cangrelor infusion . Patients took 90 mg of ticagrelor twice daily for either 6 ( n = 6 ) or 7 ( n = 6 ) doses . On study day 5 , pharmacodynamic effects were assessed before and during a bolus plus 2 - h infusion of cangrelor . RESULTS : During cangrelor infusion , extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent . After cangrelor was stopped , the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity . CONCLUSIONS : DB08816 given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor . The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor , this oral Q9H244 antagonist can be administered before , during , or after treatment with cangrelor .","DB06441 for patients undergoing percutaneous coronary intervention : evidence from a meta - analysis of randomized trials . DB06441 is a new parenteral adenosine diphosphate Q9H244 receptor inhibitor with rapid , profound and reversible inhibition of platelet activity . The aim of this meta - analysis was to evaluate efficacy and safety of this new agent in patients undergoing percutaneous coronary intervention ( P05154 ) . We searched PubMed , Cochrane Library , EMBASE , Web of Science and CINAHL databases from the inception through April 2013 . Randomized controlled trials ( RCTs ) comparing cangrelor with control ( clopidogrel / placebo ) were selected . We used the random - effects models to calculate the risk ratio . The primary efficacy outcome was risk of myocardial infarction , and the primary safety outcome was TIMI major bleeding at 48 h . Three RCTs included a total of 25 , 107 participants . Effects of DB06441 were not different against comparators for myocardial infarction ( MI ) ( Risk ratio [ RR ] 0 . 94 , 95 % confidence interval [ CI ] 0 . 78 - 1 . 13 ) and all - cause mortality ( RR 0 . 72 , 95 % CI 0 . 36 - 1 . 43 ) . However , cangrelor significantly reduced the risk of ischemia - driven revascularization ( RR 0 . 72 , 95 % CI 0 . 52 - 0 . 98 ) , stent thrombosis ( RR 0 . 60 , 95 % CI 0 . 44 - 0 . 82 ) and Q wave MI ( RR 0 . 53 , 95 % CI 0 . 30 - 0 . 92 ) without causing extra major bleeding ( Thrombolysis in Myocardial infarction criteria ) and severe or life - threatening bleeding ( Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries criteria ) . Separate analysis against only clopidogrel also showed similar findings except Q wave MI outcome . Use of cangrelor during P05154 might reduce the risk of ischemia - driven revascularization and stent thrombosis , without causing extra major bleeding .","DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .","Differential role for phospholipase D1 and phospholipase D2 in 12 - O - tetradecanoyl - 13 - phorbol acetate - stimulated MAPK activation , Cox - 2 and P10145 expression . Phospholipase D ( PLD ) is expressed in many tissues and stimulated by growth factors and cytokines . However , the role of PLD in signal transduction is still not well - understood . Human embryonic kidney ( P29320 - 293 ) cells exhibit low levels of both Q13393 and O14939 mRNA , however , only Q13393 protein was detected by Western blot . When either isoform of PLD was stably expressed in P29320 - 293 cells , we observed an increased PLD activity in a cell - free system and a 12 - O - tetradecanoyl - 13 - phorbol acetate ( TPA ) - stimulated increase in PLD activity in intact cells . This system was then used to elucidate the effects of PLD activity on TPA - stimulated signaling pathways . Two such pathways , the mitogen - activated protein kinases ( MAPK ) , extracellular regulated protein kinase ( P29323 ) and p38 are activated by growth factors and cellular stress , respectively . We found that TPA stimulated P29323 phosphorylation regardless of the expression status of PLD . In contrast to P29323 kinase , P29320 - 293 cells were unable to induce p38 phosphorylation by TPA stimulation . When P29320 - 293 cells expressed either Q13393 or O14939 , we observed elevated p38 phosphorylation in response to TPA stimulation . The P29323 and p38 MAPKs can also stimulate the expression of both cyclooxygenase - 2 ( Cox - 2 ) and interleukin - 8 ( P10145 ) . We used this system to differentiate the effect of Q13393 or O14939 activity on the expression of Cox - 2 and P10145 . Increased Cox - 2 and P10145 expression was found only in P29320 - 293 cells expressing Q13393 . These data identify a novel role for the Q13393 isoform in the induction of gene expression and provide new insight into the differential role of Q13393 and O14939 in cells .","Potentiation of platelet aggregation by heparin in human whole blood is attenuated by Q9H244 and P47900 antagonists but not aspirin . INTRODUCTION : DB01109 ( UFH ) potentiates platelet aggregation induced by some agonists . Q9H244 and P47900 receptors play a major role in amplifying platelet aggregation . We assessed the ability of cangrelor , a selective Q9H244 antagonist , A2P5P , a selective P47900 antagonist , and aspirin to block the potentiating effects of heparin . MATERIALS AND METHODS : Whole blood from healthy human volunteers was anticoagulated with either hirudin or UFH 10 IU / ml . Some tubes anticoagulated with hirudin also contained UFH 1 or 10 IU / ml . The low - molecular - weight heparin dalteparin was also assessed . Platelet aggregation was performed using whole blood single - platelet counting . Dense granule release was assessed using 14C - 5HT - labelled platelets . RESULTS : UFH and , to a lesser extent , dalteparin potentiated platelet aggregation induced by ADP , Q15004 , 5HT , U46619 , epinephrine and TRAP in a concentration - dependent manner but inhibited aggregation induced by collagen . DB06441 effectively opposed the potentiating effects of heparins on sustained aggregation induced by ADP , Q15004 , 5HT , U46619 and TRAP but had less effect on epinephrine - induced aggregation , whereas A2P5P was more effective at blocking both the initial phase of ADP - induced aggregation and the aggregation response to epinephrine , reflecting the differences in G protein coupling between the agonist receptors . DB00945 had no effect on potentiation by heparin . Heparins did not increase ADP - or TRAP - induced 14C - 5HT release . CONCLUSIONS : Heparins potentiate platelet responses to ADP and numerous other agonists . This potentiation is attenuated by cangrelor and A2P5P , and is not mediated by increased dense granule release . ADP receptor antagonists but not aspirin may have potential therapeutic benefits in counteracting the pro - thrombotic effects of heparins .","Emerging Q9H244 receptor antagonists : role in coronary artery disease . The use of oral antiplatelet therapy in reducing vascular events has been extensively studied . Currently available oral antiplatelet agents include aspirin and the thienopyridine Q9H244 receptor antagonists . These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention ( P05154 ) . Resistance to either or both of these agents is a major concern , as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes . As a result , there is a need for newer , more effective antiplatelet agents to address the limitations of currently available therapy . Prasugrel , a third generation thienopyridine , has been approved by both the FDA and European Commission . Two additional Q9H244 agents , ticagrelor and cangrelor are in advanced stages of development . The possible advantages of prasugrel over clopidogrel include a faster onset of action , reduced inter - patient variability and more potent platelet inhibition . DB08816 is an oral reversible Q9H244 antagonist with greater platelet inhibition compared with clopidogrel . DB06441 is being developed as an intravenous Q9H244 antagonist with a very fast onset and offset , which may offer advantages particularly in the setting of coronary intervention . These emerging antiplatelet agents may offer advantages such as faster onset of action , greater potency and reversibility of platelet inhibition . This article summarizes the available clinical data on the upcoming Q9H244 antiplatelet agents in the treatment of coronary artery disease ."],"string":"[\n \"Activation of Gi - coupled receptors releases a tonic state of inhibited platelet aggregation . Single - receptor pharmacology does not satisfactorily explain the physiology of the ADP - induced platelet aggregation response . It has been shown that , in addition to Gq - coupled receptor activation , one Gi - coupled receptor , either the ADP P2T or the alpha2 - adrenoceptor , is required for elicitation of aggregation . The underlying mechanism of this action , however , has not been elucidated . By systematically assaying the entire time course of the aggregation and its fade using two methods of aggregometry , we have investigated the role of graded activation of these two Gi - coupled receptors . We demonstrate that constant activation of either of two Gq - coupled receptors , the ADP P47900 or the 5 - Q13049 , and incremental activation of either of the two Gi - coupled receptors , tightly regulates the aggregation response in vitro , through the apparent release of a tonic inhibition of platelet aggregation . This tightly regulated release of inhibition , which appears analogous to the phenomena of disinhibition observed in the central nervous system , may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions .\",\n \"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK10___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"[ Recent advances on the studies of the platelet ' s inhibition and aggregation . State of the art of new Q9H244 antagonists ] . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : i ) it is a pro - drug that needs to be metabolized to its active metabolite ; ii ) it has a delayed onset and offset of action ; iii ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG ( Coronary Artery Bypass Grafting ) related bleeding complications . Two direct and reversible Q9H244 antagonists , cangrelor and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but was , like prasugrel , was associated with higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery was necessary in ticagrelor - treated patients compared to clopidogrel - treated patients to limit the severity of post - surgical bleeding .\",\n \"New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . DB08816 is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .\",\n \"( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .\",\n \"( Pro ) renin promotes fibrosis gene expression in P29320 cells through a Nox4 - dependent mechanism . The ( pro ) renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this study , we report that human embryonic kidney cells ( P29320 ) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin - converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence ( lucigenin ) and electron spin resonance spectroscopy ( hydroxylamine radical transition ) . Also , both renin and prorenin increased Nox4 expression while Nox2 , p47 ( phox ) , and p67 ( phox ) remained unchanged . In an investigation of the effects of renin and prorenin on fibrosis genes , it appeared that both proteins stimulated transforming growth factor - β ( TGF - β ) , fibronectin , and plasminogen activator inhibitor type 1 ( P05121 ) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells . When the cells were transfected with a siRNA targeting the PRR , Nox4 expression was efficiently prevented as well as the increase in superoxide production , TGF - β , fibronectin , and P05121 . Finally , we demonstrated that transfection of the cells with a Nox4 - specific small interfering ( si ) RNA also prevented fibrosis gene expression following treatment with renin or prorenin . The results demonstrate that renin and prorenin , through their specific membrane receptor and independently of angiotensin II , promote fibrosis gene expression via a Nox4 - dependent mechanism .\",\n \"Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . DB08816 is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .\",\n \"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .\",\n \"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .\",\n \"DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .\",\n \"DB06441 : a review on pharmacology and clinical trial development . Dual antiplatelet therapy with aspirin and an oral ADP Q9H244 receptor antagonist is the standard - of - care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention ( P05154 ) . However , currently available ADP Q9H244 receptor antagonists have several limitations , such as interindividual response variability , drug - drug interactions , slow onset / offset and only oral availability . DB06441 is a reversible , potent , intravenous , competitive inhibitor of the ADP Q9H244 receptor that rapidly achieves near complete and predictable platelet inhibition . Along with reversible binding to the receptor cangrelor also has a very short half - life ( 3 - 5 min ) , which in turn results in a rapid offset of action . These properties make cangrelor a promising drug for clinical use in patients undergoing P05154 or patients waiting for major surgery but still require antiplatelet protection . This manuscript provides an update of the current status of knowledge on cangrelor , focusing on its pharmacologic properties and clinical trial development , including the BRIDGE and CHAMPION - PHOENIX trials .\",\n \"B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .\",\n \"State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .\",\n \"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK88___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK88___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .\",\n \"Genetics in gestational diabetes mellitus : association with incidence , severity , pregnancy outcome and response to treatment . Constant advances in gene mapping technology have allowed research to focus from rare monogenic disorders on common complex diseases involving multiple susceptibility genes - environment interactions . Gestational diabetes mellitus ( GDM ) is a heterogeneous pathogenic condition affecting 2 - 5 % of all pregnant women during pregnancy . GDM is considered to result when genetic predisposition is triggered by increased insulin resistance during pregnancy leading to what seems to be one of the primary characteristics of GDM , the pancreatic b - cell impairment . Genetic predisposition to GDM has been suggested given the occurrence of the disease within family members . Furthermore , GDM is reported to be often present in women with maturity onset diabetes of the young ( MODY ) gene mutations . In addition , candidate susceptibility gene variants have been suggested to increase the risk of GDM . These genes include glucokinase ( GCK ) , HLA antigens , insulin receptor ( P06213 ) , insulin - like growth factor - 2 ( P01344 ) , P41235 , insulin gene ( P01308 - VNTR ) , plasminogen activator inhibitor 1 ( P05121 ) , potassium inwardly rectifying channel subfamily J , member 11 ( Q14654 ) , hepatocyte nuclear factor - 4a ( P41235 ) . Identification of the possible underlying genetic factors of GDM would eventually enrich our knowledge on the pathophysiologic mechanism of the disease and contribute to the individualization of both prevention and treatment of complications for the mother and fetus . However , so far , little is known about the genetic basis of GDM and its potential clinical significance . This review focuses on possible gestational diabetes mellitus susceptibility genes and their association with the disease incidence and severity as well as the pregnancy outcome and the response to treatment .\",\n \"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK74___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .\",\n \"Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .\",\n \"DB06441 in percutaneous coronary intervention . DB06441 is a novel , intravenous Q9H244 receptor antagonist in development for use in percutaneous coronary intervention . Currently in Phase III testing , the reversible platelet inhibitor provides several inherent advantages over other Q9H244 receptor antagonists in this setting for the prevention of adverse cardiac events . Unlike the class of thienopyridines ( ticlopidine , clopidogrel and potentially soon to be available , prasugrel ) , cangrelor has nearly immediate onset after a bolus dose and a short half - life , and achieves maximal inhibition of ADP - mediated platelet function . DB06441 ' s distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism . These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention .\",\n \"DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .\",\n \"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .\",\n \"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK72___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .\",\n \"The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .\",\n \"Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .\",\n \"A critical appraisal of the functional evolution of Q9H244 antagonists as antiplatelet drugs . Q9H244 receptor mediated inhibition of platelet aggregation is one of the most explored and exploited pathways in antiplatelet drug therapy to prevent ischemic events in patients undergoing percutaneous coronary intervention ( P05154 ) for the treatment of the acute coronary syndrome ( ACS ) . DB00208 , DB00758 , Prasugrel , DB08816 , DB06441 and Elinogrel are the Q9H244 inhibitors that act as antiplatelet drugs . In this review , the features of these drugs and the factors reported to be responsible for drug resistance or drug ineffectiveness were described . The features like drug metabolism , reversible or irreversible binding of drugs to their target protein and the mode of administration were observed to evolve along with the antiplatelet drugs . These features also include the drug - drug interactions , the pharmacogenetics and pharmacodynamics of Q9H244 inhibitors . We attempted to critically analyze how the desirable features were met by the Q9H244 inhibitors in the course of time . This review provides an overview of the evolution of Q9H244 inhibitors and may guide the researchers to develop better antiplatelet drugs in the future .\",\n \"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .\",\n \"Oxidized DB00171 ( oATP ) attenuates proinflammatory signaling via P2 receptor - independent mechanisms . Periodate - oxidized DB00171 ( oATP ) , which covalently modifies nucleotide - binding proteins , can significantly attenuate proinflammatory signaling . Although the Q99572 nucleotide receptor ( P2X7R ) is irreversibly antagonized by oATP , it is unclear whether anti - inflammatory actions of oATP are predominantly mediated via its actions on P2X7R . Here , we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X7R : human umbilical vein endothelial cells ( HUVEC ) , HEK293 cells , and 1321N1 astrocytes . oATP decreased by 40 - 70 % the secretion of interleukin ( IL ) - 8 stimulated by tumor necrosis factor - alpha ( P01375 ) in all three cell types , by IL - 1beta in HUVEC and 1321N1 cells , and by endotoxin in HUVEC . Attenuation of P01375 - stimulated P10145 secretion by oATP was similar in wild - type P29320 cells or P29320 cells stably expressing recombinant P2X7R . oATP also attenuated cytokine - stimulated expression of nuclear factor - kappaB - luciferase reporter genes expressed in P29320 or 1321N1 cells , but did not affect the rapid downregulation of IkappaB . oATP had no effect on uridine triphosphate - induced activation of native P41231 receptors in P29320 cells , but reduced the potency and efficacy of ADP as an agonist of native P47900 receptors . However , inhibition of P47900 receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on P01375 - stimulated P10145 secretion . Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes , oATP markedly inhibited ecto - ATPase activity in these cells , resulting in a significant accumulation of extracellular DB00171 . In summary , oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes .\",\n \"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK6___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK6___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .\",\n \"Transitioning patients from cangrelor to clopidogrel : pharmacodynamic evidence of a competitive effect . BACKGROUND : DB06441 is a direct , parenteral , and reversible inhibitor of the platelet Q9H244 receptor currently undergoing Phase III testing . As many individuals treated acutely with cangrelor will often be treated long - term with a thienopyridine , it is important to determine the effects of concurrent cangrelor and clopidogrel administration . METHODS AND RESULTS : Ten healthy volunteers received a 600 mg oral loading dose of clopidogrel and then underwent serial platelet function monitoring for 6 h . Two weeks later these same individuals received a 600 mg clopidogrel loading dose simultaneously with a cangrelor IV bolus ( 30 microg / kg ) and a 2 - hour infusion ( 4 microg / kg / min ) . A separate group of ten volunteers received a 600 mg clopidogrel loading dose after administration of a cangrelor bolus and a 1 - hour infusion . The effects on ADP - induced platelet activation and aggregation were evaluated by flow cytometry , whole - blood electrical impedance , and light - transmittance aggregometry . DB06441 and clopidogrel alone achieved the expected levels of platelet inhibition . However , the sustained platelet inhibition anticipated for clopidogrel treatment did not occur when cangrelor was initiated simultaneously . No such effect was found when clopidogrel was started upon completion of the cangrelor infusion . CONCLUSION : To achieve sustained platelet Q9H244 inhibition in patients treated with cangrelor , clopidogrel administration should be started when the cangrelor infusion is terminated .\",\n \"A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .\",\n \"Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .\",\n \"Spin trapping agent phenyl - N - tert - butylnitrone prevents diisopropylphosphorofluoridate - induced excitotoxicity in skeletal muscle of the rat . Indirect evidence suggests that reactive oxygen species ( ROS ) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate ( ___MASK91___ ) . Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase ( P22303 ) activity was reduced to less than 30 % of control . The spin trapping agent phenyl - N - tert - butylnitrone ( PBN ) was used in vivo to directly assess the formation of ROS during ___MASK91___ ( 1 . 75 mg / kg , s . c . ) induced muscle hyperactivity . Pretreatment with PBN ( 300 mg / kg , i . p . ) , the concentration necessary for in vivo spin trapping , prevented muscle hyperactivity as well as necrosis and attenuated the ___MASK91___ induced P22303 inhibition otherwise seen in ___MASK91___ only treated rats . PBN had no effect when given after fasciculations were established . Muscle extracts from PBN and ___MASK91___ treated rats subjected to electron spin resonance ( P03372 ) spectroscopy tested negative for ROS . While the role of PBN as an antioxidant is well established , its prophylactic effect against excitotoxity induced by an P22303 inhibitor are due to its protection of P22303 , an unexpected non - antioxidant action .\",\n \"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK98___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"DB06441 for treatment of coronary thrombosis . OBJECTIVE : To review and assess available literature on the chemistry , pharmacology , pharmacodynamics , pharmacokinetics , clinical studies , adverse events , drug interactions , special populations , and dosing and administration for cangrelor , a product in late stage Phase II clinical trials . DATA SOURCES : A literature search of MEDLINE ( 1966 - March 2006 ) , International Pharmaceutical Abstracts ( 1970 - February 2006 ) , and Cochrane database ( first quarter 2006 ) was conducted using key terms of cangrelor , AR - C69931MX , and Q9H244 receptor antagonist . Bibliographies of relevant articles were reviewed for additional references . The Medicines Company Web site was reviewed , and a company representative was contacted . STUDY SELECTION AND DATA EXTRACTION : Available English - language literature , including abstracts , preclinical studies , clinical trials , and review articles , was reviewed . DATA SYNTHESIS : DB06441 is a Q9H244 antagonist under development for treatment of acute coronary syndrome . DB06441 has been studied as an intravenous infusion in doses of 2 or 4 microg / kg / min . It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity . Published Phase II trials have demonstrated safety and inhibition of platelet aggregation . CONCLUSIONS : DB06441 is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events . Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel . Phase III trials will provide more definitive information on clinical efficacy and safety . Until then , the role of cangrelor is uncertain .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK32___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"Nerve agent exposure elicits site - specific changes in protein phosphorylation in mouse brain . Organophosphorus ( OP ) compounds cause toxic symptoms , including convulsions , coma , and death , as the result of irreversible inhibition of acetylcholinesterase ( P22303 ) . The development of effective treatments to block these effects and attenuate long - term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions . We employed a candidate method ( called CNSProfile ) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound , diisopropyl fluorophosphate ( ___MASK91___ ) . Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of ___MASK91___ - treated mice ; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho - specific antibodies . ___MASK91___ exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL / 6 and FVB mice . ___MASK91___ treatment significantly altered phosphorylation at regulatory residues on glutamate receptors , including Serine897 ( S897 ) of the Q9UHB4 DB01221 receptor . Q9UHB4 phosphorylation was bi - directionally regulated after ___MASK91___ in striatum versus hippocampus . Q9UHB4 phosphorylation was reduced in striatum , but elevated in hippocampus , compared with controls . Q9UD71 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate , Threonine75 ( T75 ) . Phencynonate hydrochloride , a muscarinic cholinergic antagonist , prevented seizure - like behaviors and the observed changes in phosphorylation induced by ___MASK91___ . The data reveal region - specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure - like behavior and which are reversed by the muscarinic receptor blockade . This approach identifies specific targets for nerve agents , including substrates for Cdk5 kinase , which may be the basis for new anti - convulsant therapies .\",\n \"Endothelial Q09428 - 8 acts in an P29323 - independent pathway during atrioventricular cushion development . Q09428 - 8 , a conserved leucine - rich repeats protein , was first identified as a positive regulator of Ras pathway in Caenorhabditis elegans . Biochemical studies indicated that Q09428 - 8 interacts with Ras and Raf , leading to the elevated P29323 activity . However , the physiological role of Q09428 - 8 during mammalian development remains unclear . Here we found that germline deletion of Q09428 - 8 in mice resulted in early embryonic lethality . Inactivated Q09428 - 8 specifically in mouse endothelial cells ( ECs ) revealed that Q09428 - 8 is essential for embryonic heart development . Q09428 - 8 deficiency in ECs resulted in late embryonic lethality , and the mutant mice displayed multiple cardiac defects . The reduced endothelial - mesenchymal transformation ( EMT ) and the reduced mesenchyme proliferation phase were observed in the atrioventricular canal ( AVC ) within the mutant hearts , leading to the formation of hypoplastic endocardial cushions . However , P29323 activation did not appear to be affected in mutant ECs , suggesting that Q09428 - 8 may act in an P29323 - independent pathway to regulate AVC development .\",\n \"Autocrine regulation of γ - irradiation - induced DNA damage response via extracellular nucleotides - mediated activation of Q15077 and Q9H244 receptors . A key component of the response to DNA damage caused by ionizing radiation is DNA repair . Release of extracellular nucleotides , such as DB00171 , from cells plays a role in signaling via P2 receptors . We show here that release of DB00171 , followed by activation of P2Y receptors , is involved in the response to γ - irradiation - induced DNA damage . Formation of phosphorylated histone variant P16104 ( γ P16104 ) foci , which are induced in nuclei by DNA damage and contribute to accumulation of DNA - repair factors , was increased at 1 - 3h after γ - ray irradiation ( 2 . 0Gy ) of human lung cancer A549 cells . Focus formation was suppressed by pre - treatment with the ecto - nucleotidase apyrase . Pre - treatment with ecto - nucleotidase inhibitor ARL67156 or post - treatment with DB00171 or UTP facilitated induction of γ P16104 , indicating that extracellular nucleotides play a role in induction of γ P16104 foci . Next , we examined the effect of P2 receptor inhibitors on activation of ataxia telangiectasia mutated ( Q13315 ; a protein kinase ) and accumulation of Q12888 ( a DNA repair factor ) , both of which are important for DNA repair , at DNA damage sites . Q15077 receptor antagonist MRS2578 , Q9H244 receptor antagonist clopidogrel , and Q99572 receptor antagonists A438079 and oxATP significantly inhibited these processes . Release of DB00171 was detected within 2 . 5min after irradiation , but was blocked by A438079 . Activation of Q13315 and accumulation of Q12888 were decreased in Q15077 or Q9H244 receptor - knockdown cells . We conclude that autocrine / paracrine signaling through Q99572 - dependent DB00171 release and activation of Q15077 and Q9H244 receptors serves to amplify the cellular response to DNA damage caused by γ - irradiation .\",\n \"Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK88___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .\",\n \"Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .\",\n \"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 is in clinical development as an orally active agent .\",\n \"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK98___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .\",\n \"Q9H244 inhibitors : pharmacologic mechanism and clinical relevance . Platelets play a critical role in the pathogenesis of atherothrombotic processes and inhibition of platelet aggregation by antiplatelet therapy is essential and really important in the acute coronary syndromes or in the setting of percutaneous coronary intervention . The first family of adenosine diphosphate Q9H244 receptors inhibiting drug is represented by thienopyridines and among these ticlopidine was the first approved by Food and Drug Administration ; actually its use is discouraged because of its potential side effects ( neutropenia , anemia , gastrointestinal distress and thrombotic thrombocytopenic purpura ) . The second generation of thienopyridines is represented by clopidogrel that has replaced ticlopidine in the clinical practice ; clopidogrel has the largest clinical experience . Prasugrel represents the third generation . It inhibits platelet aggregation by irreversibly blocking the adenosine diphosphate Q9H244 receptor . DB08816 , DB06441 and Enilogrel represent the last generation of thienopyridines . This review is focused on the effects of adenosine diphosphate Q9H244 inhibitors .\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK99___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"New frontiers in the management of acute coronary syndromes : cangrelor and elinogrel . The activation and aggregation of platelets at sites of vascular injury or near to implanted stent are pivotal in the development of thrombotic events during and after an acute coronary syndrome ( ACS ) or a percutaneous coronary intervention ( P05154 ) . For that reason , an exclusively oral dual antiplatelet treatment regimen with platelet Q9H244 receptor antagonists in addition to the cyclooxygenase inhibitor aspirin has become the cornerstone of treatment in that contest . However , every trial underlines the same problem : if maximizing antiplatelet therapy significantly attenuates ischemic events in patients with coronary artery disease , on the other side it may also increase bleeding phenomena . These limitations have prompted a search for novel antiplatelet agents with a more favorable risk - benefit ratio . Moreover , an early onset of action is desirable during P05154 and an early offset after bleeding events . Two novel antiplatelet agents , DB06441 and Elinogrel , are available in intravenous form ( Elinogrel also in oral form ) and expand this context . Recent trials have tested them against DB00758 regarding efficacy and safety outcomes . This review aimed at providing an overview on intravenous emerging compounds and recent patents in the setting of ACS and P05154 .\",\n \"Alteration of synaptic activity - regulating genes underlying functional improvement by long - term exposure to an enriched environment in the adult brain . BACKGROUND : Housing animals in an enriched environment ( EE ) enhances behavioral function . However , the mechanism underlying this EE - mediated functional improvement and the resultant changes in gene expression have yet to be elucidated . OBJECTIVES : We attempted to investigate the underlying mechanisms associated with long - term exposure to an EE by evaluating gene expression patterns . METHODS : We housed 6 - week - old CD - 1 ( ICR ) mice in standard cages or an EE comprising a running wheel , novel objects , and social interaction for 2 months . Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test , and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis ( GSEA ) . RESULTS : In behavioral assessment , an EE significantly enhanced rotarod performance and short - term working memory . Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE . GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated , whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated . In particular , both microarray and GSEA demonstrated that EE exposure increased opioid signaling , acetylcholine release cycle , and postsynaptic neurotransmitter receptors but decreased Na + / Cl - - dependent neurotransmitter transporters , including dopamine transporter Slc6a3 in the brain . Western blotting confirmed that Q01959 , Q9UD71 ( Q9UD71 ) , and Q9H244 were largely altered in a region - specific manner . CONCLUSION : An EE enhanced motor and cognitive function through the alteration of synaptic activity - regulating genes , improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters .\",\n \"Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .\",\n \"Efficacy and safety of cangrelor for patients with coronary artery disease : a meta - analysis of four randomized trials . BACKGROUND : The efficacy and safety of new intravenous Q9H244 inhibitor ( cangrelor ) for patients with coronary artery disease ( CAD ) remain unclear . METHODS AND RESULTS : Trials were identified in PubMed , Web of Science , Embase , and Cochrane Database searches . We included four randomized , placebo - controlled reports in the meta - analysis . The database consisted of 36 , 081 patients on cangrelor compared with clopidogrel or placebo . Major adverse cardiac events ( MACE ) were defined as the primary efficacy endpoint and major or severe bleeding at 48 hours was defined as the primary safety endpoint . DB06441 significantly decreased risk of MACE ( OR : 0 . 87 , P = 0 . 002 ) and stent thrombosis ( OR : 0 . 53 , P < 0 . 001 ) . However , at the same time , an increase in TIMI minor bleeding ( OR : 1 . 49 , P = 0 . 04 ) and in GUSTO moderate bleeding ( OR : 1 . 43 , P = 0 . 04 ) were observed by cangrelor . CONCLUSIONS : Intravenous administration of cangrelor is benefit to reduce risk of MACE and stent thrombosis in patients with CAD excepting for increased minor bleeding events .\",\n \"The ' allosteric modulator ' P35240 - 202676 disrupts G protein - coupled receptor function via sulphydryl - sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 - 202676 ( N -( 2 , 3 - diphenyl - 1 , 2 , 4 - thiadiazol - 5 -( 2H )- ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein - coupled receptors ( GPCRs ) . It was postulated that P35240 - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi - family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 - 202676 ( 10 (- 7 )- 10 (- 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS - based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor - mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol - based mechanism of action . 4 . In routine incubations containing DTT , P35240 - 202676 had no effect on receptor - driven G protein activity , as assessed for adenosine A1 , alpha2 - adrenergic , cannabinoid P21554 , lysophosphatidic acid Q92633 , muscarinic M2 / M4 , purinergic Q9H244 or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .\",\n \"Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .\",\n \"DB06441 AstraZeneca . AstraZeneca is developing the P2T ( P2YADP ) purinoceptor antagonist and platelet aggregation inhibitor , cangrelor , for the potential treatment of unstable angina and as an ultrafast - acting intravenous antithrombotic agent . It is in phase IIb clinical trials [ 315723 ] . NDA and MAA applications are planned for after 2003 [ 275466 ] , [ 314472 ] . It superseded the earlier compound , ARL - 67085 , which also reached phase II trials [ 328760 ] . In ex vivo samples of angina patients ' blood , cangrelor inhibits platelet / monocyte conjugate development , which indicate the drug has some degree of disease - modifying activity [ 377418 ] . AstraZeneca is also developing derivatives of cangrelor . Removal of the triphosphate side chain , modification of the ribose to a carbocycle and the purine to a triazolopyridine resulted in a potent ( IC50 = 4 nM ) orally - active P2T / Q9H244 receptor antagonist . A lead compound was scheduled to enter trials as an antithrombotic agent in July 2000 [ 377666 ] . In March 1999 , Lehman Brothers predicted a 30 % probability that the drug would reach world markets and would be launched in 2002 [ 336599 ] .\",\n \"Electrocardiographic safety of cangrelor , a new intravenous antiplatelet agent : a randomized , double - blind , placebo - and moxifloxacin - controlled thorough QT study . DB06441 is an intravenous Q9H244 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes . To determine the electrophysiologic safety of parenteral cangrelor , cardiac repolarization effects were measured in 67 healthy volunteers ( aged 18 - 45 years ) in a randomized crossover design , including 4 treatment sequences of therapeutic cangrelor , supratherapeutic cangrelor , placebo , and moxifloxacin ( positive control ) . Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1 . For both cangrelor and moxifloxacin , time - matched , placebo - adjusted change in QT from baseline was evaluated using an individual ( QTcI ) heart rate correction . After cangrelor dosing , change in QTcI was < 5 ms at all times points and all corresponding upper 2 - sided 90 % confidence intervals ( CIs ) were < 10 ms . Although moxifloxacin failed to show a lower CI > 5 ms , expected time trends and lower CI > 4 . 0 ms demonstrate assay sensitivity . QTcI was not affected by plasma concentrations of cangrelor metabolites , and cangrelor had no other adverse effects on electrocardiographic parameters . Clinically , cangrelor exposure was well tolerated . Thus , this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers ( clinicaltrials . gov ; identifier NCT00699504 ) .\",\n \"___MASK6___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK6___ , in the USA in 2003 .\",\n \"DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .\",\n \"Pharmacodynamic effects during the transition between cangrelor and ticagrelor . OBJECTIVES : This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor . BACKGROUND : DB06441 is an intravenous antagonist of Q9H244 and its use will require transition to and from oral agents . METHODS : Patients ( n = 12 ) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited . On study day 1 , they received a bolus plus 2 - h infusion of cangrelor plus a 180 - mg dose of ticagrelor at either 0 . 5 h ( n = 6 ) or 1 . 25 h ( n = 6 ) . Pharmacodynamic effects ( light transmission platelet aggregation in response to 20 and 5 μmol / l adenosine diphosphate , VerifyNow , Q9H244 assay ( Accumetrics , San Diego , California ) , vasodilator - stimulated phosphoprotein index , and flow cytometry ) were assessed during and after the cangrelor infusion . Patients took 90 mg of ticagrelor twice daily for either 6 ( n = 6 ) or 7 ( n = 6 ) doses . On study day 5 , pharmacodynamic effects were assessed before and during a bolus plus 2 - h infusion of cangrelor . RESULTS : During cangrelor infusion , extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent . After cangrelor was stopped , the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity . CONCLUSIONS : DB08816 given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor . The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor , this oral Q9H244 antagonist can be administered before , during , or after treatment with cangrelor .\",\n \"DB06441 for patients undergoing percutaneous coronary intervention : evidence from a meta - analysis of randomized trials . DB06441 is a new parenteral adenosine diphosphate Q9H244 receptor inhibitor with rapid , profound and reversible inhibition of platelet activity . The aim of this meta - analysis was to evaluate efficacy and safety of this new agent in patients undergoing percutaneous coronary intervention ( P05154 ) . We searched PubMed , Cochrane Library , EMBASE , Web of Science and CINAHL databases from the inception through April 2013 . Randomized controlled trials ( RCTs ) comparing cangrelor with control ( clopidogrel / placebo ) were selected . We used the random - effects models to calculate the risk ratio . The primary efficacy outcome was risk of myocardial infarction , and the primary safety outcome was TIMI major bleeding at 48 h . Three RCTs included a total of 25 , 107 participants . Effects of DB06441 were not different against comparators for myocardial infarction ( MI ) ( Risk ratio [ RR ] 0 . 94 , 95 % confidence interval [ CI ] 0 . 78 - 1 . 13 ) and all - cause mortality ( RR 0 . 72 , 95 % CI 0 . 36 - 1 . 43 ) . However , cangrelor significantly reduced the risk of ischemia - driven revascularization ( RR 0 . 72 , 95 % CI 0 . 52 - 0 . 98 ) , stent thrombosis ( RR 0 . 60 , 95 % CI 0 . 44 - 0 . 82 ) and Q wave MI ( RR 0 . 53 , 95 % CI 0 . 30 - 0 . 92 ) without causing extra major bleeding ( Thrombolysis in Myocardial infarction criteria ) and severe or life - threatening bleeding ( Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries criteria ) . Separate analysis against only clopidogrel also showed similar findings except Q wave MI outcome . Use of cangrelor during P05154 might reduce the risk of ischemia - driven revascularization and stent thrombosis , without causing extra major bleeding .\",\n \"DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .\",\n \"Differential role for phospholipase D1 and phospholipase D2 in 12 - O - tetradecanoyl - 13 - phorbol acetate - stimulated MAPK activation , Cox - 2 and P10145 expression . Phospholipase D ( PLD ) is expressed in many tissues and stimulated by growth factors and cytokines . However , the role of PLD in signal transduction is still not well - understood . Human embryonic kidney ( P29320 - 293 ) cells exhibit low levels of both Q13393 and O14939 mRNA , however , only Q13393 protein was detected by Western blot . When either isoform of PLD was stably expressed in P29320 - 293 cells , we observed an increased PLD activity in a cell - free system and a 12 - O - tetradecanoyl - 13 - phorbol acetate ( TPA ) - stimulated increase in PLD activity in intact cells . This system was then used to elucidate the effects of PLD activity on TPA - stimulated signaling pathways . Two such pathways , the mitogen - activated protein kinases ( MAPK ) , extracellular regulated protein kinase ( P29323 ) and p38 are activated by growth factors and cellular stress , respectively . We found that TPA stimulated P29323 phosphorylation regardless of the expression status of PLD . In contrast to P29323 kinase , P29320 - 293 cells were unable to induce p38 phosphorylation by TPA stimulation . When P29320 - 293 cells expressed either Q13393 or O14939 , we observed elevated p38 phosphorylation in response to TPA stimulation . The P29323 and p38 MAPKs can also stimulate the expression of both cyclooxygenase - 2 ( Cox - 2 ) and interleukin - 8 ( P10145 ) . We used this system to differentiate the effect of Q13393 or O14939 activity on the expression of Cox - 2 and P10145 . Increased Cox - 2 and P10145 expression was found only in P29320 - 293 cells expressing Q13393 . These data identify a novel role for the Q13393 isoform in the induction of gene expression and provide new insight into the differential role of Q13393 and O14939 in cells .\",\n \"Potentiation of platelet aggregation by heparin in human whole blood is attenuated by Q9H244 and P47900 antagonists but not aspirin . INTRODUCTION : DB01109 ( UFH ) potentiates platelet aggregation induced by some agonists . Q9H244 and P47900 receptors play a major role in amplifying platelet aggregation . We assessed the ability of cangrelor , a selective Q9H244 antagonist , A2P5P , a selective P47900 antagonist , and aspirin to block the potentiating effects of heparin . MATERIALS AND METHODS : Whole blood from healthy human volunteers was anticoagulated with either hirudin or UFH 10 IU / ml . Some tubes anticoagulated with hirudin also contained UFH 1 or 10 IU / ml . The low - molecular - weight heparin dalteparin was also assessed . Platelet aggregation was performed using whole blood single - platelet counting . Dense granule release was assessed using 14C - 5HT - labelled platelets . RESULTS : UFH and , to a lesser extent , dalteparin potentiated platelet aggregation induced by ADP , Q15004 , 5HT , U46619 , epinephrine and TRAP in a concentration - dependent manner but inhibited aggregation induced by collagen . DB06441 effectively opposed the potentiating effects of heparins on sustained aggregation induced by ADP , Q15004 , 5HT , U46619 and TRAP but had less effect on epinephrine - induced aggregation , whereas A2P5P was more effective at blocking both the initial phase of ADP - induced aggregation and the aggregation response to epinephrine , reflecting the differences in G protein coupling between the agonist receptors . DB00945 had no effect on potentiation by heparin . Heparins did not increase ADP - or TRAP - induced 14C - 5HT release . CONCLUSIONS : Heparins potentiate platelet responses to ADP and numerous other agonists . This potentiation is attenuated by cangrelor and A2P5P , and is not mediated by increased dense granule release . ADP receptor antagonists but not aspirin may have potential therapeutic benefits in counteracting the pro - thrombotic effects of heparins .\",\n \"Emerging Q9H244 receptor antagonists : role in coronary artery disease . The use of oral antiplatelet therapy in reducing vascular events has been extensively studied . Currently available oral antiplatelet agents include aspirin and the thienopyridine Q9H244 receptor antagonists . These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention ( P05154 ) . Resistance to either or both of these agents is a major concern , as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes . As a result , there is a need for newer , more effective antiplatelet agents to address the limitations of currently available therapy . Prasugrel , a third generation thienopyridine , has been approved by both the FDA and European Commission . Two additional Q9H244 agents , ticagrelor and cangrelor are in advanced stages of development . The possible advantages of prasugrel over clopidogrel include a faster onset of action , reduced inter - patient variability and more potent platelet inhibition . DB08816 is an oral reversible Q9H244 antagonist with greater platelet inhibition compared with clopidogrel . DB06441 is being developed as an intravenous Q9H244 antagonist with a very fast onset and offset , which may offer advantages particularly in the setting of coronary intervention . These emerging antiplatelet agents may offer advantages such as faster onset of action , greater potency and reversibility of platelet inhibition . This article summarizes the available clinical data on the upcoming Q9H244 antiplatelet agents in the treatment of coronary artery disease .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK10___","___MASK32___","___MASK6___","___MASK72___","___MASK74___","___MASK88___","___MASK91___","___MASK98___","___MASK99___"],"string":"[\n \"___MASK10___\",\n \"___MASK32___\",\n \"___MASK6___\",\n \"___MASK72___\",\n \"___MASK74___\",\n \"___MASK88___\",\n \"___MASK91___\",\n \"___MASK98___\",\n \"___MASK99___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK10___"},"id":{"kind":"string","value":"MH_train_94"}}},{"rowIdx":95,"cells":{"query":{"kind":"string","value":"interacts_with DB00814?"},"supports":{"kind":"list like","value":["Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK75___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .","Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","Lipopolysaccharide directly stimulates cortisol secretion by human adrenal cells by a cyclooxygenase - dependent mechanism . Activation of the hypothalamo - pituitary - adrenal axis by bacterial lipopolysaccharide ( LPS ; endotoxin ) is well documented , although there has been uncertainty about whether LPS exerts a direct effect at the level of the adrenal . The present study found that LPS caused a dose - dependent stimulation of basal cortisol secretion by the human adrenocortical cell line , NCI - H295R , without affecting aldosterone . The expression of both O60603 ( O60603 ) and O00206 was demonstrated in these cells , and the specific ligands for O00206 ( purified LPS and lipid A ) and O60603 ( Pam3Cys ) were found to stimulate cortisol release , suggesting that these receptors may mediate the effects of LPS in adrenal cells , as has been shown in other cell types . LPS was also found to stimulate prostaglandin E2 release by these cells . The effects of LPS on cortisol were attenuated in the presence of both indomethacin and a specific P35354 inhibitor , but not a P23219 inhibitor , suggesting an obligatory role for P35354 activation and prostaglandin synthesis in the adrenal response to LPS .","Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .","The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .","Substance P stimulates cyclooxygenase - 2 and prostaglandin E2 expression through JAK - P35610 activation in human colonic epithelial cells . Substance P ( SP ) via its neurokinin - 1 receptor ( P25103 ) regulates several gastrointestinal functions . We previously reported that P25103 - mediated chloride secretion in the colon involves formation of PG . DB00917 biosynthesis is controlled by cyclooxygenase - 1 ( P23219 ) and P35354 , whose induction involves the STATs . In this study , we examined whether SP stimulates DB00917 production and P35354 expression in human nontransformed NCM460 colonocytes stably transfected with the human P25103 ( NCM460 - P25103 cells ) and identified the pathways involved in this response . SP exposure time and dose dependently induced an early ( 1 - min ) phosphorylation of O60674 , P40763 , and P42229 , followed by P35354 expression and DB00917 production by 2 h . Pharmacologic experiments showed that DB00917 production is dependent on newly synthesized P35354 , but P23219 protein . Inhibition of protein kinase Ctheta ( PKCtheta ) , but not PKCepsilon and PKCdelta , significantly reduced SP - induced P35354 up - regulation , and O60674 , P40763 , and P42229 phosphorylation . Pharmacological blockade of JAK inhibited SP - induced O60674 , P40763 , and P42229 phosphorylation ; P35354 expression ; and DB00917 production . Transient transfection with O60674 short - interferring RNA reduced P35354 promoter activity and O60674 phosphorylation , while RNA interference of P35610 isoforms showed that P42229 predominantly mediates SP - induced P35354 promoter activity . Site - directed mutation of P35610 binding sites on the P35354 promoter completely abolished P35354 promoter activity . Lastly , P35354 expression was elevated in colon of mice during experimental colitis , and this effect was normalized by administration of the P25103 antagonist CJ - 12 , 255 . Our results demonstrate that SP stimulates P35354 expression and DB00917 production in human colonocytes via activation of the O60674 - P40763 / 5 pathway .","n - 3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation . This study describes specific molecular mechanisms by which supplementation with n - 3 fatty acids ( i . e . those present in fish oils ) can modulate the expression and activity of degradative and inflammatory factors that cause cartilage destruction during arthritis . Our data show that incorporation of n - 3 fatty acids ( but not other polyunsaturated or saturated fatty acids ) into articular cartilage chondrocyte membranes results in a dose - dependent reduction in : ( i ) the expression and activity of proteoglycan degrading enzymes ( aggrecanases ) and ( ii ) the expression of inflammation - inducible cytokines ( interleukin ( IL ) - 1alpha and tumor necrosis factor ( P01375 ) - alpha ) and cyclooxygenase ( P35354 ) , but not the constitutively expressed cyclooxygenase P23219 . These findings provide evidence that n - 3 fatty acid supplementation can specifically affect regulatory mechanisms involved in chondrocyte gene transcription and thus further advocate a beneficial role for dietary fish oil supplementation in alleviation of several of the physiological parameters that cause and propogate arthritic disease .","Toll - like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll - like receptor 2 but not toll - like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll - like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 , O60603 , O15455 , O60602 , and Q9NR96 but not O00206 , Q9Y2C9 , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 was also confirmed by immunohistochemistry , in contrast to O00206 , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325 - 4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 , and interleukin - 8 . Transcription of these genes was followed by production of increased amounts of interleukin - 8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S . aureus was O60603 but not O00206 or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S . aureus and its cell wall components in various inflammatory disorders of the skin .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .","Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK7___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK7___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .","Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK60___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK60___ is also being investigated as part of triplet drug regimens . ___MASK60___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .","___MASK99___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .","Dietary conjugated linoleic acid enhances spleen P37231 mRNA expression in broiler chicks . 1 . The anti - inflammatory effects of dietary conjugated linoleic acid ( DB01211 ) on broilers repeatedly challenged with lipopolysaccharide ( LPS ) were investigated . 2 . Day - old broiler chicks were allotted into three treatment groups and fed on a control diet or diets containing 5 . 0 or 10 . 0 g DB01211 / kg diet . Six chicks from each treatment were injected with LPS ( 0 . 25 mg / kg body weight ) at 16 , 18 and 20 d of age . Splenic cyclooxygenase ( P36551 ) and inducible nitric oxide synthase ( P35228 ) activities , and prostaglandin E ( 2 ) ( PGE ( 2 ) ) and nitric oxide ( NO ) production as well as peroxisome proliferator - activated receptor - gamma ( P37231 ) mRNA expression were measured at 21 d of age . 3 . Chicks fed 10 . 0 g DB01211 / kg diet had lower P36551 activities and PGE ( 2 ) production that the controls . Dietary DB01211 ( 10 . 0 g / kg ) did not significantly diminish LPS - induced enhancement of COS - 2 activity , inhibited the subsequent increase in PGE ( 2 ) production . 4 . Regulation of P23219 activity contributed to the difference in PGE ( 2 ) production . 5 . DB01211 did not markedly attenuate the increase of P35228 activity and NO production caused by LPS challenge . Chicks fed DB01211 had lower P35228 activity and NO production than the controls . 6 . Dietary DB01211 activated splenic P37231 mRNA expression and increased P37231 mRNA expression after LPS injection . 7 . These results suggest that dietary DB01211 has immunomodulatory effects in the spleen by restricting basal PGE ( 2 ) and NO to lower levels and enhancing P37231 mRNA expression . During the inflammatory response , dietary DB01211 did not alleviate the increase in P35354 and P35228 activities but enhanced Q06203 - gamma mRNA expression .","P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK56___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK56___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .","aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK98___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK49___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase - 2 by suppressing nuclear factor - kappaB in Raw264 . 7 macrophage cells . Lactobacillus casei 3260 ( L . casei 3260 ) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide ( LPS ) - induced nuclear factor - kappaB ( NF - kappaB ) and cyclooxygenase - 2 ( P35354 ) expression in Raw264 . 7 macrophage cells . The treatment of Raw264 . 7 cells with L . casei 3260 significantly inhibited the secretion of tumor necrosis factor - alpha ( P01375 ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 . To clarify the molecular mechanism , the inhibitory effect of L . casei 3260 on the NF - kappaB signaling pathway was examined based on the luciferase reporter activity . Although the treatment of Raw264 . 7 cells with L . casei 3260 did not affect the transcriptional activity of NF - kappaB , it did inhibit NF - kappaB activation , as determined by the cytosolic p65 release and degradation of I - kappaBalpha . Therefore , these findings suggest that the suppression of P35354 through inhibiting the NF - kappaB activation by LPS may be associated with the antiinflammatory effects of L . casei 3260 on Raw264 . 7 cells .","Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .","Effects of P04626 amplicon size and genomic alterations of chromosomes 1 , 3 , and 10 on patient response to trastuzumab in metastatic breast cancer . ___MASK60___ is widely used for advanced breast cancer patients with P04626 - amplified tumors . Nevertheless , over half of these patients do not have an objective response . One reason may be altered expression of genes that might compensate for P04626 inhibition . We previously mapped the gene - rich region of chromosome 17 telomeric to P04626 , and reported considerable variability in the telomeric extent of the P04626 amplicon . Here we examined whether the variable amplicon size may be associated with patient response to trastuzumab . In addition , we looked at associations between response and several signaling pathway - related genes unrelated to the P04626 amplicon , including Q9Y243 , P60484 , P42336 , and P35354 . In 35 patients with P04626 - amplified metastatic breast cancer , with 40 % overall response to trastuzumab , fluorescence in situ hybridization identified the telomeric extent of the P04626 amplicon and the status of the several pathway - related genes . Objective response strongly correlated with the telomeric amplicon size , with 62 % of patients with shorter amplicons responding , compared with only 7 % of patients with longer amplicons ( P = 0 . 0015 ) . Abnormal copy number of P35354 was marginally associated with objective response ( P = 0 . 066 ) , while abnormal copy numbers of two reference loci , 1q25 and the chromosome 10 centromere , were significantly associated with response . Pairwise combinations of copy number status of these loci and P04626 amplicon size provided stronger associations and identified a group of patients without responders . These results suggest that patient selection for trastuzumab may be improved by considering P04626 amplicon size and genomic status of the 1q25 , P35354 , and centromere 10 loci .","___MASK43___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK43___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK43___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK43___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .","Bioassay - guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F . cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen ' s egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay - guided fractionation from F . cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S - 180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S - 180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi - target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK69___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Proteomic profiling of cancer stem cells derived from primary tumors of P04626 / Neu transgenic mice . Human epidermal growth factor receptor 2 ( P04626 ) overexpression leads to mammary tumorigenesis and its elevated levels lead to increase in cancer stem cells ( CSCs ) , invasion , and metastasis . CSCs are resistant to radiation / chemotherapeutic drugs and are believed to be responsible for recurrence / relapse of cancer . CSCs are isolated using flow cytometry based sorting , although reliable , this technology hinders the convenient identification of molecular targets of CSCs . Therefore to understand the molecular players of increased CSC through P04626 overexpression and to develop meaningful targets for combination therapy , we isolated and characterized breast CSCs through convenient tumorsphere culture . We identified the altered protein expression in CSC as compared to non - CSC using LC - MS / MS and confirmed those results using qRT - PCR and Western blotting . P02794 1 ( P02794 ) was identified as a candidate gene , which is involved in iron metabolism and iron depletion significantly decreased the self - renewal of CSCs . We further performed in silico analysis of altered genes in tumorsphere and identified a set of genes ( P06454 , P26447 , P06703 , TNXRD1 , P23219 , P35354 , P02533 , and P02794 ) , representing possible molecular targets , which in combination showed a promise to be used as prognostic markers for breast cancer .","[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .","Role of the JAK - P35610 pathway in protection against myocardial ischemia / reperfusion injury . The Janus kinase ( JAK ) - signal transducers and activators of transcription ( P35610 ) pathway is a stress - responsive mechanism that transduces signals from the cell surface to the nucleus , thereby modulating gene expression . Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway . Although the functional consequences of this event remain to be elucidated , there is emerging evidence that JAK - P35610 signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning . Specifically , brief episodes of myocardial ischemia / reperfusion activate P23458 and O60674 , followed by recruitment of P42224 and P40763 , resulting in transcriptional upregulation of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) , which then mediate the infarct - sparing effects of the late phase of preconditioning . The present review focuses on this novel cardioprotective role of JAK - P35610 signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia / reperfusion injury ."],"string":"[\n \"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK75___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .\",\n \"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"Lipopolysaccharide directly stimulates cortisol secretion by human adrenal cells by a cyclooxygenase - dependent mechanism . Activation of the hypothalamo - pituitary - adrenal axis by bacterial lipopolysaccharide ( LPS ; endotoxin ) is well documented , although there has been uncertainty about whether LPS exerts a direct effect at the level of the adrenal . The present study found that LPS caused a dose - dependent stimulation of basal cortisol secretion by the human adrenocortical cell line , NCI - H295R , without affecting aldosterone . The expression of both O60603 ( O60603 ) and O00206 was demonstrated in these cells , and the specific ligands for O00206 ( purified LPS and lipid A ) and O60603 ( Pam3Cys ) were found to stimulate cortisol release , suggesting that these receptors may mediate the effects of LPS in adrenal cells , as has been shown in other cell types . LPS was also found to stimulate prostaglandin E2 release by these cells . The effects of LPS on cortisol were attenuated in the presence of both indomethacin and a specific P35354 inhibitor , but not a P23219 inhibitor , suggesting an obligatory role for P35354 activation and prostaglandin synthesis in the adrenal response to LPS .\",\n \"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .\",\n \"The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .\",\n \"Substance P stimulates cyclooxygenase - 2 and prostaglandin E2 expression through JAK - P35610 activation in human colonic epithelial cells . Substance P ( SP ) via its neurokinin - 1 receptor ( P25103 ) regulates several gastrointestinal functions . We previously reported that P25103 - mediated chloride secretion in the colon involves formation of PG . DB00917 biosynthesis is controlled by cyclooxygenase - 1 ( P23219 ) and P35354 , whose induction involves the STATs . In this study , we examined whether SP stimulates DB00917 production and P35354 expression in human nontransformed NCM460 colonocytes stably transfected with the human P25103 ( NCM460 - P25103 cells ) and identified the pathways involved in this response . SP exposure time and dose dependently induced an early ( 1 - min ) phosphorylation of O60674 , P40763 , and P42229 , followed by P35354 expression and DB00917 production by 2 h . Pharmacologic experiments showed that DB00917 production is dependent on newly synthesized P35354 , but P23219 protein . Inhibition of protein kinase Ctheta ( PKCtheta ) , but not PKCepsilon and PKCdelta , significantly reduced SP - induced P35354 up - regulation , and O60674 , P40763 , and P42229 phosphorylation . Pharmacological blockade of JAK inhibited SP - induced O60674 , P40763 , and P42229 phosphorylation ; P35354 expression ; and DB00917 production . Transient transfection with O60674 short - interferring RNA reduced P35354 promoter activity and O60674 phosphorylation , while RNA interference of P35610 isoforms showed that P42229 predominantly mediates SP - induced P35354 promoter activity . Site - directed mutation of P35610 binding sites on the P35354 promoter completely abolished P35354 promoter activity . Lastly , P35354 expression was elevated in colon of mice during experimental colitis , and this effect was normalized by administration of the P25103 antagonist CJ - 12 , 255 . Our results demonstrate that SP stimulates P35354 expression and DB00917 production in human colonocytes via activation of the O60674 - P40763 / 5 pathway .\",\n \"n - 3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation . This study describes specific molecular mechanisms by which supplementation with n - 3 fatty acids ( i . e . those present in fish oils ) can modulate the expression and activity of degradative and inflammatory factors that cause cartilage destruction during arthritis . Our data show that incorporation of n - 3 fatty acids ( but not other polyunsaturated or saturated fatty acids ) into articular cartilage chondrocyte membranes results in a dose - dependent reduction in : ( i ) the expression and activity of proteoglycan degrading enzymes ( aggrecanases ) and ( ii ) the expression of inflammation - inducible cytokines ( interleukin ( IL ) - 1alpha and tumor necrosis factor ( P01375 ) - alpha ) and cyclooxygenase ( P35354 ) , but not the constitutively expressed cyclooxygenase P23219 . These findings provide evidence that n - 3 fatty acid supplementation can specifically affect regulatory mechanisms involved in chondrocyte gene transcription and thus further advocate a beneficial role for dietary fish oil supplementation in alleviation of several of the physiological parameters that cause and propogate arthritic disease .\",\n \"Toll - like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll - like receptor 2 but not toll - like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll - like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 , O60603 , O15455 , O60602 , and Q9NR96 but not O00206 , Q9Y2C9 , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 was also confirmed by immunohistochemistry , in contrast to O00206 , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325 - 4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 , and interleukin - 8 . Transcription of these genes was followed by production of increased amounts of interleukin - 8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S . aureus was O60603 but not O00206 or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S . aureus and its cell wall components in various inflammatory disorders of the skin .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .\",\n \"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK7___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK7___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .\",\n \"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK60___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK60___ is also being investigated as part of triplet drug regimens . ___MASK60___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .\",\n \"___MASK99___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .\",\n \"Dietary conjugated linoleic acid enhances spleen P37231 mRNA expression in broiler chicks . 1 . The anti - inflammatory effects of dietary conjugated linoleic acid ( DB01211 ) on broilers repeatedly challenged with lipopolysaccharide ( LPS ) were investigated . 2 . Day - old broiler chicks were allotted into three treatment groups and fed on a control diet or diets containing 5 . 0 or 10 . 0 g DB01211 / kg diet . Six chicks from each treatment were injected with LPS ( 0 . 25 mg / kg body weight ) at 16 , 18 and 20 d of age . Splenic cyclooxygenase ( P36551 ) and inducible nitric oxide synthase ( P35228 ) activities , and prostaglandin E ( 2 ) ( PGE ( 2 ) ) and nitric oxide ( NO ) production as well as peroxisome proliferator - activated receptor - gamma ( P37231 ) mRNA expression were measured at 21 d of age . 3 . Chicks fed 10 . 0 g DB01211 / kg diet had lower P36551 activities and PGE ( 2 ) production that the controls . Dietary DB01211 ( 10 . 0 g / kg ) did not significantly diminish LPS - induced enhancement of COS - 2 activity , inhibited the subsequent increase in PGE ( 2 ) production . 4 . Regulation of P23219 activity contributed to the difference in PGE ( 2 ) production . 5 . DB01211 did not markedly attenuate the increase of P35228 activity and NO production caused by LPS challenge . Chicks fed DB01211 had lower P35228 activity and NO production than the controls . 6 . Dietary DB01211 activated splenic P37231 mRNA expression and increased P37231 mRNA expression after LPS injection . 7 . These results suggest that dietary DB01211 has immunomodulatory effects in the spleen by restricting basal PGE ( 2 ) and NO to lower levels and enhancing P37231 mRNA expression . During the inflammatory response , dietary DB01211 did not alleviate the increase in P35354 and P35228 activities but enhanced Q06203 - gamma mRNA expression .\",\n \"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK56___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK56___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .\",\n \"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK98___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK49___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase - 2 by suppressing nuclear factor - kappaB in Raw264 . 7 macrophage cells . Lactobacillus casei 3260 ( L . casei 3260 ) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide ( LPS ) - induced nuclear factor - kappaB ( NF - kappaB ) and cyclooxygenase - 2 ( P35354 ) expression in Raw264 . 7 macrophage cells . The treatment of Raw264 . 7 cells with L . casei 3260 significantly inhibited the secretion of tumor necrosis factor - alpha ( P01375 ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 . To clarify the molecular mechanism , the inhibitory effect of L . casei 3260 on the NF - kappaB signaling pathway was examined based on the luciferase reporter activity . Although the treatment of Raw264 . 7 cells with L . casei 3260 did not affect the transcriptional activity of NF - kappaB , it did inhibit NF - kappaB activation , as determined by the cytosolic p65 release and degradation of I - kappaBalpha . Therefore , these findings suggest that the suppression of P35354 through inhibiting the NF - kappaB activation by LPS may be associated with the antiinflammatory effects of L . casei 3260 on Raw264 . 7 cells .\",\n \"Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .\",\n \"Effects of P04626 amplicon size and genomic alterations of chromosomes 1 , 3 , and 10 on patient response to trastuzumab in metastatic breast cancer . ___MASK60___ is widely used for advanced breast cancer patients with P04626 - amplified tumors . Nevertheless , over half of these patients do not have an objective response . One reason may be altered expression of genes that might compensate for P04626 inhibition . We previously mapped the gene - rich region of chromosome 17 telomeric to P04626 , and reported considerable variability in the telomeric extent of the P04626 amplicon . Here we examined whether the variable amplicon size may be associated with patient response to trastuzumab . In addition , we looked at associations between response and several signaling pathway - related genes unrelated to the P04626 amplicon , including Q9Y243 , P60484 , P42336 , and P35354 . In 35 patients with P04626 - amplified metastatic breast cancer , with 40 % overall response to trastuzumab , fluorescence in situ hybridization identified the telomeric extent of the P04626 amplicon and the status of the several pathway - related genes . Objective response strongly correlated with the telomeric amplicon size , with 62 % of patients with shorter amplicons responding , compared with only 7 % of patients with longer amplicons ( P = 0 . 0015 ) . Abnormal copy number of P35354 was marginally associated with objective response ( P = 0 . 066 ) , while abnormal copy numbers of two reference loci , 1q25 and the chromosome 10 centromere , were significantly associated with response . Pairwise combinations of copy number status of these loci and P04626 amplicon size provided stronger associations and identified a group of patients without responders . These results suggest that patient selection for trastuzumab may be improved by considering P04626 amplicon size and genomic status of the 1q25 , P35354 , and centromere 10 loci .\",\n \"___MASK43___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK43___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK43___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK43___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .\",\n \"Bioassay - guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F . cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen ' s egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay - guided fractionation from F . cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S - 180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S - 180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi - target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK69___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Proteomic profiling of cancer stem cells derived from primary tumors of P04626 / Neu transgenic mice . Human epidermal growth factor receptor 2 ( P04626 ) overexpression leads to mammary tumorigenesis and its elevated levels lead to increase in cancer stem cells ( CSCs ) , invasion , and metastasis . CSCs are resistant to radiation / chemotherapeutic drugs and are believed to be responsible for recurrence / relapse of cancer . CSCs are isolated using flow cytometry based sorting , although reliable , this technology hinders the convenient identification of molecular targets of CSCs . Therefore to understand the molecular players of increased CSC through P04626 overexpression and to develop meaningful targets for combination therapy , we isolated and characterized breast CSCs through convenient tumorsphere culture . We identified the altered protein expression in CSC as compared to non - CSC using LC - MS / MS and confirmed those results using qRT - PCR and Western blotting . P02794 1 ( P02794 ) was identified as a candidate gene , which is involved in iron metabolism and iron depletion significantly decreased the self - renewal of CSCs . We further performed in silico analysis of altered genes in tumorsphere and identified a set of genes ( P06454 , P26447 , P06703 , TNXRD1 , P23219 , P35354 , P02533 , and P02794 ) , representing possible molecular targets , which in combination showed a promise to be used as prognostic markers for breast cancer .\",\n \"[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .\",\n \"Role of the JAK - P35610 pathway in protection against myocardial ischemia / reperfusion injury . The Janus kinase ( JAK ) - signal transducers and activators of transcription ( P35610 ) pathway is a stress - responsive mechanism that transduces signals from the cell surface to the nucleus , thereby modulating gene expression . Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway . Although the functional consequences of this event remain to be elucidated , there is emerging evidence that JAK - P35610 signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning . Specifically , brief episodes of myocardial ischemia / reperfusion activate P23458 and O60674 , followed by recruitment of P42224 and P40763 , resulting in transcriptional upregulation of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) , which then mediate the infarct - sparing effects of the late phase of preconditioning . The present review focuses on this novel cardioprotective role of JAK - P35610 signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia / reperfusion injury .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK43___","___MASK49___","___MASK56___","___MASK60___","___MASK69___","___MASK75___","___MASK7___","___MASK98___","___MASK99___"],"string":"[\n \"___MASK43___\",\n \"___MASK49___\",\n \"___MASK56___\",\n \"___MASK60___\",\n \"___MASK69___\",\n \"___MASK75___\",\n \"___MASK7___\",\n \"___MASK98___\",\n \"___MASK99___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK56___"},"id":{"kind":"string","value":"MH_train_95"}}},{"rowIdx":96,"cells":{"query":{"kind":"string","value":"interacts_with DB00159?"},"supports":{"kind":"list like","value":["Curcumin : getting back to the roots . The use of turmeric , derived from the root of the plant Curcuma longa , for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years . The active component of turmeric responsible for this activity , curcumin , was identified almost two centuries ago . Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets , including transcription factors ( e . g . , NF - kappaB , AP - 1 , Egr - 1 , beta - catenin , and P37231 ) , enzymes ( e . g . , P35354 , 5 - P28300 , P35228 , and hemeoxygenase - 1 ) , cell cycle proteins ( e . g . , cyclin D1 and P38936 ) , cytokines ( e . g . , P01375 , IL - 1 , P05231 , and chemokines ) , receptors ( e . g . , P00533 and P04626 ) , and cell surface adhesion molecules . Because it can modulate the expression of these targets , curcumin is now being used to treat cancer , arthritis , diabetes , Crohn ' s disease , cardiovascular diseases , osteoporosis , Alzheimer ' s disease , psoriasis , and other pathologies . Interestingly , 6 - gingerol , a natural analog of curcumin derived from the root of ginger ( Zingiber officinalis ) , exhibits a biologic activity profile similar to that of curcumin . The efficacy , pharmacologic safety , and cost effectiveness of curcuminoids prompt us to \" get back to our roots . \"","Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK95___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .","P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .","Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK46___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK46___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .","Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .","[ Anticoagulants of primary haemostasis ] . Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases . Established antiplatelet agents use different pharmacological targets for this role . Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of P23219 . DB00208 or clopidogrel are ADP - Q9H244 receptor antagonists . Tirofiban , abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb / IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation . The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase - 5 . Efforts are made to improve antiplatelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk . Current clinical studies focus on a new generation of ADP receptor antagonists ( prasugrel , cangrelor and ticagrelor ) as successors of ticlopidine and clopidogrel after coronary arterial interventions . Developments using platelet targets different from established drugs are thrombin receptor antagonists ( like SCH530348 ) or thromboxane receptor antagonists ( like S18886 / terutroban ) in patients with cerebrovascular events . Results from recent experimental studies could lead to new strategies for antiplatelet therapy ( like inhibition of GP Ib receptor , GP VI receptor , platelet - leukocyte interaction , factor XII and others ) in the future .","A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK94___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .","DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .","Identification of the amino acid sequence motif of alpha - synuclein responsible for macrophage activation . P37840 ( Syn ) is implicated in the pathogenesis of PD and related neurodegenerative disorders . Recent studies have also shown that alpha - synuclein can activate microglia and enhance dopaminergic neurodegeneration . The mechanisms of microglia activation by alpha - synuclein , however , are not well understood . In this study , we found that not only alpha - synuclein but also beta - and gamma - synucleins activated macrophages ( RAW 264 . 7 ) in vitro . Macrophages treated with synuclein proteins secreted P01375 in a dose - dependent manner . Synuclein family proteins also increased mRNA transcription of P35354 and P35228 . Two alpha - synuclein deletion mutants , SynDeltaNAC and Syn61 - 140 , activated macrophages , while deletion mutants Syn1 - 60 and Syn96 - 140 did not significantly activate them . Finally , we demonstrated that macrophage activation by alpha - synuclein was accompanied by phosphorylation of P29323 . These results suggest that synuclein family proteins can activate macrophages , and that macrophage activation needs both the N - terminal and C - terminal domains of alpha - synuclein , but not the central Q9C000 region .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK14___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .","Q13547 contributes to cell cycle and apoptosis . Histone deacetylases ( HDACs ) are generally thought to play important roles in human disease . However , little information is available concerning the specific functions of individual HDACs . We previously reported on transgenic mice that expressed human Q13547 and experienced steatosis and nuclear pleomorphism in their hepatic tissues . To find out if the over - expression of Q13547 contributes to the expression of genes related to the cell cycle , apoptosis , and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice , the expression profiles of the related genes in liver tissues were determined by reverse transcription - polymerase chain reaction ( RT - PCR ) and Western blot analysis . The activated human Q13547 significantly induced the expression levels of mRNA for p53 , P37231 and Bak and reduced the P38936 expression level compared with the levels in control littermates . However , the protein levels of p53 and P37231 were significantly decreased . In conclusion , our results indicate that Q13547 can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over - express Q13547 .","Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .","Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK5___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK58___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )","Discrete roles for peroxisome proliferator - activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators . P37231 ( PPARgamma ) plays a major role in adipogenesis . PPARgamma binds to DNA as a heterodimer with retinoid X receptor ( RXR ) , and PPARgamma - RXR can be activated by ligands specific for either receptor ; the presence of both ligands can result in a cooperative effect on the transactivation of target genes . How these ligands mediate transactivation , however , remains unclear . PPARgamma is known to interact with both the P52701 / Q15788 family of coactivators and the distinct , multisubunit coactivator complex called DRIP . A single DRIP subunit , Q15648 ( Q15648 , PBP ) , binds directly to PPARgamma . Here we report that PPARgamma and RXR selectively interacted with Q15648 and P52701 proteins in a ligand - dependent manner . At physiological concentrations , RXR - specific ligands only induced P52701 binding to RXR , and PPARgamma - specific ligands exclusively recruited Q15648 but not P52701 coactivators to PPARgamma . This selectivity was not observed in interaction assays off DNA , implying that the specificity of coactivator binding in response to ligand is strongly influenced by the allosteric effects of DNA - bound heterodimers . These coactivator - selective effects were also observed in transient - transfection assays in the presence of overexpressed P52701 or DRIP coactivators . The results suggest that the cooperative effects of PPARgamma - and RXR - specific ligands may occur at the level of selective coactivator recruitment .","DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .","Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .","Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl - containing histone deacetylase ( HDAC ) inhibitors 1 - 4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 ) and class II ( maize HD1 - A and human P56524 ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl - H3 and low acetyl - α - tubulin levels . Exceptions are compounds 3 f - i , 3 m - o , and 4 k , which showed higher tubulin acetylation than ___MASK23___ . In U937 cells , cell - cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1 - 4 . Five hydroxamates ( compounds 1 h - l ) effected a two - to greater than threefold greater percent apoptosis than ___MASK23___ , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest - scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .","Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .","Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK18___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .","Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .","Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK15___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .","Functional changes in rheumatoid fibroblast - like synovial cells through activation of peroxisome proliferator - activated receptor gamma - mediated signalling pathway . P37231 ( PPARgamma ) is a ligand dependent transcriptional factor known to be a regulator of adipogenesis . Recent studies have also shown that stimulation of PPARgamma inhibits the transcriptional activities of other nuclear factors and down - regulates proinflammatory cytokine synthesis in T cells and monocytes . We examined , in the present study , the functional significance of PPARgamma expressed in fibroblast - like synovial cells ( FLS ) isolated from patients with rheumatoid arthritis ( RA ) . Incubation of FLS with a synthetic PPARgamma ligand , troglitazone , inhibited endogenous production of P01375 , P05231 and P10145 , as well as matrix metalloprotease - 3 ( P08254 ) , without inducing apoptosis of the cells . The gelatinase activity of FLS culture media was also inhibited by troglitazone . Electrophoretic mobility shift assay ( EMSA ) showed a significant reduction in the DNA binding activity of NF - kappaB in troglitazone - treated FLS in response to P01375 or IL - 1beta . Moreover , long - term cultivation of FLS with troglitazone resulted in morphological changes with marked lipid accumulation in these cells . Our results show a negative regulatory function for PPARgamma on cytokine and MMP production together with inhibition of cytokine - mediated inflammatory responses in rheumatoid synovial cells . Our results also suggest that FLS could differentiate into adipocyte - like cells in the presence of proper stimulatory signals including PPARgamma ."],"string":"[\n \"Curcumin : getting back to the roots . The use of turmeric , derived from the root of the plant Curcuma longa , for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years . The active component of turmeric responsible for this activity , curcumin , was identified almost two centuries ago . Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets , including transcription factors ( e . g . , NF - kappaB , AP - 1 , Egr - 1 , beta - catenin , and P37231 ) , enzymes ( e . g . , P35354 , 5 - P28300 , P35228 , and hemeoxygenase - 1 ) , cell cycle proteins ( e . g . , cyclin D1 and P38936 ) , cytokines ( e . g . , P01375 , IL - 1 , P05231 , and chemokines ) , receptors ( e . g . , P00533 and P04626 ) , and cell surface adhesion molecules . Because it can modulate the expression of these targets , curcumin is now being used to treat cancer , arthritis , diabetes , Crohn ' s disease , cardiovascular diseases , osteoporosis , Alzheimer ' s disease , psoriasis , and other pathologies . Interestingly , 6 - gingerol , a natural analog of curcumin derived from the root of ginger ( Zingiber officinalis ) , exhibits a biologic activity profile similar to that of curcumin . The efficacy , pharmacologic safety , and cost effectiveness of curcuminoids prompt us to \\\" get back to our roots . \\\"\",\n \"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK95___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .\",\n \"P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .\",\n \"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK46___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK46___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .\",\n \"Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .\",\n \"[ Anticoagulants of primary haemostasis ] . Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases . Established antiplatelet agents use different pharmacological targets for this role . Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of P23219 . DB00208 or clopidogrel are ADP - Q9H244 receptor antagonists . Tirofiban , abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb / IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation . The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase - 5 . Efforts are made to improve antiplatelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk . Current clinical studies focus on a new generation of ADP receptor antagonists ( prasugrel , cangrelor and ticagrelor ) as successors of ticlopidine and clopidogrel after coronary arterial interventions . Developments using platelet targets different from established drugs are thrombin receptor antagonists ( like SCH530348 ) or thromboxane receptor antagonists ( like S18886 / terutroban ) in patients with cerebrovascular events . Results from recent experimental studies could lead to new strategies for antiplatelet therapy ( like inhibition of GP Ib receptor , GP VI receptor , platelet - leukocyte interaction , factor XII and others ) in the future .\",\n \"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK94___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .\",\n \"DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .\",\n \"Identification of the amino acid sequence motif of alpha - synuclein responsible for macrophage activation . P37840 ( Syn ) is implicated in the pathogenesis of PD and related neurodegenerative disorders . Recent studies have also shown that alpha - synuclein can activate microglia and enhance dopaminergic neurodegeneration . The mechanisms of microglia activation by alpha - synuclein , however , are not well understood . In this study , we found that not only alpha - synuclein but also beta - and gamma - synucleins activated macrophages ( RAW 264 . 7 ) in vitro . Macrophages treated with synuclein proteins secreted P01375 in a dose - dependent manner . Synuclein family proteins also increased mRNA transcription of P35354 and P35228 . Two alpha - synuclein deletion mutants , SynDeltaNAC and Syn61 - 140 , activated macrophages , while deletion mutants Syn1 - 60 and Syn96 - 140 did not significantly activate them . Finally , we demonstrated that macrophage activation by alpha - synuclein was accompanied by phosphorylation of P29323 . These results suggest that synuclein family proteins can activate macrophages , and that macrophage activation needs both the N - terminal and C - terminal domains of alpha - synuclein , but not the central Q9C000 region .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK14___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\",\n \"Q13547 contributes to cell cycle and apoptosis . Histone deacetylases ( HDACs ) are generally thought to play important roles in human disease . However , little information is available concerning the specific functions of individual HDACs . We previously reported on transgenic mice that expressed human Q13547 and experienced steatosis and nuclear pleomorphism in their hepatic tissues . To find out if the over - expression of Q13547 contributes to the expression of genes related to the cell cycle , apoptosis , and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice , the expression profiles of the related genes in liver tissues were determined by reverse transcription - polymerase chain reaction ( RT - PCR ) and Western blot analysis . The activated human Q13547 significantly induced the expression levels of mRNA for p53 , P37231 and Bak and reduced the P38936 expression level compared with the levels in control littermates . However , the protein levels of p53 and P37231 were significantly decreased . In conclusion , our results indicate that Q13547 can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over - express Q13547 .\",\n \"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .\",\n \"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK5___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK58___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Discrete roles for peroxisome proliferator - activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators . P37231 ( PPARgamma ) plays a major role in adipogenesis . PPARgamma binds to DNA as a heterodimer with retinoid X receptor ( RXR ) , and PPARgamma - RXR can be activated by ligands specific for either receptor ; the presence of both ligands can result in a cooperative effect on the transactivation of target genes . How these ligands mediate transactivation , however , remains unclear . PPARgamma is known to interact with both the P52701 / Q15788 family of coactivators and the distinct , multisubunit coactivator complex called DRIP . A single DRIP subunit , Q15648 ( Q15648 , PBP ) , binds directly to PPARgamma . Here we report that PPARgamma and RXR selectively interacted with Q15648 and P52701 proteins in a ligand - dependent manner . At physiological concentrations , RXR - specific ligands only induced P52701 binding to RXR , and PPARgamma - specific ligands exclusively recruited Q15648 but not P52701 coactivators to PPARgamma . This selectivity was not observed in interaction assays off DNA , implying that the specificity of coactivator binding in response to ligand is strongly influenced by the allosteric effects of DNA - bound heterodimers . These coactivator - selective effects were also observed in transient - transfection assays in the presence of overexpressed P52701 or DRIP coactivators . The results suggest that the cooperative effects of PPARgamma - and RXR - specific ligands may occur at the level of selective coactivator recruitment .\",\n \"DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .\",\n \"Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .\",\n \"Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl - containing histone deacetylase ( HDAC ) inhibitors 1 - 4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 ) and class II ( maize HD1 - A and human P56524 ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl - H3 and low acetyl - α - tubulin levels . Exceptions are compounds 3 f - i , 3 m - o , and 4 k , which showed higher tubulin acetylation than ___MASK23___ . In U937 cells , cell - cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1 - 4 . Five hydroxamates ( compounds 1 h - l ) effected a two - to greater than threefold greater percent apoptosis than ___MASK23___ , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest - scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .\",\n \"Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .\",\n \"Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK18___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .\",\n \"Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .\",\n \"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK15___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .\",\n \"Functional changes in rheumatoid fibroblast - like synovial cells through activation of peroxisome proliferator - activated receptor gamma - mediated signalling pathway . P37231 ( PPARgamma ) is a ligand dependent transcriptional factor known to be a regulator of adipogenesis . Recent studies have also shown that stimulation of PPARgamma inhibits the transcriptional activities of other nuclear factors and down - regulates proinflammatory cytokine synthesis in T cells and monocytes . We examined , in the present study , the functional significance of PPARgamma expressed in fibroblast - like synovial cells ( FLS ) isolated from patients with rheumatoid arthritis ( RA ) . Incubation of FLS with a synthetic PPARgamma ligand , troglitazone , inhibited endogenous production of P01375 , P05231 and P10145 , as well as matrix metalloprotease - 3 ( P08254 ) , without inducing apoptosis of the cells . The gelatinase activity of FLS culture media was also inhibited by troglitazone . Electrophoretic mobility shift assay ( EMSA ) showed a significant reduction in the DNA binding activity of NF - kappaB in troglitazone - treated FLS in response to P01375 or IL - 1beta . Moreover , long - term cultivation of FLS with troglitazone resulted in morphological changes with marked lipid accumulation in these cells . Our results show a negative regulatory function for PPARgamma on cytokine and MMP production together with inhibition of cytokine - mediated inflammatory responses in rheumatoid synovial cells . Our results also suggest that FLS could differentiate into adipocyte - like cells in the presence of proper stimulatory signals including PPARgamma .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK14___","___MASK15___","___MASK18___","___MASK23___","___MASK46___","___MASK58___","___MASK5___","___MASK94___","___MASK95___"],"string":"[\n \"___MASK14___\",\n \"___MASK15___\",\n \"___MASK18___\",\n \"___MASK23___\",\n \"___MASK46___\",\n \"___MASK58___\",\n \"___MASK5___\",\n \"___MASK94___\",\n \"___MASK95___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK18___"},"id":{"kind":"string","value":"MH_train_96"}}},{"rowIdx":97,"cells":{"query":{"kind":"string","value":"interacts_with DB00181?"},"supports":{"kind":"list like","value":["Inhibition of mutant P15056 splice variant signaling by next - generation , selective RAF inhibitors . ___MASK4___ and dabrafenib block MEK - P27361 / 2 signaling and cause tumor regression in the majority of advanced - stage P15056 ( V600E ) melanoma patients ; however , acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors . Next - generation RAF inhibitors , such as PLX7904 ( PB04 ) , effectively inhibit RAF signaling in P15056 ( V600E ) melanoma cells without paradoxical effects in wild - type cells . Furthermore , PLX7904 blocks the growth of vemurafenib - resistant P15056 ( V600E ) cells that express mutant P01111 . Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation P15056 splice variants ; thus , we tested the effects of PLX7904 and its clinical analog , PLX8394 ( PB03 ) , in P15056 ( V600E ) splice variant - mediated vemurafenib - resistant cells . We show that paradox - breaker RAF inhibitors potently block MEK - P27361 / 2 signaling , P55008 / S cell cycle events , survival and growth of vemurafenib / PLX4720 - resistant cells harboring distinct P15056 ( V600E ) splice variants . These data support the further investigation of paradox - breaker RAF inhibitors as a second - line treatment option for patients failing on vemurafenib or dabrafenib .","Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .","Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK10___ and Tissue P00747 Activator in Occluded Arteries .","Human and mouse trace amine - associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands . TAARs ( trace amine - associated receptors ) are G - protein - coupled receptors that respond to low abundance , endogenous amines such as tyramine and tryptamine , and represent potential targets for neuropsychiatric diseases . However , some members of this receptor subfamily either have no ligand identified or remain difficult to express and characterize using recombinant systems . In the present paper we report the successful expression of human and mouse Q96RJ0 , and the characterization of their responses to various natural and synthetic agonists . In P29320 ( human embryonic kidney ) - 293 / CRE - bla cells , mouse Q96RJ0 showed a robust response to trace amines as measured using either a DB02527 assay or a beta - lactamase reporter assay , whereas human Q96RJ0 showed a weaker , but still measurable , response . When certain fragments of human Q96RJ0 were replaced with the corresponding regions of mouse Q96RJ0 , the chimaeric receptor showed a much stronger response in DB02527 production . Examination of a series of agonists on these receptors revealed that the human and the chimaeric receptor are almost identical in pharmacology , but distinct from the mouse receptor . We also screened small libraries of pharmacologically active agents on Q96RJ0 and identified a series of synthetic agonists , some of which are also ligands of the enigmatic imidazoline receptor . The findings of the present study not only shed light on the pharmacological species difference of Q96RJ0 , but also raise new possibilities about the mechanism of some of the imidazoline - related agents .","De novo mutations in synaptic transmission genes including Q05193 cause epileptic encephalopathies . Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous , underscoring the need for large cohorts of well - characterized individuals to further define the genetic landscape . Through a collaboration between two consortia ( EuroEPINOMICS and Epi4K / EPGP ) , we analyzed exome - sequencing data of 356 trios with the \" classical \" epileptic encephalopathies , infantile spasms and Lennox Gastaut syndrome , including 264 trios previously analyzed by the Epi4K / EPGP consortium . In this expanded cohort , we find 429 de novo mutations , including de novo mutations in Q05193 in five individuals and de novo mutations in O75899 , P49327 , and Q15413 in two individuals each . Unlike previous studies , this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis ( p = 8 . 2 × 10 (- 4 ) ) , supporting a prominent role for de novo mutations in epileptic encephalopathies . We bring statistical evidence that mutations in Q05193 cause epileptic encephalopathy , find suggestive evidence for a role of three additional genes , and show that at least 12 % of analyzed individuals have an identifiable causal de novo mutation . Strikingly , 75 % of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission , and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well . These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies , above and beyond that caused by ion channel dysfunction .","Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .","Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .","___MASK7___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","A complex of synaptic adhesion molecule Q9BY67 , a molecule related to autism spectrum disorder , with O75970 in the cerebellum . Mutations in the synaptic adhesion protein Q9BY67 ( RA175 / SynCAM1 ) are associated with autism spectrum disorder ( P51689 ) , a neurodevelopmental disorder of uncertain molecular origin . Cadm1 - knock out ( KO ) mice exhibit smaller cerebella with decreased number of synapse of Purkinje cells and some P51689 - like symptoms , including impaired ultrasonic vocalization . In this study , we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at post - natal stages . The C - terminal peptide of Cadm1 associated with Mupp1 at P78352 / Dlg / ZO - 1 ( PDZ ) ( 1 - 5 ) , a scaffold protein containing 13 PDZ domains , which interacted with gamma - aminobutyric acid type B receptor ( GABBR ) 2 at PDZ13 , but not with P78352 . The O75899 was detected in a set of proteins interacting with Cadm1 C - terminal . Cadm1 colocalized with Mupp1 and O75899 on the dendrites of Purkinje cells in the molecular layers of the developing cerebellum and on the dendrites of hippocampal neurons cultured in vitro . These observations suggest that the Cadm1 synaptic receptor complex , including Mupp1 - O75899 , is located on the dendrites of Purkinje cells . The amount of O75899 protein , but not mRNA , was increased in the cerebella of Cadm1 KO mice , suggesting that lack of Cadm1 does not affect transcription of O75899 , but may stabilize the Mupp1 - O75899 complex ; the Mupp1 - O75899 interaction may be stabilized by conformational change in Mupp1 or association with other adhesion molecules and by anchorage to the post - synaptic membrane . Up - regulation of O75899 in the cerebellum in the absence of Q9BY67 may be associated with P51689 pathogenesis .","A novel mechanism of autophagic cell death in dystrophic muscle regulated by Q99572 receptor large - pore formation and HSP90 . Q99572 is an DB00171 - gated ion channel , which can also exhibit an open state with a considerably wider permeation . However , the functional significance of the movement of molecules through the large pore ( LP ) and the intracellular signaling events involved are not known . Here , analyzing the consequences of Q99572 activation in primary myoblasts and myotubes from the Dmd ( mdx ) mouse model of Duchenne muscular dystrophy , we found DB00171 - induced Q99572 - dependent autophagic flux , leading to P42574 - P55210 - independent cell death . Q99572 - evoked autophagy was triggered by LP formation but not Ca ( 2 +) influx or P28482 - P27361 phosphorylation , 2 canonical Q99572 - evoked signals . Phosphoproteomics , protein expression inference and signaling pathway prediction analysis of Q99572 signaling mediators pointed to P54652 and HSP90 proteins . Indeed , specific HSP90 inhibitors prevented LP formation , LC3 - II accumulation , and cell death in myoblasts and myotubes but not in macrophages . Pharmacological blockade or genetic ablation of p2rx7 also proved protective against DB00171 - induced death of muscle cells , as did inhibition of autophagy with 3 - MA . The functional significance of the Q99572 LP is one of the great unknowns of purinergic signaling . Our data demonstrate a novel outcome -- autophagy -- and show that molecules entering through the LP can be targeted to phagophores . Moreover , we show that in muscles but not in macrophages , autophagy is needed for the formation of this LP . Given that Q99572 - dependent LP and HSP90 are critically interacting in the DB00171 - evoked autophagic death of dystrophic muscles , treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy .","P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK68___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK68___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .","[ ___MASK87___ sodium ( Photofrin - II ) ] . ___MASK87___ sodium ( ___MASK87___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK87___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .","Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK54___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK12___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","DB11320 contributes to tissue remodeling via periostin expression . DB11320 is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases . Recent studies revealed that periostin , a matricelluar protein , contributed to tissue remodeling ; however , a link between periostin and histamine remains unproven . We investigated whether periostin was involved in histamine - induced collagen production . Cultured dermal fibroblasts derived from wild - type ( WT ) or periostin knockout ( PN (-/-) ) mice were stimulated with histamine , and then collagen and periostin production was evaluated . DB11320 induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase , whereas no effect on collagen expression was observed in histamine - stimulated PN (-/-) fibroblasts . In WT fibroblasts , histamine directly induced periostin expression in a dose - dependent manner , and an H1 receptor antagonist blocked both periostin and collagen expression . DB11320 activated extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) through the H1 receptor . Q15063 induction was inhibited by either H1 antagonist or P27361 / 2 inhibitor treatment in vitro and was attenuated in P35367 (-/-) mice . Elevated expression of periostin was found in lesional skin from atopic dermatitis patients . These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor - mediated P27361 / 2 pathway ; furthermore , histamine may accelerate the chronicity of atopic dermatitis .","Type B gamma - aminobutyric acid receptors modulate the function of the extracellular Ca2 +- sensing receptor and cell differentiation in murine growth plate chondrocytes . Extracellular calcium - sensing receptors ( CaRs ) and metabotropic or type B gamma - aminobutyric acid receptors ( GABA - B - Rs ) , two closely related members of family C of the G protein - coupled receptor superfamily , dimerize in the formation of signaling and membrane - anchored receptor complexes . We tested whether CaRs and two GABA - B - R subunits ( Q96GN5 and R2 ) are expressed in mouse growth plate chondrocytes ( GPCs ) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca ( 2 +)- mediated cell differentiation . Both CaRs and the Q9UBS5 and - R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs . The Q9UBS5 co - immunoprecipitated with the CaR , confirming a physical interaction between the two receptors in GPCs . In vitro knockout of Q9UBS5 genes , using a Cre - lox recombination strategy , blunted the ability of high extracellular Ca ( 2 +) concentration to activate phospholipase C and P27361 / 2 , suppressed cell proliferation , and enhanced apoptosis in cultured GPCs . In GPCs , in which the Q9UBS5 was acutely knocked down , there was reduced expression of early chondrocyte markers , aggrecan and type II collagen , and increased expression of the late differentiation markers , type X collagen and osteopontin . These results support the idea that physical interactions between CaRs and GABA - B - R1s modulate the growth and differentiation of GPCs , potentially by altering the function of CaRs .","Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane . The P01130 ( LDL - R ) promotes the specific endocytosis and lysosomal delivery of extracellular lipoprotein ligands via clathrin - coated pits . It was widely assumed that other closely related members of the LDL - R gene family would have similar functions , but recent experimental evidence has revealed that one such protein , apolipoprotein E receptor 2 ( apoER2 ) , has a critical role as an \" outside - in \" signal transducer in the brain . ApoER2 signaling appears to require interaction between its cytoplasmic domain and adapter molecules such as Dab1 , JIP 1 and JIP 2 , and P78352 . Many of the receptors for other signaling pathways affected by such adapter molecules are compartmentalized into specialized microdomains within the plasma membrane termed caveolae . Here , we show that apoER2 , but not LDL - R , is localized to caveolae , supporting the concept that its physiological role is in cell signaling , rather than in endocytosing ligands .","Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .","Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK15___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .","___MASK52___ improves endothelial function in db / db mice : role of angiotensin II type 1 receptors and oxidative stress . BACKGROUND AND PURPOSE : P04035 inhibitors , statins , with lipid - reducing properties combat against atherosclerosis and diabetes . The favourable modulation of endothelial function may play a significant role in this effect . The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes - associated endothelial dysfunction . EXPERIMENTAL APPROACH : Twelve - week - old db / db diabetic mice were treated with rosuvastatin at 20 mg · kg ⁻ ¹ · day ⁻ ¹ p . o . for 6 weeks . Isometric force was measured in isolated aortae and renal arteries . Protein expressions including angiotensin II type 1 receptor ( AT₁R ) , Q9NPH5 , O75935 ( phox ) , p67 ( phox ) , Rac - 1 , nitrotyrosine , phospho - P27361 / 2 and phospho - p38 were determined by Western blotting , while reactive oxygen species ( ROS ) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay . KEY RESULTS : ___MASK52___ treatment of db / db mice reversed the impaired ACh - induced endothelium - dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db / db mouse renal arteries and aortae . ___MASK52___ reduced the elevated expressions of AT₁R , O75935 ( phox ) and p67 ( phox ) , Q9NPH5 , Rac1 , nitrotyrosine and phosphorylation of P27361 / 2 and p38 MAPK and inhibited ROS production in aortae from db / db mice . CONCLUSIONS AND IMPLICATIONS : The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability , which is probably achieved by its inhibition of ROS production from the AT₁R - NAD ( P ) H oxidase cascade .","Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .","Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues ."],"string":"[\n \"Inhibition of mutant P15056 splice variant signaling by next - generation , selective RAF inhibitors . ___MASK4___ and dabrafenib block MEK - P27361 / 2 signaling and cause tumor regression in the majority of advanced - stage P15056 ( V600E ) melanoma patients ; however , acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors . Next - generation RAF inhibitors , such as PLX7904 ( PB04 ) , effectively inhibit RAF signaling in P15056 ( V600E ) melanoma cells without paradoxical effects in wild - type cells . Furthermore , PLX7904 blocks the growth of vemurafenib - resistant P15056 ( V600E ) cells that express mutant P01111 . Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation P15056 splice variants ; thus , we tested the effects of PLX7904 and its clinical analog , PLX8394 ( PB03 ) , in P15056 ( V600E ) splice variant - mediated vemurafenib - resistant cells . We show that paradox - breaker RAF inhibitors potently block MEK - P27361 / 2 signaling , P55008 / S cell cycle events , survival and growth of vemurafenib / PLX4720 - resistant cells harboring distinct P15056 ( V600E ) splice variants . These data support the further investigation of paradox - breaker RAF inhibitors as a second - line treatment option for patients failing on vemurafenib or dabrafenib .\",\n \"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .\",\n \"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK10___ and Tissue P00747 Activator in Occluded Arteries .\",\n \"Human and mouse trace amine - associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands . TAARs ( trace amine - associated receptors ) are G - protein - coupled receptors that respond to low abundance , endogenous amines such as tyramine and tryptamine , and represent potential targets for neuropsychiatric diseases . However , some members of this receptor subfamily either have no ligand identified or remain difficult to express and characterize using recombinant systems . In the present paper we report the successful expression of human and mouse Q96RJ0 , and the characterization of their responses to various natural and synthetic agonists . In P29320 ( human embryonic kidney ) - 293 / CRE - bla cells , mouse Q96RJ0 showed a robust response to trace amines as measured using either a DB02527 assay or a beta - lactamase reporter assay , whereas human Q96RJ0 showed a weaker , but still measurable , response . When certain fragments of human Q96RJ0 were replaced with the corresponding regions of mouse Q96RJ0 , the chimaeric receptor showed a much stronger response in DB02527 production . Examination of a series of agonists on these receptors revealed that the human and the chimaeric receptor are almost identical in pharmacology , but distinct from the mouse receptor . We also screened small libraries of pharmacologically active agents on Q96RJ0 and identified a series of synthetic agonists , some of which are also ligands of the enigmatic imidazoline receptor . The findings of the present study not only shed light on the pharmacological species difference of Q96RJ0 , but also raise new possibilities about the mechanism of some of the imidazoline - related agents .\",\n \"De novo mutations in synaptic transmission genes including Q05193 cause epileptic encephalopathies . Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous , underscoring the need for large cohorts of well - characterized individuals to further define the genetic landscape . Through a collaboration between two consortia ( EuroEPINOMICS and Epi4K / EPGP ) , we analyzed exome - sequencing data of 356 trios with the \\\" classical \\\" epileptic encephalopathies , infantile spasms and Lennox Gastaut syndrome , including 264 trios previously analyzed by the Epi4K / EPGP consortium . In this expanded cohort , we find 429 de novo mutations , including de novo mutations in Q05193 in five individuals and de novo mutations in O75899 , P49327 , and Q15413 in two individuals each . Unlike previous studies , this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis ( p = 8 . 2 × 10 (- 4 ) ) , supporting a prominent role for de novo mutations in epileptic encephalopathies . We bring statistical evidence that mutations in Q05193 cause epileptic encephalopathy , find suggestive evidence for a role of three additional genes , and show that at least 12 % of analyzed individuals have an identifiable causal de novo mutation . Strikingly , 75 % of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission , and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well . These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies , above and beyond that caused by ion channel dysfunction .\",\n \"Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .\",\n \"Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .\",\n \"___MASK7___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"A complex of synaptic adhesion molecule Q9BY67 , a molecule related to autism spectrum disorder , with O75970 in the cerebellum . Mutations in the synaptic adhesion protein Q9BY67 ( RA175 / SynCAM1 ) are associated with autism spectrum disorder ( P51689 ) , a neurodevelopmental disorder of uncertain molecular origin . Cadm1 - knock out ( KO ) mice exhibit smaller cerebella with decreased number of synapse of Purkinje cells and some P51689 - like symptoms , including impaired ultrasonic vocalization . In this study , we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at post - natal stages . The C - terminal peptide of Cadm1 associated with Mupp1 at P78352 / Dlg / ZO - 1 ( PDZ ) ( 1 - 5 ) , a scaffold protein containing 13 PDZ domains , which interacted with gamma - aminobutyric acid type B receptor ( GABBR ) 2 at PDZ13 , but not with P78352 . The O75899 was detected in a set of proteins interacting with Cadm1 C - terminal . Cadm1 colocalized with Mupp1 and O75899 on the dendrites of Purkinje cells in the molecular layers of the developing cerebellum and on the dendrites of hippocampal neurons cultured in vitro . These observations suggest that the Cadm1 synaptic receptor complex , including Mupp1 - O75899 , is located on the dendrites of Purkinje cells . The amount of O75899 protein , but not mRNA , was increased in the cerebella of Cadm1 KO mice , suggesting that lack of Cadm1 does not affect transcription of O75899 , but may stabilize the Mupp1 - O75899 complex ; the Mupp1 - O75899 interaction may be stabilized by conformational change in Mupp1 or association with other adhesion molecules and by anchorage to the post - synaptic membrane . Up - regulation of O75899 in the cerebellum in the absence of Q9BY67 may be associated with P51689 pathogenesis .\",\n \"A novel mechanism of autophagic cell death in dystrophic muscle regulated by Q99572 receptor large - pore formation and HSP90 . Q99572 is an DB00171 - gated ion channel , which can also exhibit an open state with a considerably wider permeation . However , the functional significance of the movement of molecules through the large pore ( LP ) and the intracellular signaling events involved are not known . Here , analyzing the consequences of Q99572 activation in primary myoblasts and myotubes from the Dmd ( mdx ) mouse model of Duchenne muscular dystrophy , we found DB00171 - induced Q99572 - dependent autophagic flux , leading to P42574 - P55210 - independent cell death . Q99572 - evoked autophagy was triggered by LP formation but not Ca ( 2 +) influx or P28482 - P27361 phosphorylation , 2 canonical Q99572 - evoked signals . Phosphoproteomics , protein expression inference and signaling pathway prediction analysis of Q99572 signaling mediators pointed to P54652 and HSP90 proteins . Indeed , specific HSP90 inhibitors prevented LP formation , LC3 - II accumulation , and cell death in myoblasts and myotubes but not in macrophages . Pharmacological blockade or genetic ablation of p2rx7 also proved protective against DB00171 - induced death of muscle cells , as did inhibition of autophagy with 3 - MA . The functional significance of the Q99572 LP is one of the great unknowns of purinergic signaling . Our data demonstrate a novel outcome -- autophagy -- and show that molecules entering through the LP can be targeted to phagophores . Moreover , we show that in muscles but not in macrophages , autophagy is needed for the formation of this LP . Given that Q99572 - dependent LP and HSP90 are critically interacting in the DB00171 - evoked autophagic death of dystrophic muscles , treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy .\",\n \"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK68___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK68___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .\",\n \"[ ___MASK87___ sodium ( Photofrin - II ) ] . ___MASK87___ sodium ( ___MASK87___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK87___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .\",\n \"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK54___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK12___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"DB11320 contributes to tissue remodeling via periostin expression . DB11320 is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases . Recent studies revealed that periostin , a matricelluar protein , contributed to tissue remodeling ; however , a link between periostin and histamine remains unproven . We investigated whether periostin was involved in histamine - induced collagen production . Cultured dermal fibroblasts derived from wild - type ( WT ) or periostin knockout ( PN (-/-) ) mice were stimulated with histamine , and then collagen and periostin production was evaluated . DB11320 induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase , whereas no effect on collagen expression was observed in histamine - stimulated PN (-/-) fibroblasts . In WT fibroblasts , histamine directly induced periostin expression in a dose - dependent manner , and an H1 receptor antagonist blocked both periostin and collagen expression . DB11320 activated extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) through the H1 receptor . Q15063 induction was inhibited by either H1 antagonist or P27361 / 2 inhibitor treatment in vitro and was attenuated in P35367 (-/-) mice . Elevated expression of periostin was found in lesional skin from atopic dermatitis patients . These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor - mediated P27361 / 2 pathway ; furthermore , histamine may accelerate the chronicity of atopic dermatitis .\",\n \"Type B gamma - aminobutyric acid receptors modulate the function of the extracellular Ca2 +- sensing receptor and cell differentiation in murine growth plate chondrocytes . Extracellular calcium - sensing receptors ( CaRs ) and metabotropic or type B gamma - aminobutyric acid receptors ( GABA - B - Rs ) , two closely related members of family C of the G protein - coupled receptor superfamily , dimerize in the formation of signaling and membrane - anchored receptor complexes . We tested whether CaRs and two GABA - B - R subunits ( Q96GN5 and R2 ) are expressed in mouse growth plate chondrocytes ( GPCs ) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca ( 2 +)- mediated cell differentiation . Both CaRs and the Q9UBS5 and - R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs . The Q9UBS5 co - immunoprecipitated with the CaR , confirming a physical interaction between the two receptors in GPCs . In vitro knockout of Q9UBS5 genes , using a Cre - lox recombination strategy , blunted the ability of high extracellular Ca ( 2 +) concentration to activate phospholipase C and P27361 / 2 , suppressed cell proliferation , and enhanced apoptosis in cultured GPCs . In GPCs , in which the Q9UBS5 was acutely knocked down , there was reduced expression of early chondrocyte markers , aggrecan and type II collagen , and increased expression of the late differentiation markers , type X collagen and osteopontin . These results support the idea that physical interactions between CaRs and GABA - B - R1s modulate the growth and differentiation of GPCs , potentially by altering the function of CaRs .\",\n \"Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane . The P01130 ( LDL - R ) promotes the specific endocytosis and lysosomal delivery of extracellular lipoprotein ligands via clathrin - coated pits . It was widely assumed that other closely related members of the LDL - R gene family would have similar functions , but recent experimental evidence has revealed that one such protein , apolipoprotein E receptor 2 ( apoER2 ) , has a critical role as an \\\" outside - in \\\" signal transducer in the brain . ApoER2 signaling appears to require interaction between its cytoplasmic domain and adapter molecules such as Dab1 , JIP 1 and JIP 2 , and P78352 . Many of the receptors for other signaling pathways affected by such adapter molecules are compartmentalized into specialized microdomains within the plasma membrane termed caveolae . Here , we show that apoER2 , but not LDL - R , is localized to caveolae , supporting the concept that its physiological role is in cell signaling , rather than in endocytosing ligands .\",\n \"Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .\",\n \"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK15___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .\",\n \"___MASK52___ improves endothelial function in db / db mice : role of angiotensin II type 1 receptors and oxidative stress . BACKGROUND AND PURPOSE : P04035 inhibitors , statins , with lipid - reducing properties combat against atherosclerosis and diabetes . The favourable modulation of endothelial function may play a significant role in this effect . The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes - associated endothelial dysfunction . EXPERIMENTAL APPROACH : Twelve - week - old db / db diabetic mice were treated with rosuvastatin at 20 mg · kg ⁻ ¹ · day ⁻ ¹ p . o . for 6 weeks . Isometric force was measured in isolated aortae and renal arteries . Protein expressions including angiotensin II type 1 receptor ( AT₁R ) , Q9NPH5 , O75935 ( phox ) , p67 ( phox ) , Rac - 1 , nitrotyrosine , phospho - P27361 / 2 and phospho - p38 were determined by Western blotting , while reactive oxygen species ( ROS ) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay . KEY RESULTS : ___MASK52___ treatment of db / db mice reversed the impaired ACh - induced endothelium - dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db / db mouse renal arteries and aortae . ___MASK52___ reduced the elevated expressions of AT₁R , O75935 ( phox ) and p67 ( phox ) , Q9NPH5 , Rac1 , nitrotyrosine and phosphorylation of P27361 / 2 and p38 MAPK and inhibited ROS production in aortae from db / db mice . CONCLUSIONS AND IMPLICATIONS : The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability , which is probably achieved by its inhibition of ROS production from the AT₁R - NAD ( P ) H oxidase cascade .\",\n \"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .\",\n \"Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK10___","___MASK12___","___MASK15___","___MASK4___","___MASK52___","___MASK54___","___MASK68___","___MASK7___","___MASK87___"],"string":"[\n \"___MASK10___\",\n \"___MASK12___\",\n \"___MASK15___\",\n \"___MASK4___\",\n \"___MASK52___\",\n \"___MASK54___\",\n \"___MASK68___\",\n \"___MASK7___\",\n \"___MASK87___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK68___"},"id":{"kind":"string","value":"MH_train_97"}}},{"rowIdx":98,"cells":{"query":{"kind":"string","value":"interacts_with DB00120?"},"supports":{"kind":"list like","value":["[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F - VII , F - X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non - diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F - VII , F - X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance .","P01308 resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients . OBJECTIVE : Metabolic syndrome ( MetS ) is associated with insulin resistance and increases the cardiovascular risk . Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease . The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance , and the effect of this interaction on the cardiovascular risk in MetS patients . METHODS : NADPH oxidase - dependent superoxide production and expression was evaluated by luminescence and western blot , respectively , in peripheral blood mononuclear cells obtained from 125 patients with MetS . P01308 resistance was defined by the homeostasis model assessment index . P14780 was quantified by enzyme - linked immunosorbent assay in plasma samples . To ascertain the mechanisms involved in vivo , we performed in - vitro experiments in cultured macrophages . RESULTS : Fifty - six percent of patients with MetS showed insulin resistance . Plasma matrix metalloproteinase - 9 levels were higher ( P < 0 . 05 ) in insulin - resistant patients than in patients with insulin sensitivity . NADPH oxidase - dependent superoxide production was augmented ( P < 0 . 05 ) in insulin - resistant patients with respect to insulin - sensitive patients . The interaction between insulin resistance and abnormally high NADPH oxidase - mediated superoxide production was associated with the highest matrix metalloproteinase - 9 values . Increased NADPH oxidase - dependent superoxide production was significantly associated with higher NADPH oxidase P13498 expression in insulin - resistant than in insulin - sensitive patients . Interestingly , insulin upregulated P13498 in peripheral blood mononuclear cells and in murine macrophages . CONCLUSION : P01308 resistance is associated with phagocytic NADPH oxidase activation . This association results in the highest cardiovascular risk in MetS patients .","Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .","___MASK49___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK49___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .","[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK53___ GITS , Diaprel MR ) . One daily dose of ___MASK53___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .","A Single 60 mg Dose of ___MASK41___ Might Improve Hepatic P01308 Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women . Background . The O14788 / Q9Y6Q6 / O00300 signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis . The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation . Aim . To test whether systemic blockage of O14788 by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women . Study Design . This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test . Results . A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose , insulin , or HOMA - IR at both 4 and 12 weeks . No changes could be detected in glucose response to the glucose load , Matsuda Index , or insulinogenic index . Nonetheless , 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks . Conclusions . A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients .","___MASK72___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK72___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK72___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK72___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK72___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .","P01308 growth factor - receptor ( IGF - 1R ) antibody cixutumumab combined with the P42345 inhibitor temsirolimus in patients with refractory Ewing ' s sarcoma family tumors . PURPOSE : ___MASK59___ was combined with cixutumumab , a fully human IgG1 monoclonal antibody directed at the insulin growth factor - 1 receptor ( IGF - 1R ) . EXPERIMENTAL DESIGN : Patients received cixutumumab , 6 mg / kg i . v . weekly , and temsirolimus , 25 to 37 . 5 mg i . v . weekly ( 4 - week cycles ) , with restaging after 8 weeks . Median follow - up was 8 . 9 months . RESULTS : Twenty patients [ 17 with Ewing ' s sarcoma ( Q01844 ) , 3 with desmoplastic small - round cell tumor ( DSRCT ) ] were enrolled . Twelve patients ( 60 % ) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting . The most frequent toxicities were thrombocytopenia ( 85 % ) , mucositis ( 80 % ) , hypercholesterolemia ( 75 % ) , hypertriglyceridemia ( 70 % ) , and hyperglycemia ( 65 % ; mostly grade I - II ) . Seven of 20 patients ( 35 % ) achieved stable disease ( SD ) for more than 5 months or complete / partial ( CR / PR ) responses . Tumor regression of more than 20 % ( 23 % , 23 % , 27 % , 100 % , 100 % ) occurred in five of 17 ( 29 % ) patients with Q01844 , and they remained on study for 8 to 27 months . One of six patients with Q01844 who previously developed resistance to a different IGF - 1R inhibitor antibody achieved a CR . Four of the seven best responders developed grade III mucositis , myelosuppression , or hyperglycemia , which were controlled while maintaining drug dose . CONCLUSION : Cixutumumab combined with temsirolimus was well - tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated Q01844 family tumors .","The P04035 inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides . The 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids . Because pravastatin is a water - soluble organic anion , it can not easily penetrate the lipid bilayer of the cell membrane . As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified , we examined the roles of the organic anion transporter family on pravastatin - treated islet and adipocyte functions . Rat oatp1 / slco1a1 , oatp2 / slco1a4 and oatp3 / slco1a5 were expressed in the pancreas , and rat oatp3 / slco1a5 was also detected in rat insulinoma cell line P01308 - 1e . ___MASK100___ was transported not only by oatp1 / slco1a1 and oatp2 / slco1a4 , but also by rat oatp3 / slco1a5 . ___MASK100___ uptake into P01308 - 1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin , both of which are known to inhibit oatp family - mediated uptake . In addition , pravastatin enhanced the glucose - stimulated insulin secretion from P01308 - 1e cells . When fat - loaded db / db mice were treated with pravastatin , glucose intolerance and insulin resistance were prevented . In addition , insulin secretion from isolated islets was enhanced by pravastatin . These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat / glucose conditions .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK20___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .","Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux .","P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .","[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK19___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .","A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .","___MASK67___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .","P01308 like growth factor - 1 selectively regulates the expression of matrix metalloproteinase - 2 in malignant H - ras transformed cells . The present study demonstrates alterations in the regulation of matrix metalloproteinase - 2 ( P08253 ) expression in response to insulin like growth factor - 1 ( DB01277 ) in a H - ras transformed cell line , P01024 , which is capable of metastasis formation . These changes in P08253 expression in response to DB01277 treatment did not occur in either non - transformed parental 10 T 1 / 2 cells or in H - ras transformed cells ( Q13224 cells ) which are capable of benign tumour formation . DB01277 treatment of P01024 cells resulted in increased expression of P08253 gelatinolytic activity and increased expression of P08253 mRNA levels . The DB01277 mediated alterations in P08253 mRNA levels were dependent upon de novo protein synthesis and independent of transcriptional events , but dependent upon post - transcriptional regulatory events . Most notably , DB01277 can regulate P08253 mRNA expression in P01024 cells through a mechanism involving P08253 message stabilization . This study demonstrates aspects of the temporal regulatory mechanisms of P08253 expression in response to insulin - like growth factor - 1 in a H - ras transformed fibrosarcoma cell line capable of metastasis formation and thereby , provides further insight into the altered growth regulatory program associated with H - ras mediated cellular transformation and malignant progression ."],"string":"[\n \"[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F - VII , F - X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non - diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F - VII , F - X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance .\",\n \"P01308 resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients . OBJECTIVE : Metabolic syndrome ( MetS ) is associated with insulin resistance and increases the cardiovascular risk . Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease . The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance , and the effect of this interaction on the cardiovascular risk in MetS patients . METHODS : NADPH oxidase - dependent superoxide production and expression was evaluated by luminescence and western blot , respectively , in peripheral blood mononuclear cells obtained from 125 patients with MetS . P01308 resistance was defined by the homeostasis model assessment index . P14780 was quantified by enzyme - linked immunosorbent assay in plasma samples . To ascertain the mechanisms involved in vivo , we performed in - vitro experiments in cultured macrophages . RESULTS : Fifty - six percent of patients with MetS showed insulin resistance . Plasma matrix metalloproteinase - 9 levels were higher ( P < 0 . 05 ) in insulin - resistant patients than in patients with insulin sensitivity . NADPH oxidase - dependent superoxide production was augmented ( P < 0 . 05 ) in insulin - resistant patients with respect to insulin - sensitive patients . The interaction between insulin resistance and abnormally high NADPH oxidase - mediated superoxide production was associated with the highest matrix metalloproteinase - 9 values . Increased NADPH oxidase - dependent superoxide production was significantly associated with higher NADPH oxidase P13498 expression in insulin - resistant than in insulin - sensitive patients . Interestingly , insulin upregulated P13498 in peripheral blood mononuclear cells and in murine macrophages . CONCLUSION : P01308 resistance is associated with phagocytic NADPH oxidase activation . This association results in the highest cardiovascular risk in MetS patients .\",\n \"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .\",\n \"___MASK49___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK49___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .\",\n \"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK53___ GITS , Diaprel MR ) . One daily dose of ___MASK53___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .\",\n \"A Single 60 mg Dose of ___MASK41___ Might Improve Hepatic P01308 Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women . Background . The O14788 / Q9Y6Q6 / O00300 signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis . The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation . Aim . To test whether systemic blockage of O14788 by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women . Study Design . This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test . Results . A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose , insulin , or HOMA - IR at both 4 and 12 weeks . No changes could be detected in glucose response to the glucose load , Matsuda Index , or insulinogenic index . Nonetheless , 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks . Conclusions . A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients .\",\n \"___MASK72___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK72___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK72___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK72___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK72___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .\",\n \"P01308 growth factor - receptor ( IGF - 1R ) antibody cixutumumab combined with the P42345 inhibitor temsirolimus in patients with refractory Ewing ' s sarcoma family tumors . PURPOSE : ___MASK59___ was combined with cixutumumab , a fully human IgG1 monoclonal antibody directed at the insulin growth factor - 1 receptor ( IGF - 1R ) . EXPERIMENTAL DESIGN : Patients received cixutumumab , 6 mg / kg i . v . weekly , and temsirolimus , 25 to 37 . 5 mg i . v . weekly ( 4 - week cycles ) , with restaging after 8 weeks . Median follow - up was 8 . 9 months . RESULTS : Twenty patients [ 17 with Ewing ' s sarcoma ( Q01844 ) , 3 with desmoplastic small - round cell tumor ( DSRCT ) ] were enrolled . Twelve patients ( 60 % ) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting . The most frequent toxicities were thrombocytopenia ( 85 % ) , mucositis ( 80 % ) , hypercholesterolemia ( 75 % ) , hypertriglyceridemia ( 70 % ) , and hyperglycemia ( 65 % ; mostly grade I - II ) . Seven of 20 patients ( 35 % ) achieved stable disease ( SD ) for more than 5 months or complete / partial ( CR / PR ) responses . Tumor regression of more than 20 % ( 23 % , 23 % , 27 % , 100 % , 100 % ) occurred in five of 17 ( 29 % ) patients with Q01844 , and they remained on study for 8 to 27 months . One of six patients with Q01844 who previously developed resistance to a different IGF - 1R inhibitor antibody achieved a CR . Four of the seven best responders developed grade III mucositis , myelosuppression , or hyperglycemia , which were controlled while maintaining drug dose . CONCLUSION : Cixutumumab combined with temsirolimus was well - tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated Q01844 family tumors .\",\n \"The P04035 inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides . The 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids . Because pravastatin is a water - soluble organic anion , it can not easily penetrate the lipid bilayer of the cell membrane . As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified , we examined the roles of the organic anion transporter family on pravastatin - treated islet and adipocyte functions . Rat oatp1 / slco1a1 , oatp2 / slco1a4 and oatp3 / slco1a5 were expressed in the pancreas , and rat oatp3 / slco1a5 was also detected in rat insulinoma cell line P01308 - 1e . ___MASK100___ was transported not only by oatp1 / slco1a1 and oatp2 / slco1a4 , but also by rat oatp3 / slco1a5 . ___MASK100___ uptake into P01308 - 1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin , both of which are known to inhibit oatp family - mediated uptake . In addition , pravastatin enhanced the glucose - stimulated insulin secretion from P01308 - 1e cells . When fat - loaded db / db mice were treated with pravastatin , glucose intolerance and insulin resistance were prevented . In addition , insulin secretion from isolated islets was enhanced by pravastatin . These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat / glucose conditions .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK20___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .\",\n \"Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux .\",\n \"P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .\",\n \"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK19___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .\",\n \"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .\",\n \"___MASK67___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .\",\n \"P01308 like growth factor - 1 selectively regulates the expression of matrix metalloproteinase - 2 in malignant H - ras transformed cells . The present study demonstrates alterations in the regulation of matrix metalloproteinase - 2 ( P08253 ) expression in response to insulin like growth factor - 1 ( DB01277 ) in a H - ras transformed cell line , P01024 , which is capable of metastasis formation . These changes in P08253 expression in response to DB01277 treatment did not occur in either non - transformed parental 10 T 1 / 2 cells or in H - ras transformed cells ( Q13224 cells ) which are capable of benign tumour formation . DB01277 treatment of P01024 cells resulted in increased expression of P08253 gelatinolytic activity and increased expression of P08253 mRNA levels . The DB01277 mediated alterations in P08253 mRNA levels were dependent upon de novo protein synthesis and independent of transcriptional events , but dependent upon post - transcriptional regulatory events . Most notably , DB01277 can regulate P08253 mRNA expression in P01024 cells through a mechanism involving P08253 message stabilization . This study demonstrates aspects of the temporal regulatory mechanisms of P08253 expression in response to insulin - like growth factor - 1 in a H - ras transformed fibrosarcoma cell line capable of metastasis formation and thereby , provides further insight into the altered growth regulatory program associated with H - ras mediated cellular transformation and malignant progression .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK100___","___MASK19___","___MASK20___","___MASK41___","___MASK49___","___MASK53___","___MASK59___","___MASK67___","___MASK72___"],"string":"[\n \"___MASK100___\",\n \"___MASK19___\",\n \"___MASK20___\",\n \"___MASK41___\",\n \"___MASK49___\",\n \"___MASK53___\",\n \"___MASK59___\",\n \"___MASK67___\",\n \"___MASK72___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK41___"},"id":{"kind":"string","value":"MH_train_98"}}},{"rowIdx":99,"cells":{"query":{"kind":"string","value":"interacts_with DB00051?"},"supports":{"kind":"list like","value":["[ The importance of biologicals in the treatment of SoJIA ] . Systemic onset juvenile idiopathic arthritis ( SoJIA ) remains difficult to treat . In addition to conventional antirheumatic therapy with non - steroidal antirheumatic drugs ( NSARDs ) , steroids or disease - modifying antirheumatic drugs ( DMARDs ) , biologicals offer a new therapeutic approach for this disease in that they are able to target pathogenically relevant cytokines and effector cells . Some biologicals are already approved for use in children with rheumatic disease . In order to assess the currently available data on the use of biologicals in SoJIA , we performed a Medline search for the period 2005 to March 2010 , including the MeSH terms \" SoJIA \" , \" systemic juvenile idiopathic arthritis \" and \" biologicals \" , as well as an NIH study registry search . At Present there are scant and unconvincing data on the use of DB00005 or DB00051 for the treatment of SoJIA . No results are published on the use of DB00065 or other new P01375 inhibitors . The inhibition of IL - 1 or P05231 shows promising results . Data on the efficacy of DB01281 is limited due to very low numbers of SoJIA patients in the studies . Further studies on the use of biologicals in SoJIA while taking individual factors into consideration are required . The long - term safety of all biologicals should be investigated in prospective registers .","DB00051 - induced noncaseating granuloma in the bone marrow of a patient being treated for rheumatoid arthritis . Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration , primarily of the lungs and lymphatic system . While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed , the more widely used infliximab has demonstrated clear efficacy in this disease . The association between tumor necrosis factor ( P01375 ) - inhibitors and noncaseating granulomas in the lung has been reported in literature . With the exception of one patient treated with adalimumab , who developed pulmonary granuloma , the remaining patients described in literature were treated with etanercept . The current case study is , to our knowledge , the first to describe adalimumab - induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although P01375 - inhibitors are used in the treatment of granulomatous disorders , their use should be carefully monitored as , in rare cases , P01375 - inhibitors may leave sufficient cytokine activation to support granuloma formation .","The therapeutic potential of P01375 antagonists for skin psoriasis comorbidities . IMPORTANCE OF THE FIELD : Alopecia , psoriatic arthritis , the metabolic syndrome , inflammatory bowel diseases and cardiovascular diseases may occur as skin psoriatic comorbidities . P01375 antagonists are used to treat psoriasis . DB00051 is one of the recognized active agents for this indication . AREAS COVERED IN THIS REVIEW : The current peer - reviewed publications and presentation of original findings . WHAT THE READER WILL GAIN : DB00051 is active on recalcitrant psoriasis and some of its comorbidities , particularly arthropathies and Crohn ' s disease . However , the progression of the radiological alterations is limited with regression of the bony erosions . Psoriatic enthesopathy also regresses . Mortality associated with psoriasis arthropathy is on the decline . Crohn ' s disease , the most frequent inflammatory bowel comorbidity of psoriasis , is responsive to adalimumab . The effect of adalimumab on the metabolic syndrome and cardiovascular involvement is more erratic . The spectacular effects of adalimumab may be associated with some adverse effects . In particular , despite a marked reduction in the psoriasis area - and - severity index ( PASI ) score some new acute lesions of cutaneous psoriasis may develop corresponding to paradoxical psoriasis . Other potential adverse effects include infections , granulomas , rapid growth of cancers and occurrence of lymphomas . TAKE HOME MESSAGE : DB00051 frequently controls moderate - to - severe forms of cutaneous psoriasis and some of its comorbidities .","[ Cutaneous infection due to Mycobacterium chelonae during anti - P01375 therapy ] . BACKGROUND : Mycobacterium chelonae is a ubiquitous , rapidly growing , opportunistic , non - tuberculous mycobacterium that can cause skin and bone tissue infections . We report a case of cutaneous infection due to M . chelonae following anti - P01375 therapy . CASE REPORT : A 70 - year - old woman with a medical history of rheumatoid arthritis was admitted for several purple nodular cutaneous lesions on her right leg evolving for 2 months . At admission , she was on prednisone , methotrexate and adalimumab for her rheumatoid arthritis . Skin lesions appeared 5 days before etanercept , which was taken for 5 months before being discontinued for adalimumab . Both the histopathological examination and bacterial culture of involved skin showed the presence of M . chelonae . DB00051 was immediately discontinued and a combination of amoxicillin - clavulanic acid and tigecyclin was started . DISCUSSION : P01375 plays a pivotal role in immune reaction to intracellular pathogens . Very few cases of cutaneous infection involving M . chelonae in association with an anti - P01375 therapy have been reported in the literature . To our knowledge , this is the first case occurring during treatment with etanercept and symptoms worsened with the introduction of adalimumab . In addition , this case underlines the difficulties of effectively treating this mycobacterium .","DB00051 for the treatment of rheumatoid arthritis . Rheumatoid arthritis ( RA ) is characterized by massive synovial proliferation resulting in joint destruction and deterioration in quality of life . P01375 has been implicated in the central pathogenesis of RA , and its blockade ? by anti - P01375 monoclonal antibodies ( infliximab and adalimumab ) and the soluble P01375 receptor ( etanercept ) has caused a paradigm shift in the treatment of RA . DB00051 can be used alone or concomitantly with methotrexate , but the combination of both is significantly superior to monotherapy with adalimumab . DB00051 can not only ameliorate the signs and symptoms of the disease , but can also inhibit the progression of joint destruction and improve quality of life . Approximately 50 % of patients with early , aggressive RA receiving combination therapy with adalimumab and methotrexate can be introduced into disease remission ( disease activity score < 2 . 6 ) . DB00051 is even effective in patients with RA treated previously with other biologics . Long - term treatment with adalimumab is safe and well tolerated in patients with RA .","[ DB00051 ] . Recently , the anti - tumor necrosis factor ( P01375 )- alpha treatments for RA are successful in alleviating the discomforts associated with swollen , painful joints . DB00051 ( D2E7 ) is the first fully human anti - P01375 monoclonal antibody ( IgG1 ) . Therefore , it has low immunogenicity and possibly greater therapeutic potential compared with other anti - P01375 antibodies . This is administered subcutaneously at a dose of 1 mg / kg biweekly . The combined therapy with methotrexate ( MTX ) is efficacious to the patients who receive MTX alone and are insufficient to control symptoms of RA . The therapeutic effects become evident within 24 hours to one week after administration and reached maximum effect after one to two weeks . In adalimumab recipient , radiographic progression is also controlled and serum levels of matrix metalloproteinase - 1 ( P03956 ) and P08254 decrease . For patients with RA , the treatment of adalimumab will set a new standard for symptom control and joint protection .","Human anti - tumor necrosis factor monoclonal antibody ( adalimumab ) in Crohn ' s disease : the CLASSIC - I trial . BACKGROUND & AIMS : P01375 blockade has been shown to be an effective treatment strategy in Crohn ' s disease ( CD ) . DB00051 is a human immunoglobulin P55008 ( IgG ( 1 ) ) monoclonal antibody targeting tumor necrosis factor ( P01375 ) . A randomized , double - blind , placebo - controlled , dose - ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD . METHODS : A total of 299 patients with moderate to severe CD naive to anti - P01375 therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg / 20 mg , 80 mg / 40 mg , or 160 mg / 80 mg or placebo . The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 ( defined as a Crohn ' s Disease Activity Index score < 150 points ) among the 80 mg / 40 mg , 160 mg / 80 mg , and placebo groups . RESULTS : The rates of remission at week 4 in the adalimumab 40 mg / 20 mg , 80 mg / 40 mg , and 160 mg / 80 mg groups were 18 % ( P = . 36 ) , 24 % ( P = . 06 ) , and 36 % ( P = . 001 ) , respectively , and 12 % in the placebo group . Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions , which were more common in adalimumab - treated patients . CONCLUSIONS : DB00051 was superior to placebo for induction of remission in patients with moderate to severe Crohn ' s disease naive to anti - P01375 therapy . The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2 . DB00051 was well tolerated .","[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK55___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .","Selective targeting of the repressive transcription factors P25490 and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 (+) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ). cMyc and P25490 are two transcription factors that are recruited as part of well - described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 , Q92769 , O15379 , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( DB02546 ) enhanced the increase in LTR transcription in cells that were depleted of P25490 . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency .","[ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1 . carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 , etc . ) , 2 . DNA repair enzymes ( O15527 , P18887 , P18074 , etc . ) , 3 . DNA synthesis and methylation ( P42898 , MS , etc . ) , 4 . cytokines and inflammation - related enzymes ( IL - 1B , P01375 - A , P05164 , etc . ) , and 5 . sex hormone metabolizing enzymes and the receptors ( P11511 , P31213 , ER , etc . ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene - environment interaction ) , opens the door to genotype applications for disease prevention practice .","DB00051 in juvenile rheumatoid arthritis / juvenile idiopathic arthritis . Chronic arthritis in childhood is the most common pediatric rheumatic disease and can lead to significant short - and long - term disability . P01375 is a cytokine involved in joint inflammation and destruction . It has been suggested that early and aggressive treatment leads to improved outcomes by ameliorating clinical signs and symptoms , inhibiting joint destruction and improving functional disability . The early and aggressive use of disease - modifying antirheumatic drugs and biologic response modifiers are key to achieving this goal . Anti - P01375 agents are effective biologic modifiers that have had a major impact on the clinical course of arthritis . DB00051 , a recombinant monoclonal antibody to P01375 , is emerging as a valuable new therapy for juvenile arthritis .","DB00051 - induced acute interstitial lung disease in a patient with rheumatoid arthritis . The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice . Anti - P01375 therapies have been increasingly used in refractory autoimmune diseases , especially rheumatoid arthritis , with promising results . However , the use of such therapies has been associated with an increased risk of developing other autoimmune diseases . In addition , the use of anti - P01375 agents can cause pulmonary complications , such as reactivation of mycobacterial and fungal infections , as well as sarcoidosis and other interstitial lung diseases ( ILDs ) . There is evidence of an association between ILD and the use of anti - P01375 agents , etanercept and infliximab in particular . DB00051 is the newest drug in this class , and some authors have suggested that its use might induce or exacerbate preexisting ILDs . In this study , we report the first case of acute ILD secondary to the use of adalimumab in Brazil , in a patient with rheumatoid arthritis and without a history of ILD .","Effective long - term control of refractory hidradenitis suppurativa with adalimumab after failure of conventional therapy . BACKGROUND : Hidradenitis suppurativa is a chronic suppurative condition featuring inflammatory nodules , fistulas and scars . It occurs predominantly in the axillae and groin . The disease is poorly responsive to any treatment and is connected with significant morbidity . Systemic therapy , including oral antibiotics , retinoids and antiandrogens , usually has only limited effect . Surgical treatment of affected areas is necessary in advanced stages . OBJECTIVES : Several reports support the beneficial effect of tumor necrosis factor - α ( P01375 - α ) antagonists for the treatment of severe hidradenitis suppurativa . By contrast with data on infliximab and etanercept , data describing the potential positive influence of adalimumab on disease outcome are limited and refer to only small cohorts of patients . METHODS : Eight patients with severe , recalcitrant hidradenitis were treated for 1 year with adalimumab in a standard regimen and were subsequently followed for 1 year . RESULTS : All patients improved within 4 - 6 weeks and laboratory parameters of P02741 ( CRP ) and leukocyte count reduced significantly during treatment . Three patients demonstrated long - lasting improvement and five showed recurrences several months after discontinuation of the therapy . The average recurrence - free interval was 9 . 5 months . CONCLUSIONS : DB00051 is suitable for the long - term treatment of hidradenitis suppurativa and presents a further conservative treatment approach .","[ Biologics in the early treatment of ankylosing spondylitis and related forms of spondyloarthritis ] . New pathogenetic insights have identified the key role of P01375 in inflammatory rheumatic diseases and have revolutionized the therapy of spondyloarthritides . P01375 - antagonists specifically inhibit the pro - inflammatory effects of P01375 . Clinical studies with infliximab ( Remicade ) , DB00005 ( Enbrel ) or DB00051 ( Humira ) in ankylosing spondylitis or related diseases demonstrate superior efficacy to conventional drugs like non - steroidal antirheumatic drugs or traditional disease modifying antirheumatic drugs .","Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK48___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK48___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK48___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK48___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK48___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .","DB00051 ( antitumour necrosis factor - α ) treatment of hidradenitis suppurativa ameliorates skin inflammation : an in situ and ex vivo study . BACKGROUND : Hidradenitis suppurativa ( HS ) is a difficult - to - manage disease . Randomized controlled trials with antitumour necrosis factor ( P01375 ) - α biologics have been conducted and in most studies disease activity was reduced . However , the mechanism of action in HS skin is so far unknown . OBJECTIVES : To assess whether anti - P01375 - α treatment affects in situ cytokine production and frequency of inflammatory cell populations in HS lesional skin . METHODS : Nine patients with HS , participating in a larger placebo - controlled , double - blind phase IIb clinical trial on the efficacy and safety of adalimumab in patients with moderate to severe HS ( M10 - 467 ) , were randomized and treated for 16weeks . In a mechanism - of - action substudy , biopsies were obtained at fixed time points pre - and post - treatment . One part of the biopsy was cultured for 24h for cytokine release in the culture medium , while another part was used for in situ analysis . RESULTS : Secretion of cytokines , including interleukin ( IL ) - 1β , Q07325 [ monokine induced by interferon - γ ( Q07325 ) ] , P22301 , IL - 11 , B - lymphocyte chemoattractant ( O43927 ) and Q16552 , was significantly elevated in HS . DB00051 treatment was associated with decreased production of cytokines in HS skin , especially IL - 1β , Q07325 ( Q07325 ) and O43927 . Treatment significantly reduced the number of CD11c +, P08571 + and P34810 + cells in HS lesional skin . The numbers of CD3 + and P01730 + T cells , and P11836 + and CD138 + B cells were also reduced by adalimumab treatment . CONCLUSIONS : DB00051 treatment inhibits important cytokines and inflammatory cell numbers in lesional HS skin , especially levels of IL - 1β and numbers of inflammatory CD11c + dendritic cells .","[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK88___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .","DB00051 ( P01375 α Inhibitor ) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient . DB00051 ( Humira ) is a tumour necrosis factor α ( P01375 α ) inhibitor that is approved for the treatment of rheumatoid arthritis , psoriasis , psoriatic arthritis , Crohn ' s disease , ankylosing spondylitis , and juvenile idiopathic arthritis ( Sullivan and Preda ( 2009 ) , Klinkhoff ( 2004 ) , and Medicare Australia ) . Use of P01375 α inhibitors is associated with the induction of autoimmunity ( systemic lupus erythematosus , vasculitis , and sarcoidosis or sarcoid - like granulomas ) ( Ramos - Casals et al . ( 2010 ) ) . We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab . He has renal biopsy proven IgA nephritis instead . Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure . He made a remarkable recovery after adalimumab cessation and steroid treatment . To our knowledge , this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab .","___MASK24___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK24___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .","The p65 ( RelA ) subunit of NF - kappaB interacts with the histone deacetylase ( HDAC ) corepressors Q13547 and Q92769 to negatively regulate gene expression . Regulation of NF - kappaB transactivation function is controlled at several levels , including interactions with coactivator proteins . Here we show that the transactivation function of NF - kappaB is also regulated through interaction of the p65 ( RelA ) subunit with histone deacetylase ( HDAC ) corepressor proteins . Our results show that inhibition of HDAC activity with trichostatin A ( P32119 ) results in an increase in both basal and induced expression of an integrated NF - kappaB - dependent reporter gene . Chromatin immunoprecipitation ( ChIP ) assays show that P32119 treatment causes hyperacetylation of the wild - type integrated NF - kappaB - dependent reporter but not of a mutant version in which the NF - kappaB binding sites were mutated . Expression of Q13547 and Q92769 repressed tumor necrosis factor ( P01375 ) - induced NF - kappaB - dependent gene expression . Consistent with this , we show that Q13547 and Q92769 target NF - kappaB through a direct association of Q13547 with the Rel homology domain of p65 . Q92769 does not interact with NF - kappaB directly but can regulate NF - kappaB activity through its association with Q13547 . Finally , we show that inhibition of HDAC activity with P32119 causes an increase in both basal and P01375 - induced expression of the NF - kappaB - regulated interleukin - 8 ( P10145 ) gene . Similar to the wild - type integrated NF - kappaB - dependent reporter , ChIP assays showed that P32119 treatment resulted in hyperacetylation of the P10145 promoter . These data indicate that the transactivation function of NF - kappaB is regulated in part through its association with HDAC corepressor proteins . Moreover , it suggests that the association of NF - kappaB with the Q13547 and Q92769 corepressor proteins functions to repress expression of NF - kappaB - regulated genes as well as to control the induced level of expression of these genes .","___MASK89___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","DB00051 in the management of Behçet ' s disease . Behçet ' s disease ( BD ) is a relapsing , systemic , inflammatory disorder that affects various organ systems . Most of the manifestations of BD are self - limiting , but ocular attacks are an exception . Gastrointestinal tract , central nervous system , and cardiovascular system manifestations are relatively infrequent but may be resistant to conventional immunosuppressive treatment and therefore life - threatening . P01375 alpha antagonists are increasingly being used in patients whose BD is inadequately controlled by standard immunosuppressive regimens . Most of the current experience regarding the treatment of refractory BD involves the use of infliximab ; however , adalimumab has also been successfully used in cases of BD refractory to both conventional therapy and infliximab . Compared with infliximab , adalimumab offers several other advantages , such as the ability to self - administer at home , better patient compliance , and an improved side effect profile . Here , we review clinical experience of the use of adalimumab to treat the serious manifestations of BD . DB00051 is a promising drug for the treatment of BD , and its randomized , prospective study in a large number of patients is warranted to fully determine its efficacy in the refractory BD setting .","Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .","DB00051 : new indication . Ankylosing spondylitis : just another P01375 alpha antagonist . No comparisons with other P01375 alpha antagonists .","Mucosal expression of basic fibroblastic growth factor , syndecan 1 and tumour necrosis factor - α in Crohn ' s disease in deep remission under treatment with anti - TNFα antibodies . BACKGROUND AND AIMS : Both inflammation and fibrosis may be detected in Crohn ' s disease ( CD ) . The molecular pattern of Basic Fibroblastic Growth Factor ( P09038 ) and P18827 ( SD1 ) expression is altered in stenosing CD , but we do not know what the behaviour of this teamwork factor is in CD in deep remission under treatment with anti - TNFα antibodies . Our aim was to compare the expression of P09038 , SD1 and P01375 - α in patients with CD in deep remission under treatment with DB00065 ( IFX ) or DB00051 ( P00813 ) and a control group of patients with active CD . METHODS : We assessed the expression of P09038 , SD1 and P01375 - α in 10 patients with active CD and in 28 patients with CD in sustained deep remission for at least 6 months . All patients underwent surveillance colonoscopy with biopsies , while receiving maintenance therapy with IFX or P00813 . Analysis was conducted by real - time reverse transcriptase PCR ( RT - PCR ) in biopsy samples . RESULTS : We found that P09038 , SD1 and P01375 - α were significantly reduced under treatment with anti - TNFα versus controls ( p = 0 . 000 ) . P09038 and SD1 expression were similar between IFX and P00813 patients ( p = 0 . 335 and p = 0 . 289 , respectively ) , while P01375 - α was significantly under - expressed in P00813 patients ( p = 0 . 008 ) . CONCLUSIONS : P09038 , SD1 and P01375 - α are significantly reduced in CD patients in deep remission under treatment with anti - TNFα , likely as an expression of optimal control of inflammation . The significance of the P01375 - α under - expression in patients under treatment with P00813 with respect to those under treatment with IFX should be elucidated in further studies .","Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK73___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","___MASK46___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK46___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK46___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .","Treatment of ankylosing spondylitis with P01375 blockers : a meta - analysis . Biological agents directed against tumor necrosis factor ( P01375 ) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non - steroidal anti - inflammatory drugs . To evaluate the efficacy and safety of the anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , and certolizumab for the treatment of ankylosing spondylitis , we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE , MEDLINE , Cochrane Controlled Trials Register and LILACS databases ( September / 2012 ) , manual literature search , and the gray literature . Study selections and data collection were performed by two independent reviewers , with disagreements solved by a third reviewer . The following outcomes were evaluated : ASAS 20 response , disease activity , physical function , vertebral mobility , adverse events , and withdraws . The meta - analysis was performed using the Review Manager (®) 5 . 1 software by applying the random effects model . Eighteen studies were included in this review . No study of certolizumab was included . Patients treated with anti - P01375 agents were more likely to display an ASAS 20 response after 12 / 14 weeks ( RR 2 . 21 ; 95 % CI 1 . 91 ; 2 . 56 ) and 24 weeks ( RR 2 . 68 ; 95 % CI 2 . 06 ; 3 . 48 ) compared with controls , which was also true for several other efficacy outcomes . Meta - analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks . DB00051 , infliximab , etanercept , and DB06674 can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis . Safety outcomes deserve further study , especially with respect to long - term follow - ups .","DB00051 , etanercept , infliximab , and the risk of tuberculosis : data from clinical trials , national registries , and postmarketing surveillance . This review evaluates the risk of tuberculosis ( TB ) , adherence with recommendations for TB prevention , and host - related risk in patients with rheumatoid arthritis ( RA ) , psoriatic arthritis , and ankylosing spondylitis receiving infliximab ( IFX ) , adalimumab ( P00813 ) , and etanercept ( DB01613 ) through an analysis of phase III randomized controlled trials ( RCT ) , postmarketing surveillance , and national registries . Ten ( 0 . 21 % ) TB cases occurred among 4590 patients in 16 RCT of IFX , 9 ( 0 . 12 % ) among 7009 patients in 21 RCT of P00813 , and 4 ( 0 . 05 % ) among 7741 patients in 26 RCT of DB01613 . Overall , 19 / 23 ( 83 % ) TB cases occurred in patients with RA . Data from national registries and postmarketing surveillance showed an increased risk of TB in patients receiving any of the 3 anti - tumor necrosis factor ( P01375 ) drugs , with a 3 - 4 times higher risk associated with IFX and P00813 than with DB01613 . Deviations from recommended TB prevention procedures were observed in up to 80 % of patients , and most registries did not include data on host - related risk factors for TB . TB occurrence was reduced in recent RCT but not in real - life practice . TB risk was lower for DB01613 than for monoclonal antibody anti - P01375 agents . More complete data collection , including host - related TB risk factors , is advisable to avoid biased results .","DB00051 - associated antiphospholipid syndrome : a case report and review of the literature . This study aims for the presentation of the first reported case of adalimumab - associated antiphospholipid syndrome ( APS ) and review of the literature on adalimumab - induced vasculitis and APS . A case of APS associated with adalimumab use in a 67 - year - old woman is reported . The English medical literature was reviewed for antitumor necrosis factor ( P01375 ) agents and their association with APS and vasculitis . DB00051 is a fully humanized monoclonal antibody targeted against P01375 alpha that is widely used in the treatment of rheumatoid arthritis , juvenile idiopathic arthritis , ankylosing spondylitis , psoriatic arthritis , psoriasis , and Crohn ' s disease . Literature review reveals several cases of anti - P01375 - induced vasculitis including cases associated with adalimumab . We report the first case of adalimumab - induced APS in a 67 - year - old woman who developed APS and vasculitis associated with de novo positive anti - cardiolipin ( aCL ) antibody following the third dose of adalimumab therapy for the treatment of spondyloarthropathy . This is the first case demonstrating that a short course of adalimumab therapy may induce immunoglobulin M aCL autoantibodies leading to APS . With the growing use of anti - P01375 medications in immune - mediated and inflammatory diseases , adalimumab and other anti - P01375 medications should be considered as a possible explanation for APS .","DB00051 therapy for refractory uveitis : results of a multicentre , open - label , prospective trial . OBJECTIVE : Tumour necrosis factor ( P01375 ) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases . We conducted a prospective , multicentre , open - label Phase II clinical trial to assess the effectiveness and safety of adalimumab , a fully human anti - P01375 monoclonal antibody , in treating refractory uveitis . METHODS : Subjects with non - infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled . Treatment outcome was ascertained by a composite endpoint comprised of visual acuity , intraocular inflammation , ability to taper immunosuppressives , and posterior segment imaging . Clinical response was defined by improvement in at least one parameter , worsening in none , and well controlled intraocular inflammation . Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks . RESULTS : Twenty - one of 31 patients ( 68 % ) were characterised as clinical responders at 10 weeks , of whom 12 patients ( 39 % ) exhibited durable response after 50 weeks . The most common reason for study termination was primary or secondary inefficacy . No patients experienced treatment - limiting toxicity clearly related to study therapy . CONCLUSIONS : DB00051 was safe and effective in 68 % of refractory uveitis patients 10 weeks after study enrolment , and maintained in 39 % after 1 year . Ongoing study is required to determine the place of adalimumab and other P01375 blockers in the treatment of uveitis .","Probable diffuse retinopathy caused by adalimumab in a patient with Crohn ' s disease . DB00051 is a tumor necrosis factor - α ( P01375 - α ) antagonist used to treat several immunologic diseases . It is believed that unexpected adverse events related to anti - P01375 drugs will occur as administration of this drug becomes more widespread . We report the case of a 37 - year - old woman who complained of nonspecific abnormalities of vision in both eyes one month after beginning treatment with adalimumab for Crohn ' s disease . The results of the initial ophthalmologic examination were normal . The visual fields showed diffuse and severe depression in both eyes . Other diseases that could have caused the visual field defects were ruled out . The results of electrophysiological tests were compatible with diffuse bilateral retinopathy . Treatment with adalimumab was discontinued . Six months later , visual field loss persists , although it has improved slightly . To our knowledge , this is the first report of diffuse retinopathy probable caused by systemic administration of adalimumab . This form of retinal toxicity should be considered in patients with disorders of vision treated with this drug .","Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and / or infliximab . To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis ( JIA ) who had failed treatment with etanercept and / or infliximab in a single paediatric rheumatology clinic . Patients with JIA with active polyarthritis refractory to metotrexate ( MTX ) ( > or = 20 mg / m2 / week ) for at least 3 months and to etanercept ( up to 1 mg / kg twice weekly ) and / or infliximab ( up to 10 mg / kg every 4 weeks ) for at least 6 months were included . All patients received adalimumab 24 mg / m2 / week concomitantly with MTX 7 . 5 - 10 mg / week . Evaluation of efficacy included improvement as defined by the P10323 paediatric 30 criteria , 50 % and 70 % improvement and remission . Six patients were included . Three patients met improvement criteria ; 50 % and 70 % improvement occurred in two children . Improvement was sustained for 12 , 24 and 36 months , respectively . Remission occurred in one patient . DB00051 was discontinued due to lack of efficacy in three patients . No side effects were observed . DB00051 appears to be effective and safe in patients with JIA refractory to other anti - P01375 agents . Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA .","DB00051 ( HUMIRA ) : a review . DB00051 ( HUMIRA , Abbott Laboratories ) is a new fully human P01375 monoclonal antibody recently approved for the treatment of rheumatoid arthritis and undergoing trials for use in treating other conditions , including psoriasis and psoriatic arthritis . This article reviews its mechanisms of action , clinical trial results , and related discussion .","Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .","Open - label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab . BACKGROUND : The aim of this study was to assess the clinical benefit and tolerability of adalimumab , a fully human monoclonal antibody to tumor necrosis factor ( P01375 ) , in patients with ulcerative colitis ( UC ) . METHODS : Patients with active UC , including those who had lost response or developed intolerance to the chimeric anti - P01375 antibody infliximab , were enrolled in a 24 - week uncontrolled trial . Patients were treated with subcutaneous adalimumab 160 mg at week 0 , 80 mg at week 2 , and 40 mg every other week starting at week 4 . After week 8 the dose could be escalated to 40 mg weekly for incomplete response . Outcome measures included clinical response and remission and mucosal healing . RESULTS : Twenty patients were enrolled , of whom 13 had previously received infliximab . Seven patients had dose escalation of adalimumab between weeks 8 and 16 , from 40 mg every other week to 40 mg weekly , due to incomplete response . The rates of clinical response were 25 % at week 8 and 50 % at week 24 . The rates of clinical remission were 5 % at week 8 and 20 % at week 24 . The rate of mucosal healing was 30 % at week 8 . The rates of clinical response and remission and mucosal healing were similar in infliximab - naïve and previously exposed patients . None of the patients experienced hypersensitivity reactions during treatment with adalimumab . CONCLUSIONS : DB00051 is well tolerated and appears to be a clinically beneficial option for patients with UC , including those who have previously lost their response to or can not tolerate infliximab .","Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti - tumor necrosis factor treatment during primary simian immunodeficiency virus infection . BACKGROUND : Human immunodeficiency virus ( HIV ) and simian immunodeficiency virus ( SIV ) infections induce robust , generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation , fibrotic damage of lymphoid tissues , and CD4 ⁺ T - cell loss , pathogenic processes that contribute to disease progression . METHODS : To better understand the contribution of tumor necrosis factor ( P01375 ) , a key regulator of acute inflammation , to lentiviral pathogenesis , rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab ( Humira ) , a human anti - P01375 monoclonal antibody . RESULTS : DB00051 did not affect plasma SIV RNA levels or measures of T - cell immune activation ( P28907 or Ki67 ) in peripheral blood or lymph node T cells . However , compared with untreated rhesus macaques , adalimumab - treated rhesus macaques showed attenuated expression of proinflammatory genes , decreased infiltration of polymorphonuclear cells into the T - cell zone of lymphoid tissues , and weaker antiinflammatory regulatory responses to SIV infection ( ie , fewer presumed alternatively activated [ ie , CD163 ⁺ ] macrophages , interleukin 10 - producing cells , and transforming growth factor β - producing cells ) , along with reduced lymphoid tissue fibrosis and better preservation of CD4 ⁺ T cells . CONCLUSIONS : While HIV / SIV replication drives pathogenesis , these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis , and they suggest that early modulation of the inflammatory response may help attenuate disease progression .","Long - term follow - up of adalimumab monotherapy for rheumatoid arthritis in Japanese patients : a report of six cases . We present six cases of patients with Japanese rheumatoid arthritis ( RA ) treated with a tumor necrosis factor ( P01375 ) - alpha blocking agent , adalimumab as monotherapy for 220 weeks . All six patients were women , and the median age was 54 . 0 ± 7 . 07 years old . The median duration of the disease was 7 . 43 ± 11 . 1 years , and the median disease activity score ( DAS28 - CRP ) was 5 . 35 ± 0 . 69 . Three of six patients were able to continue to receive this treatment for 220 weeks successfully , and the DAS28 - CRP decreased to 1 . 89 ± 0 . 75 . Two patients withdrew because of lack of efficacy , and one patient withdrew because of adverse events ( non - Hodgkin lymphoma ) . DB00051 resulted in a sustained clinical response in RA patients during 220 - week follow - up .","Usefulness of DB00051 for Treating a Case of Intestinal Behçet ' s Disease With Trisomy 8 Myelodysplastic Syndrome . Behçet ' s disease ( BD ) is a systemic vasculitis , while myelodysplastic syndrome ( P43034 ) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis . Some studies suggest a relationship between P43034 and BD , especially intestinal BD , and trisomy 8 seems to play an important role in both diseases . There are several reports on patients with BD comorbid with P43034 involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies . P01375 ( P01375 ) - α is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis , inflammatory bowel disease , and BD . In addition , P01375 - α plays an important role in the pathophysiology of P43034 by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal P28906 + cells . Recent clinical reports demonstrate the favorable effect of P01375 - α antagonists in patients with refractory intestinal BD and in those with P43034 . We present the case of a patient with intestinal BD and P43034 involving trisomy 8 who was successfully treated with adalimumab .","Monomeric IgA can be produced in planta as efficient as IgG , yet receives different N - glycans . The unique features of IgA , such as the ability to recruit neutrophils and suppress the inflammatory responses mediated by IgG and IgE , make it a promising antibody isotype for several therapeutic applications . However , in contrast to IgG , reports on plant production of IgA are scarce . We produced IgA1κ and IgG1κ versions of three therapeutic antibodies directed against pro - inflammatory cytokines in Nicotiana benthamiana : DB00065 and DB00051 , directed against P01375 - α , and Ustekinumab , directed against the interleukin - 12p40 subunit . We evaluated antibody yield , quality and N - glycosylation . All six antibodies had comparable levels of expression between 3 . 5 and 9 % of total soluble protein content and were shown to have neutralizing activity in a cell - based assay . However , IgA1κ - based DB00051 and Ustekinumab were poorly secreted compared to their IgG counterparts . DB00065 was poorly secreted regardless of isotype backbone . This corresponded with the observation that both IgA1κ - and IgG1κ - based DB00065 were enriched in oligomannose - type N - glycan structures . For IgG1κ - based Ustekinumab and DB00051 , the major N - glycan type was the typical plant complex N - glycan , biantennary with terminal N - acetylglucosamine , β1 , 2 - xylose and core α1 , 3 - fucose . In contrast , the major N - glycan on the IgA - based antibodies was xylosylated , but lacked core α1 , 3 - fucose and one terminal N - acetylglucosamine . This type of N - glycan occurs usually in marginal percentages in plants and was never shown to be the main fraction of a plant - produced recombinant protein . Our data demonstrate that the antibody isotype may have a profound influence on the type of N - glycan an antibody receives .","DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .","Onychomycosis in patients of nail psoriasis on biologic therapy : a randomized , prospective open label study comparing DB00005 , DB00065 and DB00051 . INTRODUCTION AND OBJECTIVE : The association between patients of psoriasis on anti P01375 therapy and onychomycosis has not been explored . The aim of this study was to determine the rate of onychomycosis in patients of psoriasis with nail involvement on anti P01375 therapy . MATERIALS AND METHODS : All patients of psoriasis with nail involvement seen between February 2007 - July 2012 were examined . All the patients with negative nail scrapings for fungus were enrolled . Patients found fit for biologics after investigations were randomly divided into 3 groups ( Group A : DB00065 , Group B : DB00005 and Group C : DB00051 ) . The patients were followed up every 4 weeks for 24 weeks . Repeat nail scrapings were done at week 24 . The results were compared with controls . RESULT : In total , 315 ( 178 males and 137 females ) patients were enrolled . The mean age was 37 . 5 ± 11 . 4 years . The results for scraping for fungus at the end of 24 weeks were as follows : 33 % ( 33 / 100 ) in patients on DB00065 followed by 15 . 45 % ( 17 / 110 ) , 13 . 33 % ( 14 / 105 ) in patients on treatment with DB00005 and DB00051 respectively as compared to 13 . 89 % ( 25 / 180 ) among controls . Onychomycosis in association with nail psoriasis was more common in males . CONCLUSION : This study revealed statistically significant association between fungal infections of the nail in patients of psoriasis on treatment with DB00065 .","DB00051 : a new tumor necrosis factor antagonist and the treatment of Crohn ' s disease . Antibody - neutralization studies have implicated tumor necrosis factor - alpha ( P01375 ) and IL - 12 p40 in the pathogenesis of Crohn ' s disease ( CD ) . Many randomized controlled trials ( RCTs ) have demonstrated the efficacy of infliximab , a chimeric monoclonal antibody to P01375 , in inducing and maintaining disease remission in patients with moderate to severe CD , including those with draining fistulas . However , infliximab is administered intravenously and is associated with immunological reactions and development of antibodies , and hence reduced efficacy . In this article , we describe the efficacy and safety profiles of a newly available recombinant , fully humanized , subcutaneously - administered , anti - P01375 monoclonal antibody , adalimumab ( Humira ) in patients with moderate to severe CD . Many recent RCTs have shown that adalimumab is not only similar to infliximab in the mode of action , efficacy , and safety , but it has the advantages of causing less anaphylactic or immunological reactions , being administered by the subcutaneous route , less need for hospitalization , and a half - life of 2 weeks that allows every other week dosage . DB00051 has also shown some efficacy in infliximab - intolerant or resistant cases . Therefore , it represents a new horizon in the treatment of CD patients , and may reduce the number of patients who require surgical intervention .","DB00051 , a fully human anti - P01375 monoclonal antibody , treatment does not influence experimental UV response in the skin of rheumatoid arthritis patients . P01375 is known to play an important role in UV - induced immunomodulation and photodamage . It plays a role in UVB - mediated induction of apoptosis and is a strong inducer of the c - Jun N - terminal kinase ( JNK ) pathway , which eventually leads to the loss of dermal collagen and elastin content . Recently chimeric anti - P01375 has been introduced as a therapy for rheumatoid arthritis . The aim of the present study was to investigate the effect of anti - P01375 treatment on UV - induced DNA damage , apoptosis , and induction of matrix metallo proteinases . Twelve patients with rheumatoid arthritis were included and irradiated with 2 Q9UQD0 broadband UVB before and after administration of 0 . 5 mg / kg anti - P01375 monoclonal antibody . Twenty - four hours after irradiation biopsies were taken . Frozen and paraffin sections were stained for p53 , c - Jun , phosphorylated c - Jun , sunburn cells and P03956 . No significant changes were observed in the expression of p53 and sunburn cells and P03956 content after treatment with anti - P01375 , whereas a slight but significant decrease in c - Jun and phosphorylated c - Jun expression was noted ( P = 0 . 0250 and P = 0 . 0431 , respectively ) . Our results showed no influence of anti - P01375 on UV response at therapeutic doses in patients with rheumatoid arthritis .","Pharmacoeconomics of adalimumab for rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis and Crohn ' s disease . DB00051 is a monoclonal antibody that inhibits P01375 , an osteogenic cytokine involved in the pathogenesis of chronic , disabling inflammatory diseases . DB00051 is indicated for rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis and Crohn ' s disease . It alleviates the symptoms of these diseases , prevents disease progression in some patients and , in the case of Crohn ' s disease , induces and maintains remission . Compared with traditional disease - modifying antirheumatic drugs that offer significantly less benefit , adalimumab is much more costly . However , most studies to date demonstrate the cost - effectiveness of adalimumab treatment . Cost - effectiveness data for newer indications of adalimumab , including ankylosing spondylitis and Crohn ' s disease , are needed . As longer term data for adalimumab become available , the cost - effectiveness data will have greater precision .","A human monoclonal anti - P01375 alpha antibody ( adalimumab ) reduces airway inflammation and ameliorates lung histology in a murine model of acute asthma . BACKGROUND : A few experimental studies related to asthma have unveiled the beneficial effects of P01375 alpha blocking agents on the airway histology , cytokine levels in bronchoalveolar lavage and bronchial hyper - responsiveness . In the current study , we aimed to assess the effect of adalimumab on the inflammation and histology of asthma in a murine model . METHOD : Twelve - week - old BALB / c ( H - 2d / d ) female rats ( n = 18 ) were allocated into three groups , including ( group I ) control ( phosphate - buffered saline was implemented ) , ( group II ) asthma induced with OVA ( n = 6 ) , and ( group III ) asthma induced with OVA + treated with adalimumab ( n = 6 ) . Rats were executed on the 28th day of the study . The lung samples were fixed in 10 % neutral buffered formalin . Lung parenchyma , alveolus , peribronchial and perivascular inflammation were assessed . Lung pathological scoring was performed . RESULT : Severity of lung damage was found to be reduced significantly in the asthma induced with OVA + treated with adalimumab group . When compared with the untreated group , adalimumab significantly reduced the inflammatory cells around the bronchi and bronchioles , and reduced inflammation of the alveolar wall and alveolar wall thickness as well ( median score = 1 , p = 0 . 52 ) . Peribronchial smooth muscle hypertrophy and oedema were significantly reduced after adalimumab administration . CONCLUSION : DB00051 ( a human monoclonal anti - P01375 alpha antibody ) therapy significantly reduced the severity of lung damage by decreasing cellular infiltration and improvement on the lung histology in a murine model of acute asthma .","DB00051 for the treatment of ankylosing spondylitis . Ankylosing spondylitis is a chronic inflammatory disease , with a prevalence of approximately 0 . 5 % , which starts in the third decade of life . Treatment was , until recently , limited . Conventional disease - modifying drugs are not effective for the spinal manifestations , and NSAIDs and physical therapy were the standard treatment , without any other options for patients who did not respond to this treatment . Therefore , the high efficacy of the new group of P01375 - blockers for the treatment of active ankylosing spondylitis represents a breakthrough for NSAID - refractory patients . Following the introduction of the two P01375 - blockers , infliximab and etanercept , the fully humanized , anti - P01375 monoclonal antibody adalimumab is now the third product that has been approved for the treatment of ankylosing spondylitis . DB00051 is given subcutaneously every 2 weeks at a dose of 40 mg . In open and placebo - controlled trials , the drug was shown to be safe and effective in ankylosing spondylitis patients . Long - term treatment data of up to 2 years are now available , confirming efficacy and acceptable safety .","DB00051 treatment in Crohn ' s disease does not induce early changes in regulatory T cells . OBJECTIVE : Anti - P01375 - α antibodies has been suggested to modulate regulatory T cell ( Treg ) percentages in rheumatoid arthritis , but results from studies of Crohn ' s disease ( CD ) are conflicting . We investigated dynamic changes of circulating Tregs in CD during treatment with the anti - P01375 - α - antibody adalimumab ( Humira ® , Abbott Laboratories A / S , Emdrupvej 28C , DK - 2100 Copenhagen ) . MATERIAL AND METHODS : Blood samples from 26 CD patients were analysed using flow cytometry before and 1 and 26 weeks after initiation of adalimumab treatment to determine the percentage of Tregs among P01730 + T cells . RESULTS : In spite of a significant decline in disease activity scores and biochemical markers of inflammation , during the first week of treatment , we did not observe early modulating effects of adalimumab on Treg percentages . However , we found a long - term increase in Treg percentages in responders who had low Treg percentages ( < 5 % ) at baseline ( p = 0 . 04 ) . Treg percentage was inversely associated with disease activity ( CD activity index or CDAI ) ( Spearman ' s rank correlation , ρ = - 0 . 47 , p = 0 . 02 ) . High Treg percentages among P01730 + T cells at baseline predicted clinical response to adalimumab . CONCLUSIONS : DB00051 treatment did not induce early modulatory effects on Treg percentage , even in responders . This finding suggests that adalimumab does not have a direct or selective effect on Tregs . However , Treg percentage was associated with disease activity and high Treg percentage predicted response to adalimumab .","Refractory dissecting Cellulitis of the Scalp Successfully controlled with DB00051 . Dissecting cellulitis of the scalp ( DB00260 ) is an uncommon inflammatory disease that often results in scarring alopecia . Numerous therapies have either proved ineffective or only temporarily effective in the management of this condition . Recent reports show adequate responses to tumor necrosis factor ( P01375 ) inhibitors in cases of DB00260 . We report a case of severe recalcitrant DB00260 successfully treated with adalimumab .","Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .","[ Differences in pharmacology of tumor necrosis factor ( P01375 ) antagonists ] . The commercially available inhibitors of P01375 are constituted by two classes of molecules : the soluble receptors ( DB00005 : Amgen Inc . Wyeth ) and the monoclonal antibodies ( DB00051 : Abbott Laboratories and DB00065 : Centocor , Inc . ) . The differences in their molecular structure , mechanism of action , pharmacokinetics ( PK ) and pharmacodynamics ( PD ) are discussed , along with the differences concerning dose , administration regimens , drug concentrations and pharmacological interactions . In order to explain the clinical differences observed when these agents are used in the \" real world \" , which can arise from the respective PK characteristics ( kinetics , route and frequency of administration , type of P01375 binding , effects on cytokines ) and PD responses and peculiar mechanisms of action , with distinctive immune function ( LFTα inactivation ; apoptosis induction , P01375 immunoprecipitation , C1q binding and CDC induction ; Fcγ cross - linking and ADCC induction ) , the dynamics of interaction of the two classes of neutralizing molecules with P01375 , and the ability in restoring P01375 homeostasis , are outlined .","P01375 inhibitors to treat ulcerative colitis in a metastatic breast cancer patient : a case report and literature review . DB00051 ( P00813 ) is a tumor necrosis factor ( P01375 ) inhibitor , used for the treatment of inflammatory bowel disease . Previous studies have reported an increased risk of cancer following exposure to P01375 inhibitors , but little has been reported for patients with cancer receiving P01375 - inhibitor treatment . We present a female patient with metastatic breast cancer and ulcerative colitis ( UC ) who was treated with P00813 . A 54 - year - old African American female with a past history of left - sided breast cancer ( BC ) diagnosed at age 30 was initially treated with left - breast lumpectomy , axillary dissection , followed by chemotherapy and radiation therapy . Years after initial diagnosis , she developed recurrent , bilateral BC and had bilateral mastectomy . Subsequent restaging computed tomography ( CT ) scan demonstrated distant metastases to the bone and lymph nodes . Three years into her treatment of metastatic breast cancer , she was diagnosed with UC by colonoscopy . Her UC was not controlled for 5 mo with 5 - aminosalicylates . Subcutaneous P00813 was started and resulted in dramatic improvement of UC . Four months after starting P00813 , along with ongoing chemotherapy , restaging CT scan showed resolution of the previously seen metastatic lymph nodes . Bone scan and follow - up positron emission tomography / CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on P00813 . While P01375 - α inhibitors could theoretically promote further metastases in patients with prior cancer , this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after P00813 initiation for UC .","Serum cytokine profile in adalimumab - treated refractory uveitis patients : decreased Q9GZX6 correlates with clinical responses . PURPOSE : To report the effect of adalimumab on serum cytokines in chronic refractory uveitis . METHODS : Prospective study on the effects of adalimumab on serum cytokine levels at different time points in a cohort of 12 refractory chronic uveitis patients . Results were analyzed according to clinical outcomes and compared with systemic steroid - treated recurrent uveitis patients . RESULTS : Before treatment , patients exhibited significantly increased IL - 1β , P05231 , P01375 α , IL - 12 P08133 , P22301 , and Q9GZX6 . DB00051 significantly decreased P05231 , and IL - 12p70 at early time points ( after 1 month of treatment ) . DB00051 effects on P22301 and Q9GZX6 appeared later ( after 6 months of treatment ) . IL - 1β , Q16552 , and P01375 α were not modified at any time point . Only decreased Q9GZX6 serum levels correlated with disease activity ( p = 0 . 011 ) . These effects were not observed in steroid - treated patients . CONCLUSIONS : DB00051 induced drug - specific and time - dependent declines in serum levels of particular cytokines , although only Q9GZX6 correlated with disease activity in 10 out 12 patients .","DB00051 : a review of its use in adult patients with rheumatoid arthritis . DB00051 ( Humira ) is a recombinant , fully human anti - tumor necrosis factor ( P01375 ) monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe , active rheumatoid arthritis ( RA ) . In combination with methotrexate or standard antirheumatic therapy or as monotherapy , adalimumab effectively reduced signs and symptoms of RA , induced remission , improved physical function and inhibited the progression of structural damage in several randomized , double - blind , placebo - controlled phase III trials . The drug was generally well tolerated , with most adverse events being mild to moderate , and the serious adverse events profile being similar to that generally seen in patients with RA not receiving anti - P01375 agents . DB00051 was at least as cost effective as other anti - P01375 agents used in the therapy of RA , and provided significant improvements in patients ' health - related quality of life . Overall , adalimumab in combination with methotrexate or standard antirheumatic therapy is valuable as a first - line therapeutic option in patients with early , aggressive RA , and a second - line therapeutic option in patients with long - standing , moderate to severe RA . For the latter indication , adalimumab may also be used as monotherapy .","___MASK6___ attenuates inflammation and oxidative stress in pelvic ganglia neurons after bilateral cavernosal nerve damage . Erectile dysfunction is a common complication for patients undergoing surgeries for prostate , bladder , and colorectal cancers , due to damage of the nerves associated with the major pelvic ganglia ( P29372 ) . Functional re - innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype . O76074 inhibitors ( PDE5i ) have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage ( BCNR ) by up - regulating the expression of neurotrophic factors in P29372 . However , little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR . This study aimed to investigate the changes in gene and protein expression profiles of inflammatory , anti - inflammatory cytokines and oxidative stress related - pathways in P29372 neurons after BCNR and subsequent treatment with sildenafil . Our results showed that BCNR in Fisher - 344 rats promoted up - regulation of cytokines ( interleukin - 1 ( IL - 1 ) β , P05231 , P22301 , transforming growth factor β 1 ( TGFβ1 ) , and oxidative stress factors ( DB02701 adenine dinucleotide phosphate ( NADPH ) oxidase , P05164 ( P05164 ) , inducible nitric oxide synthase ( P35228 ) , P01375 receptor superfamily member 5 ( P25942 ) that were normalized by sildenafil treatment given in the drinking water . In summary , PDE5i can attenuate the production of damaging factors and can up - regulate the expression of beneficial factors in the P29372 that may ameliorate neuropathic pain , promote neuroprotection , and favor nerve regeneration .","DB00051 in recalcitrant severe psoriasis associated with atopic dermatitis . P01375 - α inhibitors may induce various cutaneous side effects including eczematous - like lesions . The management of such side effects can be challenging . Herein , we report a case of a 55 - year - old man who had a flare - up and subsequent improvement of atopic dermatitis during treatment of severe psoriasis with adalimumab .","DB00051 , a human anti - P01375 monoclonal antibody , outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis : the HOPEFUL 1 study . OBJECTIVES : To evaluate the efficacy and safety of adalimumab + methotrexate ( MTX ) in Japanese patients with early rheumatoid arthritis ( RA ) who had not previously received MTX or biologics . METHODS : This randomised , double - blind , placebo - controlled , multicentre study evaluated adalimumab 40 mg every other week + MTX 6 - 8 mg every week versus MTX 6 - 8 mg every week alone for 26 weeks in patients with RA ( ≤ 2 - year duration ) . The primary endpoint was inhibition of radiographic progression ( change ( Δ ) from baseline in modified total Sharp score ( mTSS ) ) at week 26 . RESULTS : A total of 171 patients received adalimumab + MTX ( mean dose , 6 . 2 ± 0 . 8 mg / week ) and 163 patients received MTX alone ( mean dose , 6 . 6 ± 0 . 6 mg / week , p < 0 . 001 ) . The mean RA duration was 0 . 3 years and 315 ( 94 . 3 % ) had high disease activity ( DAS28 > 5 . 1 ) . DB00051 + MTX significantly inhibited radiographic progression at week 26 versus MTX alone ( ΔmTSS , 1 . 5 ± 6 . 1 vs 2 . 4 ± 3 . 2 , respectively ; p < 0 . 001 ) . Significantly more patients in the adalimumab + MTX group ( 62 . 0 % ) did not show radiographic progression ( ΔmTSS ≤ 0 . 5 ) versus the MTX alone group ( 35 . 4 % ; p < 0 . 001 ) . Patients treated with adalimumab + MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission , using various definitions , at 26 weeks versus MTX alone . Combination therapy was well tolerated , and no new safety signals were observed . CONCLUSIONS : DB00051 in combination with low - dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity .","Alopecia areata universalis elicited during treatment with adalimumab . DB00051 is a fully humanized recombinant anti - tumour - necrosis - factor ( P01375 ) monoclonal antibody which has been approved for rheumatoid arthritis , active ankylosing spondylitis , psoriatic arthritis and Crohn ' s disease . We report a case of alopecia areata ( AA ) universalis occurring 6 months after administration of adalimumab monotherapy in a patient with a long - standing history of psoriatic arthritis and psoriasis . The diagnosis was confirmed by a scalp biopsy which showed a peribulbar infiltrate of both P01730 + and CD8 + T cells , CD1a + dendritic cells as well as P34810 + and Q86VB7 + macrophages . In addition , immunofluorescence staining for P01375 was found in the mononuclear cell infiltrate . This case suggests a complex role of P01375 in the induction of AA .","Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK29___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy ."],"string":"[\n \"[ The importance of biologicals in the treatment of SoJIA ] . Systemic onset juvenile idiopathic arthritis ( SoJIA ) remains difficult to treat . In addition to conventional antirheumatic therapy with non - steroidal antirheumatic drugs ( NSARDs ) , steroids or disease - modifying antirheumatic drugs ( DMARDs ) , biologicals offer a new therapeutic approach for this disease in that they are able to target pathogenically relevant cytokines and effector cells . Some biologicals are already approved for use in children with rheumatic disease . In order to assess the currently available data on the use of biologicals in SoJIA , we performed a Medline search for the period 2005 to March 2010 , including the MeSH terms \\\" SoJIA \\\" , \\\" systemic juvenile idiopathic arthritis \\\" and \\\" biologicals \\\" , as well as an NIH study registry search . At Present there are scant and unconvincing data on the use of DB00005 or DB00051 for the treatment of SoJIA . No results are published on the use of DB00065 or other new P01375 inhibitors . The inhibition of IL - 1 or P05231 shows promising results . Data on the efficacy of DB01281 is limited due to very low numbers of SoJIA patients in the studies . Further studies on the use of biologicals in SoJIA while taking individual factors into consideration are required . The long - term safety of all biologicals should be investigated in prospective registers .\",\n \"DB00051 - induced noncaseating granuloma in the bone marrow of a patient being treated for rheumatoid arthritis . Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration , primarily of the lungs and lymphatic system . While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed , the more widely used infliximab has demonstrated clear efficacy in this disease . The association between tumor necrosis factor ( P01375 ) - inhibitors and noncaseating granulomas in the lung has been reported in literature . With the exception of one patient treated with adalimumab , who developed pulmonary granuloma , the remaining patients described in literature were treated with etanercept . The current case study is , to our knowledge , the first to describe adalimumab - induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although P01375 - inhibitors are used in the treatment of granulomatous disorders , their use should be carefully monitored as , in rare cases , P01375 - inhibitors may leave sufficient cytokine activation to support granuloma formation .\",\n \"The therapeutic potential of P01375 antagonists for skin psoriasis comorbidities . IMPORTANCE OF THE FIELD : Alopecia , psoriatic arthritis , the metabolic syndrome , inflammatory bowel diseases and cardiovascular diseases may occur as skin psoriatic comorbidities . P01375 antagonists are used to treat psoriasis . DB00051 is one of the recognized active agents for this indication . AREAS COVERED IN THIS REVIEW : The current peer - reviewed publications and presentation of original findings . WHAT THE READER WILL GAIN : DB00051 is active on recalcitrant psoriasis and some of its comorbidities , particularly arthropathies and Crohn ' s disease . However , the progression of the radiological alterations is limited with regression of the bony erosions . Psoriatic enthesopathy also regresses . Mortality associated with psoriasis arthropathy is on the decline . Crohn ' s disease , the most frequent inflammatory bowel comorbidity of psoriasis , is responsive to adalimumab . The effect of adalimumab on the metabolic syndrome and cardiovascular involvement is more erratic . The spectacular effects of adalimumab may be associated with some adverse effects . In particular , despite a marked reduction in the psoriasis area - and - severity index ( PASI ) score some new acute lesions of cutaneous psoriasis may develop corresponding to paradoxical psoriasis . Other potential adverse effects include infections , granulomas , rapid growth of cancers and occurrence of lymphomas . TAKE HOME MESSAGE : DB00051 frequently controls moderate - to - severe forms of cutaneous psoriasis and some of its comorbidities .\",\n \"[ Cutaneous infection due to Mycobacterium chelonae during anti - P01375 therapy ] . BACKGROUND : Mycobacterium chelonae is a ubiquitous , rapidly growing , opportunistic , non - tuberculous mycobacterium that can cause skin and bone tissue infections . We report a case of cutaneous infection due to M . chelonae following anti - P01375 therapy . CASE REPORT : A 70 - year - old woman with a medical history of rheumatoid arthritis was admitted for several purple nodular cutaneous lesions on her right leg evolving for 2 months . At admission , she was on prednisone , methotrexate and adalimumab for her rheumatoid arthritis . Skin lesions appeared 5 days before etanercept , which was taken for 5 months before being discontinued for adalimumab . Both the histopathological examination and bacterial culture of involved skin showed the presence of M . chelonae . DB00051 was immediately discontinued and a combination of amoxicillin - clavulanic acid and tigecyclin was started . DISCUSSION : P01375 plays a pivotal role in immune reaction to intracellular pathogens . Very few cases of cutaneous infection involving M . chelonae in association with an anti - P01375 therapy have been reported in the literature . To our knowledge , this is the first case occurring during treatment with etanercept and symptoms worsened with the introduction of adalimumab . In addition , this case underlines the difficulties of effectively treating this mycobacterium .\",\n \"DB00051 for the treatment of rheumatoid arthritis . Rheumatoid arthritis ( RA ) is characterized by massive synovial proliferation resulting in joint destruction and deterioration in quality of life . P01375 has been implicated in the central pathogenesis of RA , and its blockade ? by anti - P01375 monoclonal antibodies ( infliximab and adalimumab ) and the soluble P01375 receptor ( etanercept ) has caused a paradigm shift in the treatment of RA . DB00051 can be used alone or concomitantly with methotrexate , but the combination of both is significantly superior to monotherapy with adalimumab . DB00051 can not only ameliorate the signs and symptoms of the disease , but can also inhibit the progression of joint destruction and improve quality of life . Approximately 50 % of patients with early , aggressive RA receiving combination therapy with adalimumab and methotrexate can be introduced into disease remission ( disease activity score < 2 . 6 ) . DB00051 is even effective in patients with RA treated previously with other biologics . Long - term treatment with adalimumab is safe and well tolerated in patients with RA .\",\n \"[ DB00051 ] . Recently , the anti - tumor necrosis factor ( P01375 )- alpha treatments for RA are successful in alleviating the discomforts associated with swollen , painful joints . DB00051 ( D2E7 ) is the first fully human anti - P01375 monoclonal antibody ( IgG1 ) . Therefore , it has low immunogenicity and possibly greater therapeutic potential compared with other anti - P01375 antibodies . This is administered subcutaneously at a dose of 1 mg / kg biweekly . The combined therapy with methotrexate ( MTX ) is efficacious to the patients who receive MTX alone and are insufficient to control symptoms of RA . The therapeutic effects become evident within 24 hours to one week after administration and reached maximum effect after one to two weeks . In adalimumab recipient , radiographic progression is also controlled and serum levels of matrix metalloproteinase - 1 ( P03956 ) and P08254 decrease . For patients with RA , the treatment of adalimumab will set a new standard for symptom control and joint protection .\",\n \"Human anti - tumor necrosis factor monoclonal antibody ( adalimumab ) in Crohn ' s disease : the CLASSIC - I trial . BACKGROUND & AIMS : P01375 blockade has been shown to be an effective treatment strategy in Crohn ' s disease ( CD ) . DB00051 is a human immunoglobulin P55008 ( IgG ( 1 ) ) monoclonal antibody targeting tumor necrosis factor ( P01375 ) . A randomized , double - blind , placebo - controlled , dose - ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD . METHODS : A total of 299 patients with moderate to severe CD naive to anti - P01375 therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg / 20 mg , 80 mg / 40 mg , or 160 mg / 80 mg or placebo . The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 ( defined as a Crohn ' s Disease Activity Index score < 150 points ) among the 80 mg / 40 mg , 160 mg / 80 mg , and placebo groups . RESULTS : The rates of remission at week 4 in the adalimumab 40 mg / 20 mg , 80 mg / 40 mg , and 160 mg / 80 mg groups were 18 % ( P = . 36 ) , 24 % ( P = . 06 ) , and 36 % ( P = . 001 ) , respectively , and 12 % in the placebo group . Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions , which were more common in adalimumab - treated patients . CONCLUSIONS : DB00051 was superior to placebo for induction of remission in patients with moderate to severe Crohn ' s disease naive to anti - P01375 therapy . The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2 . DB00051 was well tolerated .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK55___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"Selective targeting of the repressive transcription factors P25490 and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 (+) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ). cMyc and P25490 are two transcription factors that are recruited as part of well - described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 , Q92769 , O15379 , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( DB02546 ) enhanced the increase in LTR transcription in cells that were depleted of P25490 . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency .\",\n \"[ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1 . carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 , etc . ) , 2 . DNA repair enzymes ( O15527 , P18887 , P18074 , etc . ) , 3 . DNA synthesis and methylation ( P42898 , MS , etc . ) , 4 . cytokines and inflammation - related enzymes ( IL - 1B , P01375 - A , P05164 , etc . ) , and 5 . sex hormone metabolizing enzymes and the receptors ( P11511 , P31213 , ER , etc . ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene - environment interaction ) , opens the door to genotype applications for disease prevention practice .\",\n \"DB00051 in juvenile rheumatoid arthritis / juvenile idiopathic arthritis . Chronic arthritis in childhood is the most common pediatric rheumatic disease and can lead to significant short - and long - term disability . P01375 is a cytokine involved in joint inflammation and destruction . It has been suggested that early and aggressive treatment leads to improved outcomes by ameliorating clinical signs and symptoms , inhibiting joint destruction and improving functional disability . The early and aggressive use of disease - modifying antirheumatic drugs and biologic response modifiers are key to achieving this goal . Anti - P01375 agents are effective biologic modifiers that have had a major impact on the clinical course of arthritis . DB00051 , a recombinant monoclonal antibody to P01375 , is emerging as a valuable new therapy for juvenile arthritis .\",\n \"DB00051 - induced acute interstitial lung disease in a patient with rheumatoid arthritis . The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice . Anti - P01375 therapies have been increasingly used in refractory autoimmune diseases , especially rheumatoid arthritis , with promising results . However , the use of such therapies has been associated with an increased risk of developing other autoimmune diseases . In addition , the use of anti - P01375 agents can cause pulmonary complications , such as reactivation of mycobacterial and fungal infections , as well as sarcoidosis and other interstitial lung diseases ( ILDs ) . There is evidence of an association between ILD and the use of anti - P01375 agents , etanercept and infliximab in particular . DB00051 is the newest drug in this class , and some authors have suggested that its use might induce or exacerbate preexisting ILDs . In this study , we report the first case of acute ILD secondary to the use of adalimumab in Brazil , in a patient with rheumatoid arthritis and without a history of ILD .\",\n \"Effective long - term control of refractory hidradenitis suppurativa with adalimumab after failure of conventional therapy . BACKGROUND : Hidradenitis suppurativa is a chronic suppurative condition featuring inflammatory nodules , fistulas and scars . It occurs predominantly in the axillae and groin . The disease is poorly responsive to any treatment and is connected with significant morbidity . Systemic therapy , including oral antibiotics , retinoids and antiandrogens , usually has only limited effect . Surgical treatment of affected areas is necessary in advanced stages . OBJECTIVES : Several reports support the beneficial effect of tumor necrosis factor - α ( P01375 - α ) antagonists for the treatment of severe hidradenitis suppurativa . By contrast with data on infliximab and etanercept , data describing the potential positive influence of adalimumab on disease outcome are limited and refer to only small cohorts of patients . METHODS : Eight patients with severe , recalcitrant hidradenitis were treated for 1 year with adalimumab in a standard regimen and were subsequently followed for 1 year . RESULTS : All patients improved within 4 - 6 weeks and laboratory parameters of P02741 ( CRP ) and leukocyte count reduced significantly during treatment . Three patients demonstrated long - lasting improvement and five showed recurrences several months after discontinuation of the therapy . The average recurrence - free interval was 9 . 5 months . CONCLUSIONS : DB00051 is suitable for the long - term treatment of hidradenitis suppurativa and presents a further conservative treatment approach .\",\n \"[ Biologics in the early treatment of ankylosing spondylitis and related forms of spondyloarthritis ] . New pathogenetic insights have identified the key role of P01375 in inflammatory rheumatic diseases and have revolutionized the therapy of spondyloarthritides . P01375 - antagonists specifically inhibit the pro - inflammatory effects of P01375 . Clinical studies with infliximab ( Remicade ) , DB00005 ( Enbrel ) or DB00051 ( Humira ) in ankylosing spondylitis or related diseases demonstrate superior efficacy to conventional drugs like non - steroidal antirheumatic drugs or traditional disease modifying antirheumatic drugs .\",\n \"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK48___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK48___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK48___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK48___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK48___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .\",\n \"DB00051 ( antitumour necrosis factor - α ) treatment of hidradenitis suppurativa ameliorates skin inflammation : an in situ and ex vivo study . BACKGROUND : Hidradenitis suppurativa ( HS ) is a difficult - to - manage disease . Randomized controlled trials with antitumour necrosis factor ( P01375 ) - α biologics have been conducted and in most studies disease activity was reduced . However , the mechanism of action in HS skin is so far unknown . OBJECTIVES : To assess whether anti - P01375 - α treatment affects in situ cytokine production and frequency of inflammatory cell populations in HS lesional skin . METHODS : Nine patients with HS , participating in a larger placebo - controlled , double - blind phase IIb clinical trial on the efficacy and safety of adalimumab in patients with moderate to severe HS ( M10 - 467 ) , were randomized and treated for 16weeks . In a mechanism - of - action substudy , biopsies were obtained at fixed time points pre - and post - treatment . One part of the biopsy was cultured for 24h for cytokine release in the culture medium , while another part was used for in situ analysis . RESULTS : Secretion of cytokines , including interleukin ( IL ) - 1β , Q07325 [ monokine induced by interferon - γ ( Q07325 ) ] , P22301 , IL - 11 , B - lymphocyte chemoattractant ( O43927 ) and Q16552 , was significantly elevated in HS . DB00051 treatment was associated with decreased production of cytokines in HS skin , especially IL - 1β , Q07325 ( Q07325 ) and O43927 . Treatment significantly reduced the number of CD11c +, P08571 + and P34810 + cells in HS lesional skin . The numbers of CD3 + and P01730 + T cells , and P11836 + and CD138 + B cells were also reduced by adalimumab treatment . CONCLUSIONS : DB00051 treatment inhibits important cytokines and inflammatory cell numbers in lesional HS skin , especially levels of IL - 1β and numbers of inflammatory CD11c + dendritic cells .\",\n \"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK88___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .\",\n \"DB00051 ( P01375 α Inhibitor ) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient . DB00051 ( Humira ) is a tumour necrosis factor α ( P01375 α ) inhibitor that is approved for the treatment of rheumatoid arthritis , psoriasis , psoriatic arthritis , Crohn ' s disease , ankylosing spondylitis , and juvenile idiopathic arthritis ( Sullivan and Preda ( 2009 ) , Klinkhoff ( 2004 ) , and Medicare Australia ) . Use of P01375 α inhibitors is associated with the induction of autoimmunity ( systemic lupus erythematosus , vasculitis , and sarcoidosis or sarcoid - like granulomas ) ( Ramos - Casals et al . ( 2010 ) ) . We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab . He has renal biopsy proven IgA nephritis instead . Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure . He made a remarkable recovery after adalimumab cessation and steroid treatment . To our knowledge , this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab .\",\n \"___MASK24___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK24___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .\",\n \"The p65 ( RelA ) subunit of NF - kappaB interacts with the histone deacetylase ( HDAC ) corepressors Q13547 and Q92769 to negatively regulate gene expression . Regulation of NF - kappaB transactivation function is controlled at several levels , including interactions with coactivator proteins . Here we show that the transactivation function of NF - kappaB is also regulated through interaction of the p65 ( RelA ) subunit with histone deacetylase ( HDAC ) corepressor proteins . Our results show that inhibition of HDAC activity with trichostatin A ( P32119 ) results in an increase in both basal and induced expression of an integrated NF - kappaB - dependent reporter gene . Chromatin immunoprecipitation ( ChIP ) assays show that P32119 treatment causes hyperacetylation of the wild - type integrated NF - kappaB - dependent reporter but not of a mutant version in which the NF - kappaB binding sites were mutated . Expression of Q13547 and Q92769 repressed tumor necrosis factor ( P01375 ) - induced NF - kappaB - dependent gene expression . Consistent with this , we show that Q13547 and Q92769 target NF - kappaB through a direct association of Q13547 with the Rel homology domain of p65 . Q92769 does not interact with NF - kappaB directly but can regulate NF - kappaB activity through its association with Q13547 . Finally , we show that inhibition of HDAC activity with P32119 causes an increase in both basal and P01375 - induced expression of the NF - kappaB - regulated interleukin - 8 ( P10145 ) gene . Similar to the wild - type integrated NF - kappaB - dependent reporter , ChIP assays showed that P32119 treatment resulted in hyperacetylation of the P10145 promoter . These data indicate that the transactivation function of NF - kappaB is regulated in part through its association with HDAC corepressor proteins . Moreover , it suggests that the association of NF - kappaB with the Q13547 and Q92769 corepressor proteins functions to repress expression of NF - kappaB - regulated genes as well as to control the induced level of expression of these genes .\",\n \"___MASK89___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"DB00051 in the management of Behçet ' s disease . Behçet ' s disease ( BD ) is a relapsing , systemic , inflammatory disorder that affects various organ systems . Most of the manifestations of BD are self - limiting , but ocular attacks are an exception . Gastrointestinal tract , central nervous system , and cardiovascular system manifestations are relatively infrequent but may be resistant to conventional immunosuppressive treatment and therefore life - threatening . P01375 alpha antagonists are increasingly being used in patients whose BD is inadequately controlled by standard immunosuppressive regimens . Most of the current experience regarding the treatment of refractory BD involves the use of infliximab ; however , adalimumab has also been successfully used in cases of BD refractory to both conventional therapy and infliximab . Compared with infliximab , adalimumab offers several other advantages , such as the ability to self - administer at home , better patient compliance , and an improved side effect profile . Here , we review clinical experience of the use of adalimumab to treat the serious manifestations of BD . DB00051 is a promising drug for the treatment of BD , and its randomized , prospective study in a large number of patients is warranted to fully determine its efficacy in the refractory BD setting .\",\n \"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .\",\n \"DB00051 : new indication . Ankylosing spondylitis : just another P01375 alpha antagonist . No comparisons with other P01375 alpha antagonists .\",\n \"Mucosal expression of basic fibroblastic growth factor , syndecan 1 and tumour necrosis factor - α in Crohn ' s disease in deep remission under treatment with anti - TNFα antibodies . BACKGROUND AND AIMS : Both inflammation and fibrosis may be detected in Crohn ' s disease ( CD ) . The molecular pattern of Basic Fibroblastic Growth Factor ( P09038 ) and P18827 ( SD1 ) expression is altered in stenosing CD , but we do not know what the behaviour of this teamwork factor is in CD in deep remission under treatment with anti - TNFα antibodies . Our aim was to compare the expression of P09038 , SD1 and P01375 - α in patients with CD in deep remission under treatment with DB00065 ( IFX ) or DB00051 ( P00813 ) and a control group of patients with active CD . METHODS : We assessed the expression of P09038 , SD1 and P01375 - α in 10 patients with active CD and in 28 patients with CD in sustained deep remission for at least 6 months . All patients underwent surveillance colonoscopy with biopsies , while receiving maintenance therapy with IFX or P00813 . Analysis was conducted by real - time reverse transcriptase PCR ( RT - PCR ) in biopsy samples . RESULTS : We found that P09038 , SD1 and P01375 - α were significantly reduced under treatment with anti - TNFα versus controls ( p = 0 . 000 ) . P09038 and SD1 expression were similar between IFX and P00813 patients ( p = 0 . 335 and p = 0 . 289 , respectively ) , while P01375 - α was significantly under - expressed in P00813 patients ( p = 0 . 008 ) . CONCLUSIONS : P09038 , SD1 and P01375 - α are significantly reduced in CD patients in deep remission under treatment with anti - TNFα , likely as an expression of optimal control of inflammation . The significance of the P01375 - α under - expression in patients under treatment with P00813 with respect to those under treatment with IFX should be elucidated in further studies .\",\n \"Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK73___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"___MASK46___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK46___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK46___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .\",\n \"Treatment of ankylosing spondylitis with P01375 blockers : a meta - analysis . Biological agents directed against tumor necrosis factor ( P01375 ) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non - steroidal anti - inflammatory drugs . To evaluate the efficacy and safety of the anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , and certolizumab for the treatment of ankylosing spondylitis , we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE , MEDLINE , Cochrane Controlled Trials Register and LILACS databases ( September / 2012 ) , manual literature search , and the gray literature . Study selections and data collection were performed by two independent reviewers , with disagreements solved by a third reviewer . The following outcomes were evaluated : ASAS 20 response , disease activity , physical function , vertebral mobility , adverse events , and withdraws . The meta - analysis was performed using the Review Manager (®) 5 . 1 software by applying the random effects model . Eighteen studies were included in this review . No study of certolizumab was included . Patients treated with anti - P01375 agents were more likely to display an ASAS 20 response after 12 / 14 weeks ( RR 2 . 21 ; 95 % CI 1 . 91 ; 2 . 56 ) and 24 weeks ( RR 2 . 68 ; 95 % CI 2 . 06 ; 3 . 48 ) compared with controls , which was also true for several other efficacy outcomes . Meta - analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks . DB00051 , infliximab , etanercept , and DB06674 can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis . Safety outcomes deserve further study , especially with respect to long - term follow - ups .\",\n \"DB00051 , etanercept , infliximab , and the risk of tuberculosis : data from clinical trials , national registries , and postmarketing surveillance . This review evaluates the risk of tuberculosis ( TB ) , adherence with recommendations for TB prevention , and host - related risk in patients with rheumatoid arthritis ( RA ) , psoriatic arthritis , and ankylosing spondylitis receiving infliximab ( IFX ) , adalimumab ( P00813 ) , and etanercept ( DB01613 ) through an analysis of phase III randomized controlled trials ( RCT ) , postmarketing surveillance , and national registries . Ten ( 0 . 21 % ) TB cases occurred among 4590 patients in 16 RCT of IFX , 9 ( 0 . 12 % ) among 7009 patients in 21 RCT of P00813 , and 4 ( 0 . 05 % ) among 7741 patients in 26 RCT of DB01613 . Overall , 19 / 23 ( 83 % ) TB cases occurred in patients with RA . Data from national registries and postmarketing surveillance showed an increased risk of TB in patients receiving any of the 3 anti - tumor necrosis factor ( P01375 ) drugs , with a 3 - 4 times higher risk associated with IFX and P00813 than with DB01613 . Deviations from recommended TB prevention procedures were observed in up to 80 % of patients , and most registries did not include data on host - related risk factors for TB . TB occurrence was reduced in recent RCT but not in real - life practice . TB risk was lower for DB01613 than for monoclonal antibody anti - P01375 agents . More complete data collection , including host - related TB risk factors , is advisable to avoid biased results .\",\n \"DB00051 - associated antiphospholipid syndrome : a case report and review of the literature . This study aims for the presentation of the first reported case of adalimumab - associated antiphospholipid syndrome ( APS ) and review of the literature on adalimumab - induced vasculitis and APS . A case of APS associated with adalimumab use in a 67 - year - old woman is reported . The English medical literature was reviewed for antitumor necrosis factor ( P01375 ) agents and their association with APS and vasculitis . DB00051 is a fully humanized monoclonal antibody targeted against P01375 alpha that is widely used in the treatment of rheumatoid arthritis , juvenile idiopathic arthritis , ankylosing spondylitis , psoriatic arthritis , psoriasis , and Crohn ' s disease . Literature review reveals several cases of anti - P01375 - induced vasculitis including cases associated with adalimumab . We report the first case of adalimumab - induced APS in a 67 - year - old woman who developed APS and vasculitis associated with de novo positive anti - cardiolipin ( aCL ) antibody following the third dose of adalimumab therapy for the treatment of spondyloarthropathy . This is the first case demonstrating that a short course of adalimumab therapy may induce immunoglobulin M aCL autoantibodies leading to APS . With the growing use of anti - P01375 medications in immune - mediated and inflammatory diseases , adalimumab and other anti - P01375 medications should be considered as a possible explanation for APS .\",\n \"DB00051 therapy for refractory uveitis : results of a multicentre , open - label , prospective trial . OBJECTIVE : Tumour necrosis factor ( P01375 ) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases . We conducted a prospective , multicentre , open - label Phase II clinical trial to assess the effectiveness and safety of adalimumab , a fully human anti - P01375 monoclonal antibody , in treating refractory uveitis . METHODS : Subjects with non - infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled . Treatment outcome was ascertained by a composite endpoint comprised of visual acuity , intraocular inflammation , ability to taper immunosuppressives , and posterior segment imaging . Clinical response was defined by improvement in at least one parameter , worsening in none , and well controlled intraocular inflammation . Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks . RESULTS : Twenty - one of 31 patients ( 68 % ) were characterised as clinical responders at 10 weeks , of whom 12 patients ( 39 % ) exhibited durable response after 50 weeks . The most common reason for study termination was primary or secondary inefficacy . No patients experienced treatment - limiting toxicity clearly related to study therapy . CONCLUSIONS : DB00051 was safe and effective in 68 % of refractory uveitis patients 10 weeks after study enrolment , and maintained in 39 % after 1 year . Ongoing study is required to determine the place of adalimumab and other P01375 blockers in the treatment of uveitis .\",\n \"Probable diffuse retinopathy caused by adalimumab in a patient with Crohn ' s disease . DB00051 is a tumor necrosis factor - α ( P01375 - α ) antagonist used to treat several immunologic diseases . It is believed that unexpected adverse events related to anti - P01375 drugs will occur as administration of this drug becomes more widespread . We report the case of a 37 - year - old woman who complained of nonspecific abnormalities of vision in both eyes one month after beginning treatment with adalimumab for Crohn ' s disease . The results of the initial ophthalmologic examination were normal . The visual fields showed diffuse and severe depression in both eyes . Other diseases that could have caused the visual field defects were ruled out . The results of electrophysiological tests were compatible with diffuse bilateral retinopathy . Treatment with adalimumab was discontinued . Six months later , visual field loss persists , although it has improved slightly . To our knowledge , this is the first report of diffuse retinopathy probable caused by systemic administration of adalimumab . This form of retinal toxicity should be considered in patients with disorders of vision treated with this drug .\",\n \"Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and / or infliximab . To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis ( JIA ) who had failed treatment with etanercept and / or infliximab in a single paediatric rheumatology clinic . Patients with JIA with active polyarthritis refractory to metotrexate ( MTX ) ( > or = 20 mg / m2 / week ) for at least 3 months and to etanercept ( up to 1 mg / kg twice weekly ) and / or infliximab ( up to 10 mg / kg every 4 weeks ) for at least 6 months were included . All patients received adalimumab 24 mg / m2 / week concomitantly with MTX 7 . 5 - 10 mg / week . Evaluation of efficacy included improvement as defined by the P10323 paediatric 30 criteria , 50 % and 70 % improvement and remission . Six patients were included . Three patients met improvement criteria ; 50 % and 70 % improvement occurred in two children . Improvement was sustained for 12 , 24 and 36 months , respectively . Remission occurred in one patient . DB00051 was discontinued due to lack of efficacy in three patients . No side effects were observed . DB00051 appears to be effective and safe in patients with JIA refractory to other anti - P01375 agents . Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA .\",\n \"DB00051 ( HUMIRA ) : a review . DB00051 ( HUMIRA , Abbott Laboratories ) is a new fully human P01375 monoclonal antibody recently approved for the treatment of rheumatoid arthritis and undergoing trials for use in treating other conditions , including psoriasis and psoriatic arthritis . This article reviews its mechanisms of action , clinical trial results , and related discussion .\",\n \"Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .\",\n \"Open - label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab . BACKGROUND : The aim of this study was to assess the clinical benefit and tolerability of adalimumab , a fully human monoclonal antibody to tumor necrosis factor ( P01375 ) , in patients with ulcerative colitis ( UC ) . METHODS : Patients with active UC , including those who had lost response or developed intolerance to the chimeric anti - P01375 antibody infliximab , were enrolled in a 24 - week uncontrolled trial . Patients were treated with subcutaneous adalimumab 160 mg at week 0 , 80 mg at week 2 , and 40 mg every other week starting at week 4 . After week 8 the dose could be escalated to 40 mg weekly for incomplete response . Outcome measures included clinical response and remission and mucosal healing . RESULTS : Twenty patients were enrolled , of whom 13 had previously received infliximab . Seven patients had dose escalation of adalimumab between weeks 8 and 16 , from 40 mg every other week to 40 mg weekly , due to incomplete response . The rates of clinical response were 25 % at week 8 and 50 % at week 24 . The rates of clinical remission were 5 % at week 8 and 20 % at week 24 . The rate of mucosal healing was 30 % at week 8 . The rates of clinical response and remission and mucosal healing were similar in infliximab - naïve and previously exposed patients . None of the patients experienced hypersensitivity reactions during treatment with adalimumab . CONCLUSIONS : DB00051 is well tolerated and appears to be a clinically beneficial option for patients with UC , including those who have previously lost their response to or can not tolerate infliximab .\",\n \"Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti - tumor necrosis factor treatment during primary simian immunodeficiency virus infection . BACKGROUND : Human immunodeficiency virus ( HIV ) and simian immunodeficiency virus ( SIV ) infections induce robust , generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation , fibrotic damage of lymphoid tissues , and CD4 ⁺ T - cell loss , pathogenic processes that contribute to disease progression . METHODS : To better understand the contribution of tumor necrosis factor ( P01375 ) , a key regulator of acute inflammation , to lentiviral pathogenesis , rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab ( Humira ) , a human anti - P01375 monoclonal antibody . RESULTS : DB00051 did not affect plasma SIV RNA levels or measures of T - cell immune activation ( P28907 or Ki67 ) in peripheral blood or lymph node T cells . However , compared with untreated rhesus macaques , adalimumab - treated rhesus macaques showed attenuated expression of proinflammatory genes , decreased infiltration of polymorphonuclear cells into the T - cell zone of lymphoid tissues , and weaker antiinflammatory regulatory responses to SIV infection ( ie , fewer presumed alternatively activated [ ie , CD163 ⁺ ] macrophages , interleukin 10 - producing cells , and transforming growth factor β - producing cells ) , along with reduced lymphoid tissue fibrosis and better preservation of CD4 ⁺ T cells . CONCLUSIONS : While HIV / SIV replication drives pathogenesis , these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis , and they suggest that early modulation of the inflammatory response may help attenuate disease progression .\",\n \"Long - term follow - up of adalimumab monotherapy for rheumatoid arthritis in Japanese patients : a report of six cases . We present six cases of patients with Japanese rheumatoid arthritis ( RA ) treated with a tumor necrosis factor ( P01375 ) - alpha blocking agent , adalimumab as monotherapy for 220 weeks . All six patients were women , and the median age was 54 . 0 ± 7 . 07 years old . The median duration of the disease was 7 . 43 ± 11 . 1 years , and the median disease activity score ( DAS28 - CRP ) was 5 . 35 ± 0 . 69 . Three of six patients were able to continue to receive this treatment for 220 weeks successfully , and the DAS28 - CRP decreased to 1 . 89 ± 0 . 75 . Two patients withdrew because of lack of efficacy , and one patient withdrew because of adverse events ( non - Hodgkin lymphoma ) . DB00051 resulted in a sustained clinical response in RA patients during 220 - week follow - up .\",\n \"Usefulness of DB00051 for Treating a Case of Intestinal Behçet ' s Disease With Trisomy 8 Myelodysplastic Syndrome . Behçet ' s disease ( BD ) is a systemic vasculitis , while myelodysplastic syndrome ( P43034 ) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis . Some studies suggest a relationship between P43034 and BD , especially intestinal BD , and trisomy 8 seems to play an important role in both diseases . There are several reports on patients with BD comorbid with P43034 involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies . P01375 ( P01375 ) - α is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis , inflammatory bowel disease , and BD . In addition , P01375 - α plays an important role in the pathophysiology of P43034 by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal P28906 + cells . Recent clinical reports demonstrate the favorable effect of P01375 - α antagonists in patients with refractory intestinal BD and in those with P43034 . We present the case of a patient with intestinal BD and P43034 involving trisomy 8 who was successfully treated with adalimumab .\",\n \"Monomeric IgA can be produced in planta as efficient as IgG , yet receives different N - glycans . The unique features of IgA , such as the ability to recruit neutrophils and suppress the inflammatory responses mediated by IgG and IgE , make it a promising antibody isotype for several therapeutic applications . However , in contrast to IgG , reports on plant production of IgA are scarce . We produced IgA1κ and IgG1κ versions of three therapeutic antibodies directed against pro - inflammatory cytokines in Nicotiana benthamiana : DB00065 and DB00051 , directed against P01375 - α , and Ustekinumab , directed against the interleukin - 12p40 subunit . We evaluated antibody yield , quality and N - glycosylation . All six antibodies had comparable levels of expression between 3 . 5 and 9 % of total soluble protein content and were shown to have neutralizing activity in a cell - based assay . However , IgA1κ - based DB00051 and Ustekinumab were poorly secreted compared to their IgG counterparts . DB00065 was poorly secreted regardless of isotype backbone . This corresponded with the observation that both IgA1κ - and IgG1κ - based DB00065 were enriched in oligomannose - type N - glycan structures . For IgG1κ - based Ustekinumab and DB00051 , the major N - glycan type was the typical plant complex N - glycan , biantennary with terminal N - acetylglucosamine , β1 , 2 - xylose and core α1 , 3 - fucose . In contrast , the major N - glycan on the IgA - based antibodies was xylosylated , but lacked core α1 , 3 - fucose and one terminal N - acetylglucosamine . This type of N - glycan occurs usually in marginal percentages in plants and was never shown to be the main fraction of a plant - produced recombinant protein . Our data demonstrate that the antibody isotype may have a profound influence on the type of N - glycan an antibody receives .\",\n \"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .\",\n \"Onychomycosis in patients of nail psoriasis on biologic therapy : a randomized , prospective open label study comparing DB00005 , DB00065 and DB00051 . INTRODUCTION AND OBJECTIVE : The association between patients of psoriasis on anti P01375 therapy and onychomycosis has not been explored . The aim of this study was to determine the rate of onychomycosis in patients of psoriasis with nail involvement on anti P01375 therapy . MATERIALS AND METHODS : All patients of psoriasis with nail involvement seen between February 2007 - July 2012 were examined . All the patients with negative nail scrapings for fungus were enrolled . Patients found fit for biologics after investigations were randomly divided into 3 groups ( Group A : DB00065 , Group B : DB00005 and Group C : DB00051 ) . The patients were followed up every 4 weeks for 24 weeks . Repeat nail scrapings were done at week 24 . The results were compared with controls . RESULT : In total , 315 ( 178 males and 137 females ) patients were enrolled . The mean age was 37 . 5 ± 11 . 4 years . The results for scraping for fungus at the end of 24 weeks were as follows : 33 % ( 33 / 100 ) in patients on DB00065 followed by 15 . 45 % ( 17 / 110 ) , 13 . 33 % ( 14 / 105 ) in patients on treatment with DB00005 and DB00051 respectively as compared to 13 . 89 % ( 25 / 180 ) among controls . Onychomycosis in association with nail psoriasis was more common in males . CONCLUSION : This study revealed statistically significant association between fungal infections of the nail in patients of psoriasis on treatment with DB00065 .\",\n \"DB00051 : a new tumor necrosis factor antagonist and the treatment of Crohn ' s disease . Antibody - neutralization studies have implicated tumor necrosis factor - alpha ( P01375 ) and IL - 12 p40 in the pathogenesis of Crohn ' s disease ( CD ) . Many randomized controlled trials ( RCTs ) have demonstrated the efficacy of infliximab , a chimeric monoclonal antibody to P01375 , in inducing and maintaining disease remission in patients with moderate to severe CD , including those with draining fistulas . However , infliximab is administered intravenously and is associated with immunological reactions and development of antibodies , and hence reduced efficacy . In this article , we describe the efficacy and safety profiles of a newly available recombinant , fully humanized , subcutaneously - administered , anti - P01375 monoclonal antibody , adalimumab ( Humira ) in patients with moderate to severe CD . Many recent RCTs have shown that adalimumab is not only similar to infliximab in the mode of action , efficacy , and safety , but it has the advantages of causing less anaphylactic or immunological reactions , being administered by the subcutaneous route , less need for hospitalization , and a half - life of 2 weeks that allows every other week dosage . DB00051 has also shown some efficacy in infliximab - intolerant or resistant cases . Therefore , it represents a new horizon in the treatment of CD patients , and may reduce the number of patients who require surgical intervention .\",\n \"DB00051 , a fully human anti - P01375 monoclonal antibody , treatment does not influence experimental UV response in the skin of rheumatoid arthritis patients . P01375 is known to play an important role in UV - induced immunomodulation and photodamage . It plays a role in UVB - mediated induction of apoptosis and is a strong inducer of the c - Jun N - terminal kinase ( JNK ) pathway , which eventually leads to the loss of dermal collagen and elastin content . Recently chimeric anti - P01375 has been introduced as a therapy for rheumatoid arthritis . The aim of the present study was to investigate the effect of anti - P01375 treatment on UV - induced DNA damage , apoptosis , and induction of matrix metallo proteinases . Twelve patients with rheumatoid arthritis were included and irradiated with 2 Q9UQD0 broadband UVB before and after administration of 0 . 5 mg / kg anti - P01375 monoclonal antibody . Twenty - four hours after irradiation biopsies were taken . Frozen and paraffin sections were stained for p53 , c - Jun , phosphorylated c - Jun , sunburn cells and P03956 . No significant changes were observed in the expression of p53 and sunburn cells and P03956 content after treatment with anti - P01375 , whereas a slight but significant decrease in c - Jun and phosphorylated c - Jun expression was noted ( P = 0 . 0250 and P = 0 . 0431 , respectively ) . Our results showed no influence of anti - P01375 on UV response at therapeutic doses in patients with rheumatoid arthritis .\",\n \"Pharmacoeconomics of adalimumab for rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis and Crohn ' s disease . DB00051 is a monoclonal antibody that inhibits P01375 , an osteogenic cytokine involved in the pathogenesis of chronic , disabling inflammatory diseases . DB00051 is indicated for rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis and Crohn ' s disease . It alleviates the symptoms of these diseases , prevents disease progression in some patients and , in the case of Crohn ' s disease , induces and maintains remission . Compared with traditional disease - modifying antirheumatic drugs that offer significantly less benefit , adalimumab is much more costly . However , most studies to date demonstrate the cost - effectiveness of adalimumab treatment . Cost - effectiveness data for newer indications of adalimumab , including ankylosing spondylitis and Crohn ' s disease , are needed . As longer term data for adalimumab become available , the cost - effectiveness data will have greater precision .\",\n \"A human monoclonal anti - P01375 alpha antibody ( adalimumab ) reduces airway inflammation and ameliorates lung histology in a murine model of acute asthma . BACKGROUND : A few experimental studies related to asthma have unveiled the beneficial effects of P01375 alpha blocking agents on the airway histology , cytokine levels in bronchoalveolar lavage and bronchial hyper - responsiveness . In the current study , we aimed to assess the effect of adalimumab on the inflammation and histology of asthma in a murine model . METHOD : Twelve - week - old BALB / c ( H - 2d / d ) female rats ( n = 18 ) were allocated into three groups , including ( group I ) control ( phosphate - buffered saline was implemented ) , ( group II ) asthma induced with OVA ( n = 6 ) , and ( group III ) asthma induced with OVA + treated with adalimumab ( n = 6 ) . Rats were executed on the 28th day of the study . The lung samples were fixed in 10 % neutral buffered formalin . Lung parenchyma , alveolus , peribronchial and perivascular inflammation were assessed . Lung pathological scoring was performed . RESULT : Severity of lung damage was found to be reduced significantly in the asthma induced with OVA + treated with adalimumab group . When compared with the untreated group , adalimumab significantly reduced the inflammatory cells around the bronchi and bronchioles , and reduced inflammation of the alveolar wall and alveolar wall thickness as well ( median score = 1 , p = 0 . 52 ) . Peribronchial smooth muscle hypertrophy and oedema were significantly reduced after adalimumab administration . CONCLUSION : DB00051 ( a human monoclonal anti - P01375 alpha antibody ) therapy significantly reduced the severity of lung damage by decreasing cellular infiltration and improvement on the lung histology in a murine model of acute asthma .\",\n \"DB00051 for the treatment of ankylosing spondylitis . Ankylosing spondylitis is a chronic inflammatory disease , with a prevalence of approximately 0 . 5 % , which starts in the third decade of life . Treatment was , until recently , limited . Conventional disease - modifying drugs are not effective for the spinal manifestations , and NSAIDs and physical therapy were the standard treatment , without any other options for patients who did not respond to this treatment . Therefore , the high efficacy of the new group of P01375 - blockers for the treatment of active ankylosing spondylitis represents a breakthrough for NSAID - refractory patients . Following the introduction of the two P01375 - blockers , infliximab and etanercept , the fully humanized , anti - P01375 monoclonal antibody adalimumab is now the third product that has been approved for the treatment of ankylosing spondylitis . DB00051 is given subcutaneously every 2 weeks at a dose of 40 mg . In open and placebo - controlled trials , the drug was shown to be safe and effective in ankylosing spondylitis patients . Long - term treatment data of up to 2 years are now available , confirming efficacy and acceptable safety .\",\n \"DB00051 treatment in Crohn ' s disease does not induce early changes in regulatory T cells . OBJECTIVE : Anti - P01375 - α antibodies has been suggested to modulate regulatory T cell ( Treg ) percentages in rheumatoid arthritis , but results from studies of Crohn ' s disease ( CD ) are conflicting . We investigated dynamic changes of circulating Tregs in CD during treatment with the anti - P01375 - α - antibody adalimumab ( Humira ® , Abbott Laboratories A / S , Emdrupvej 28C , DK - 2100 Copenhagen ) . MATERIAL AND METHODS : Blood samples from 26 CD patients were analysed using flow cytometry before and 1 and 26 weeks after initiation of adalimumab treatment to determine the percentage of Tregs among P01730 + T cells . RESULTS : In spite of a significant decline in disease activity scores and biochemical markers of inflammation , during the first week of treatment , we did not observe early modulating effects of adalimumab on Treg percentages . However , we found a long - term increase in Treg percentages in responders who had low Treg percentages ( < 5 % ) at baseline ( p = 0 . 04 ) . Treg percentage was inversely associated with disease activity ( CD activity index or CDAI ) ( Spearman ' s rank correlation , ρ = - 0 . 47 , p = 0 . 02 ) . High Treg percentages among P01730 + T cells at baseline predicted clinical response to adalimumab . CONCLUSIONS : DB00051 treatment did not induce early modulatory effects on Treg percentage , even in responders . This finding suggests that adalimumab does not have a direct or selective effect on Tregs . However , Treg percentage was associated with disease activity and high Treg percentage predicted response to adalimumab .\",\n \"Refractory dissecting Cellulitis of the Scalp Successfully controlled with DB00051 . Dissecting cellulitis of the scalp ( DB00260 ) is an uncommon inflammatory disease that often results in scarring alopecia . Numerous therapies have either proved ineffective or only temporarily effective in the management of this condition . Recent reports show adequate responses to tumor necrosis factor ( P01375 ) inhibitors in cases of DB00260 . We report a case of severe recalcitrant DB00260 successfully treated with adalimumab .\",\n \"Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .\",\n \"[ Differences in pharmacology of tumor necrosis factor ( P01375 ) antagonists ] . The commercially available inhibitors of P01375 are constituted by two classes of molecules : the soluble receptors ( DB00005 : Amgen Inc . Wyeth ) and the monoclonal antibodies ( DB00051 : Abbott Laboratories and DB00065 : Centocor , Inc . ) . The differences in their molecular structure , mechanism of action , pharmacokinetics ( PK ) and pharmacodynamics ( PD ) are discussed , along with the differences concerning dose , administration regimens , drug concentrations and pharmacological interactions . In order to explain the clinical differences observed when these agents are used in the \\\" real world \\\" , which can arise from the respective PK characteristics ( kinetics , route and frequency of administration , type of P01375 binding , effects on cytokines ) and PD responses and peculiar mechanisms of action , with distinctive immune function ( LFTα inactivation ; apoptosis induction , P01375 immunoprecipitation , C1q binding and CDC induction ; Fcγ cross - linking and ADCC induction ) , the dynamics of interaction of the two classes of neutralizing molecules with P01375 , and the ability in restoring P01375 homeostasis , are outlined .\",\n \"P01375 inhibitors to treat ulcerative colitis in a metastatic breast cancer patient : a case report and literature review . DB00051 ( P00813 ) is a tumor necrosis factor ( P01375 ) inhibitor , used for the treatment of inflammatory bowel disease . Previous studies have reported an increased risk of cancer following exposure to P01375 inhibitors , but little has been reported for patients with cancer receiving P01375 - inhibitor treatment . We present a female patient with metastatic breast cancer and ulcerative colitis ( UC ) who was treated with P00813 . A 54 - year - old African American female with a past history of left - sided breast cancer ( BC ) diagnosed at age 30 was initially treated with left - breast lumpectomy , axillary dissection , followed by chemotherapy and radiation therapy . Years after initial diagnosis , she developed recurrent , bilateral BC and had bilateral mastectomy . Subsequent restaging computed tomography ( CT ) scan demonstrated distant metastases to the bone and lymph nodes . Three years into her treatment of metastatic breast cancer , she was diagnosed with UC by colonoscopy . Her UC was not controlled for 5 mo with 5 - aminosalicylates . Subcutaneous P00813 was started and resulted in dramatic improvement of UC . Four months after starting P00813 , along with ongoing chemotherapy , restaging CT scan showed resolution of the previously seen metastatic lymph nodes . Bone scan and follow - up positron emission tomography / CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on P00813 . While P01375 - α inhibitors could theoretically promote further metastases in patients with prior cancer , this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after P00813 initiation for UC .\",\n \"Serum cytokine profile in adalimumab - treated refractory uveitis patients : decreased Q9GZX6 correlates with clinical responses . PURPOSE : To report the effect of adalimumab on serum cytokines in chronic refractory uveitis . METHODS : Prospective study on the effects of adalimumab on serum cytokine levels at different time points in a cohort of 12 refractory chronic uveitis patients . Results were analyzed according to clinical outcomes and compared with systemic steroid - treated recurrent uveitis patients . RESULTS : Before treatment , patients exhibited significantly increased IL - 1β , P05231 , P01375 α , IL - 12 P08133 , P22301 , and Q9GZX6 . DB00051 significantly decreased P05231 , and IL - 12p70 at early time points ( after 1 month of treatment ) . DB00051 effects on P22301 and Q9GZX6 appeared later ( after 6 months of treatment ) . IL - 1β , Q16552 , and P01375 α were not modified at any time point . Only decreased Q9GZX6 serum levels correlated with disease activity ( p = 0 . 011 ) . These effects were not observed in steroid - treated patients . CONCLUSIONS : DB00051 induced drug - specific and time - dependent declines in serum levels of particular cytokines , although only Q9GZX6 correlated with disease activity in 10 out 12 patients .\",\n \"DB00051 : a review of its use in adult patients with rheumatoid arthritis . DB00051 ( Humira ) is a recombinant , fully human anti - tumor necrosis factor ( P01375 ) monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe , active rheumatoid arthritis ( RA ) . In combination with methotrexate or standard antirheumatic therapy or as monotherapy , adalimumab effectively reduced signs and symptoms of RA , induced remission , improved physical function and inhibited the progression of structural damage in several randomized , double - blind , placebo - controlled phase III trials . The drug was generally well tolerated , with most adverse events being mild to moderate , and the serious adverse events profile being similar to that generally seen in patients with RA not receiving anti - P01375 agents . DB00051 was at least as cost effective as other anti - P01375 agents used in the therapy of RA , and provided significant improvements in patients ' health - related quality of life . Overall , adalimumab in combination with methotrexate or standard antirheumatic therapy is valuable as a first - line therapeutic option in patients with early , aggressive RA , and a second - line therapeutic option in patients with long - standing , moderate to severe RA . For the latter indication , adalimumab may also be used as monotherapy .\",\n \"___MASK6___ attenuates inflammation and oxidative stress in pelvic ganglia neurons after bilateral cavernosal nerve damage . Erectile dysfunction is a common complication for patients undergoing surgeries for prostate , bladder , and colorectal cancers , due to damage of the nerves associated with the major pelvic ganglia ( P29372 ) . Functional re - innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype . O76074 inhibitors ( PDE5i ) have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage ( BCNR ) by up - regulating the expression of neurotrophic factors in P29372 . However , little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR . This study aimed to investigate the changes in gene and protein expression profiles of inflammatory , anti - inflammatory cytokines and oxidative stress related - pathways in P29372 neurons after BCNR and subsequent treatment with sildenafil . Our results showed that BCNR in Fisher - 344 rats promoted up - regulation of cytokines ( interleukin - 1 ( IL - 1 ) β , P05231 , P22301 , transforming growth factor β 1 ( TGFβ1 ) , and oxidative stress factors ( DB02701 adenine dinucleotide phosphate ( NADPH ) oxidase , P05164 ( P05164 ) , inducible nitric oxide synthase ( P35228 ) , P01375 receptor superfamily member 5 ( P25942 ) that were normalized by sildenafil treatment given in the drinking water . In summary , PDE5i can attenuate the production of damaging factors and can up - regulate the expression of beneficial factors in the P29372 that may ameliorate neuropathic pain , promote neuroprotection , and favor nerve regeneration .\",\n \"DB00051 in recalcitrant severe psoriasis associated with atopic dermatitis . P01375 - α inhibitors may induce various cutaneous side effects including eczematous - like lesions . The management of such side effects can be challenging . Herein , we report a case of a 55 - year - old man who had a flare - up and subsequent improvement of atopic dermatitis during treatment of severe psoriasis with adalimumab .\",\n \"DB00051 , a human anti - P01375 monoclonal antibody , outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis : the HOPEFUL 1 study . OBJECTIVES : To evaluate the efficacy and safety of adalimumab + methotrexate ( MTX ) in Japanese patients with early rheumatoid arthritis ( RA ) who had not previously received MTX or biologics . METHODS : This randomised , double - blind , placebo - controlled , multicentre study evaluated adalimumab 40 mg every other week + MTX 6 - 8 mg every week versus MTX 6 - 8 mg every week alone for 26 weeks in patients with RA ( ≤ 2 - year duration ) . The primary endpoint was inhibition of radiographic progression ( change ( Δ ) from baseline in modified total Sharp score ( mTSS ) ) at week 26 . RESULTS : A total of 171 patients received adalimumab + MTX ( mean dose , 6 . 2 ± 0 . 8 mg / week ) and 163 patients received MTX alone ( mean dose , 6 . 6 ± 0 . 6 mg / week , p < 0 . 001 ) . The mean RA duration was 0 . 3 years and 315 ( 94 . 3 % ) had high disease activity ( DAS28 > 5 . 1 ) . DB00051 + MTX significantly inhibited radiographic progression at week 26 versus MTX alone ( ΔmTSS , 1 . 5 ± 6 . 1 vs 2 . 4 ± 3 . 2 , respectively ; p < 0 . 001 ) . Significantly more patients in the adalimumab + MTX group ( 62 . 0 % ) did not show radiographic progression ( ΔmTSS ≤ 0 . 5 ) versus the MTX alone group ( 35 . 4 % ; p < 0 . 001 ) . Patients treated with adalimumab + MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission , using various definitions , at 26 weeks versus MTX alone . Combination therapy was well tolerated , and no new safety signals were observed . CONCLUSIONS : DB00051 in combination with low - dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity .\",\n \"Alopecia areata universalis elicited during treatment with adalimumab . DB00051 is a fully humanized recombinant anti - tumour - necrosis - factor ( P01375 ) monoclonal antibody which has been approved for rheumatoid arthritis , active ankylosing spondylitis , psoriatic arthritis and Crohn ' s disease . We report a case of alopecia areata ( AA ) universalis occurring 6 months after administration of adalimumab monotherapy in a patient with a long - standing history of psoriatic arthritis and psoriasis . The diagnosis was confirmed by a scalp biopsy which showed a peribulbar infiltrate of both P01730 + and CD8 + T cells , CD1a + dendritic cells as well as P34810 + and Q86VB7 + macrophages . In addition , immunofluorescence staining for P01375 was found in the mononuclear cell infiltrate . This case suggests a complex role of P01375 in the induction of AA .\",\n \"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK29___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .\"\n]","isConversational":false},"candidates":{"kind":"list like","value":["___MASK24___","___MASK29___","___MASK46___","___MASK48___","___MASK55___","___MASK6___","___MASK73___","___MASK88___","___MASK89___"],"string":"[\n \"___MASK24___\",\n \"___MASK29___\",\n \"___MASK46___\",\n \"___MASK48___\",\n \"___MASK55___\",\n \"___MASK6___\",\n \"___MASK73___\",\n \"___MASK88___\",\n \"___MASK89___\"\n]","isConversational":false},"answer":{"kind":"string","value":"___MASK46___"},"id":{"kind":"string","value":"MH_train_99"}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":0,"numItemsPerPage":100,"numTotalItems":1620,"offset":0,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc3Mzc3NjM1MCwic3ViIjoiL2RhdGFzZXRzL2NvbW11bml0eS1kYXRhc2V0cy9xYW5nYXJvbyIsImV4cCI6MTc3Mzc3OTk1MCwiaXNzIjoiaHR0cHM6Ly9odWdnaW5nZmFjZS5jbyJ9.peGTZvU95Fg2Xmq5rffdT4WnJdKz1cUbhJponeBR0wYIO3NGlWUNoJB1efCJ8fo7XsFLDd4zJYBpIeGV4qQtAg","displayUrls":true,"splitSizeSummaries":[{"config":"masked_medhop","split":"train","numRows":1620,"numBytesParquet":50027308},{"config":"masked_medhop","split":"validation","numRows":342,"numBytesParquet":8774415},{"config":"masked_wikihop","split":"train","numRows":43738,"numBytesParquet":187716381},{"config":"masked_wikihop","split":"validation","numRows":5129,"numBytesParquet":23586614},{"config":"medhop","split":"train","numRows":1620,"numBytesParquet":49190527},{"config":"medhop","split":"validation","numRows":342,"numBytesParquet":8647233},{"config":"wikihop","split":"train","numRows":43738,"numBytesParquet":179876427},{"config":"wikihop","split":"validation","numRows":5129,"numBytesParquet":22578535}]},"discussionsStats":{"closed":6,"open":0,"total":6},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
query stringclasses 320 values | supports listlengths 5 64 | candidates listlengths 2 9 | answer stringclasses 100 values | id stringlengths 10 13 |
|---|---|---|---|---|
interacts_with DB00773? | [
"Induction of apoptosis of Beta cells of the pancreas by advanced glycation end - products , important mediators of chronic complications of diabetes mellitus . We herein report cytotoxicity of advanced glycation end - products ( AGEs ) on pancreatic beta cells . AGEs stimulated reactive oxygen species ( ROS ) gene... | [
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"___MASK66___",
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"___MASK92___"
] | ___MASK51___ | MH_train_0 |
interacts_with DB09079? | [
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion inde... | [
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"___MASK23___",
"___MASK25___",
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"___MASK27___",
"___MASK39___",
"___MASK58___",
"___MASK62___",
"___MASK6___"
] | ___MASK25___ | MH_train_1 |
interacts_with DB00083? | [
"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarke... | [
"___MASK11___",
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"___MASK33___",
"___MASK40___",
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"___MASK49___",
"___MASK50___",
"___MASK78___",
"___MASK90___"
] | ___MASK11___ | MH_train_2 |
interacts_with DB00083? | [
"A protein chip membrane - capture assay for botulinum neurotoxin activity . Botulinum neurotoxins A and B ( DB00083 and B ) are neuromuscular blocking agents which inhibit neurotransmission by cleaving the intra - cellular presynaptic SNARE proteins P60880 and P63027 , localized respectively in plasma membrane and... | [
"___MASK12___",
"___MASK13___",
"___MASK26___",
"___MASK28___",
"___MASK3___",
"___MASK57___",
"___MASK70___",
"___MASK78___",
"___MASK91___"
] | ___MASK57___ | MH_train_3 |
interacts_with DB06813? | [
"P21554 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice . BACKGROUND : The endocannabinoid system is known to play a role in regulating myocardial contractility , but the influence of cannabinoid receptor 1 ( P21554 ) deficiency on chronic heart failure ( CHF ) remai... | [
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"___MASK59___",
"___MASK77___",
"___MASK78___",
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"___MASK98___"
] | ___MASK8___ | MH_train_4 |
interacts_with DB06288? | [
"Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated... | [
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"___MASK45___",
"___MASK47___",
"___MASK58___",
"___MASK62___",
"___MASK68___",
"___MASK72___",
"___MASK78___",
"___MASK82___"
] | ___MASK82___ | MH_train_5 |
interacts_with DB00862? | [
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly becau... | [
"___MASK19___",
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"___MASK4___",
"___MASK51___",
"___MASK65___",
"___MASK90___",
"___MASK92___",
"___MASK97___",
"___MASK98___"
] | ___MASK92___ | MH_train_6 |
interacts_with DB00773? | [
"Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer ... | [
"___MASK100___",
"___MASK23___",
"___MASK2___",
"___MASK36___",
"___MASK43___",
"___MASK52___",
"___MASK56___",
"___MASK63___",
"___MASK79___"
] | ___MASK36___ | MH_train_7 |
interacts_with DB01233? | [
"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that... | [
"___MASK14___",
"___MASK17___",
"___MASK21___",
"___MASK23___",
"___MASK78___",
"___MASK80___",
"___MASK8___",
"___MASK91___",
"___MASK95___"
] | ___MASK17___ | MH_train_8 |
interacts_with DB00277? | [
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK22___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast ca... | [
"___MASK100___",
"___MASK12___",
"___MASK22___",
"___MASK41___",
"___MASK50___",
"___MASK57___",
"___MASK63___",
"___MASK64___",
"___MASK93___"
] | ___MASK93___ | MH_train_9 |
interacts_with DB01367? | [
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS ... | [
"___MASK11___",
"___MASK23___",
"___MASK29___",
"___MASK34___",
"___MASK3___",
"___MASK44___",
"___MASK68___",
"___MASK79___",
"___MASK90___"
] | ___MASK11___ | MH_train_10 |
interacts_with DB09079? | [
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients thes... | [
"___MASK14___",
"___MASK30___",
"___MASK31___",
"___MASK33___",
"___MASK37___",
"___MASK42___",
"___MASK47___",
"___MASK88___",
"___MASK94___"
] | ___MASK42___ | MH_train_11 |
interacts_with DB05773? | [
"Emerging therapeutic targets in bladder cancer . Treatment of muscle invasive urothelial bladder carcinoma ( BCa ) remains a major challenge . Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets . This manuscript discusses relevant molecular drivers o... | [
"___MASK20___",
"___MASK32___",
"___MASK41___",
"___MASK75___",
"___MASK80___",
"___MASK81___",
"___MASK85___",
"___MASK93___",
"___MASK94___"
] | ___MASK80___ | MH_train_12 |
interacts_with DB00921? | [
"Molecular basis of functional gastrointestinal disorders . There are a number of abnormalities of gastrointestinal function , including sensory and motor dysfunction , which are believed to play a role in the manifestation of symptoms in patients with functional gastrointestinal disorders ( FGID ) . In addition , ... | [
"___MASK21___",
"___MASK33___",
"___MASK35___",
"___MASK3___",
"___MASK40___",
"___MASK71___",
"___MASK73___",
"___MASK7___",
"___MASK90___"
] | ___MASK33___ | MH_train_13 |
interacts_with DB00700? | [
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any... | [
"___MASK18___",
"___MASK1___",
"___MASK32___",
"___MASK33___",
"___MASK34___",
"___MASK3___",
"___MASK70___",
"___MASK79___",
"___MASK93___"
] | ___MASK79___ | MH_train_14 |
interacts_with DB01006? | [
"P46937 ( P46937 ) promotes human gallbladder tumor growth via activation of the P30530 / MAPK pathway . The transcriptional coactivator P46937 ( P46937 ) , a key regulator of cell proliferation and organ size in vertebrates , has been implicated in various malignancies . However , little is known about the express... | [
"___MASK10___",
"___MASK25___",
"___MASK2___",
"___MASK30___",
"___MASK31___",
"___MASK36___",
"___MASK46___",
"___MASK60___",
"___MASK97___"
] | ___MASK60___ | MH_train_15 |
interacts_with DB01233? | [
"___MASK7___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK7___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated ... | [
"___MASK16___",
"___MASK36___",
"___MASK4___",
"___MASK65___",
"___MASK6___",
"___MASK7___",
"___MASK81___",
"___MASK82___",
"___MASK85___"
] | ___MASK82___ | MH_train_16 |
interacts_with DB09030? | [
"Thrombin induces slug - mediated P12830 transcriptional repression and the parallel up - regulation of P19022 by a transcription - independent mechanism in Q96AT9 cells . The proliferation , directional migration to the vitreous and epithelial - mesenchymal transition ( EMT ) of quiescent , differentiated retinal ... | [
"___MASK16___",
"___MASK1___",
"___MASK31___",
"___MASK40___",
"___MASK51___",
"___MASK52___",
"___MASK85___",
"___MASK94___",
"___MASK95___"
] | ___MASK1___ | MH_train_17 |
interacts_with DB04817? | [
"A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading ... | [
"___MASK100___",
"___MASK12___",
"___MASK13___",
"___MASK43___",
"___MASK44___",
"___MASK45___",
"___MASK47___",
"___MASK52___",
"___MASK75___"
] | ___MASK44___ | MH_train_18 |
interacts_with DB00083? | [
"Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell - derived neuron networks prior to network silencing . Botulinum neurotoxins ( BoNTs ) are extremely potent toxins that specifically cleave SNARE proteins in peripheral synapses , preventing neurotransmitter release . Ne... | [
"___MASK28___",
"___MASK29___",
"___MASK60___",
"___MASK62___",
"___MASK76___",
"___MASK80___",
"___MASK85___",
"___MASK90___",
"___MASK96___"
] | ___MASK80___ | MH_train_19 |
interacts_with DB01101? | [
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK83___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit... | [
"___MASK1___",
"___MASK33___",
"___MASK35___",
"___MASK41___",
"___MASK51___",
"___MASK60___",
"___MASK65___",
"___MASK83___",
"___MASK97___"
] | ___MASK33___ | MH_train_20 |
interacts_with DB00790? | [
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK32___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administra... | [
"___MASK27___",
"___MASK32___",
"___MASK42___",
"___MASK50___",
"___MASK57___",
"___MASK59___",
"___MASK73___",
"___MASK92___",
"___MASK93___"
] | ___MASK42___ | MH_train_21 |
interacts_with DB00087? | [
"Glomerular mRNA expression of prothrombotic and antithrombotic factors in renal transplants with thrombotic microangiopathy . BACKGROUND : Thrombotic microangiopathy ( TMA ) in renal transplants ( rTx - TMA ) is a serious complication and is usually either recurrent TMA ( RecTMA ) due to humoral rejection ( HR - T... | [
"___MASK11___",
"___MASK22___",
"___MASK34___",
"___MASK55___",
"___MASK67___",
"___MASK68___",
"___MASK69___",
"___MASK8___",
"___MASK94___"
] | ___MASK94___ | MH_train_22 |
interacts_with DB00700? | [
"Modulation of sympathetic nerve activity by microinjection of the P08908 receptor agonist 8 - OH - DPAT into the rostroventrolateral medulla . In the present study , renal sympathetic nerve activity was recorded simultaneously with sympathetic nerve activity to skeletal muscle vasculature to determine if the sympa... | [
"___MASK1___",
"___MASK23___",
"___MASK26___",
"___MASK36___",
"___MASK52___",
"___MASK55___",
"___MASK56___",
"___MASK77___",
"___MASK95___"
] | ___MASK77___ | MH_train_23 |
interacts_with DB01012? | [
"Absence of p21Waf1 / Cip1 / Sdi1 modulates macrophage differentiation and inflammatory response and protects against atherosclerosis . BACKGROUND : The tumor suppressor p53 protects against atherosclerosis progression in several different mouse models . A major target of p53 is P38936 , the cyclin - dependent kina... | [
"___MASK23___",
"___MASK24___",
"___MASK41___",
"___MASK54___",
"___MASK65___",
"___MASK77___",
"___MASK82___",
"___MASK86___",
"___MASK8___"
] | ___MASK8___ | MH_train_24 |
interacts_with DB00998? | [
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P... | [
"___MASK100___",
"___MASK22___",
"___MASK25___",
"___MASK26___",
"___MASK65___",
"___MASK76___",
"___MASK78___",
"___MASK91___",
"___MASK93___"
] | ___MASK65___ | MH_train_25 |
interacts_with DB00731? | [
"Development of a cell - based assay for the detection of anti - aquaporin 1 antibodies in neuromyelitis optica spectrum disorders . OBJECTIVE : To develop a cell - based assay ( CBA ) to detect aquaporin 1 ( P29972 ) antibodies and determine sensitivity / specificity in patients with neuromyelitis optica ( NMO ) s... | [
"___MASK12___",
"___MASK21___",
"___MASK31___",
"___MASK32___",
"___MASK34___",
"___MASK38___",
"___MASK56___",
"___MASK64___",
"___MASK92___"
] | ___MASK56___ | MH_train_26 |
interacts_with DB09045? | [
"Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole : possible roles of acetylcholine function and neurotrophic factor expression . Increases in dopamine D ( 2 ) receptor sensitivity are known to be common in drug abuse and neurological disorders . Past data f... | [
"___MASK28___",
"___MASK40___",
"___MASK51___",
"___MASK56___",
"___MASK70___",
"___MASK73___",
"___MASK79___",
"___MASK95___",
"___MASK98___"
] | ___MASK98___ | MH_train_27 |
interacts_with DB00887? | [
"___MASK55___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK55___ ( Juxtapid , Aeger... | [
"___MASK16___",
"___MASK21___",
"___MASK25___",
"___MASK47___",
"___MASK55___",
"___MASK60___",
"___MASK62___",
"___MASK88___",
"___MASK95___"
] | ___MASK25___ | MH_train_28 |
interacts_with DB08916? | [
"DB08916 enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem - like cells . Cancer stem cells ( CSC ) have garnered significant attention as a therapeutic focus , based on evidence that they may represent an etiologic root of treatment - resistant cells . Indeed , expression of ... | [
"___MASK1___",
"___MASK46___",
"___MASK50___",
"___MASK60___",
"___MASK62___",
"___MASK69___",
"___MASK76___",
"___MASK80___",
"___MASK99___"
] | ___MASK50___ | MH_train_29 |
interacts_with DB00181? | [
"Transmitter neurochemistry of the efferent neuron system innervating the labyrinth . It is likely that several mechanisms contribute to the efferent control of cochlear and vestibular function . Different effects are probably mediated by different neuronal transmitters . In spite of a number of transmitter candida... | [
"___MASK19___",
"___MASK33___",
"___MASK3___",
"___MASK48___",
"___MASK78___",
"___MASK81___",
"___MASK85___",
"___MASK88___",
"___MASK93___"
] | ___MASK48___ | MH_train_30 |
interacts_with DB00136? | [
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to... | [
"___MASK19___",
"___MASK21___",
"___MASK25___",
"___MASK41___",
"___MASK74___",
"___MASK87___",
"___MASK92___",
"___MASK96___",
"___MASK97___"
] | ___MASK19___ | MH_train_31 |
interacts_with DB08868? | [
"DB03203 - 1 - phosphate induces thrombin receptor Q96RI0 expression to enhance cell migration and P35354 formation in human monocytes . Thrombin is not only a central factor in blood coagulation but also stimulates inflammatory processes , including monocyte responses , via activation of PARs . The signaling lipid... | [
"___MASK11___",
"___MASK15___",
"___MASK2___",
"___MASK31___",
"___MASK33___",
"___MASK54___",
"___MASK73___",
"___MASK7___",
"___MASK80___"
] | ___MASK11___ | MH_train_32 |
interacts_with DB01221? | [
"Nuclear translocation of glyceraldehyde - 3 - phosphate dehydrogenase isoforms during neuronal apoptosis . Treatment with cytosine beta - D - arabinoside ( AraC ; 300 microM ) induced a time - dependent accumulation of glyceraldehyde - 3 - phosphate dehydrogenase ( P04406 ) protein in nuclei purified from cultured... | [
"___MASK13___",
"___MASK1___",
"___MASK25___",
"___MASK51___",
"___MASK61___",
"___MASK75___",
"___MASK79___",
"___MASK94___",
"___MASK97___"
] | ___MASK25___ | MH_train_33 |
interacts_with DB06288? | [
"Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth ,... | [
"___MASK10___",
"___MASK25___",
"___MASK27___",
"___MASK39___",
"___MASK50___",
"___MASK54___",
"___MASK70___",
"___MASK77___",
"___MASK97___"
] | ___MASK10___ | MH_train_34 |
interacts_with DB06719? | [
"DB11320 influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons . The preoptic area / anterior hypothalamus , a region that contains neurons that control thermoregulation , is the main locus at which histamine affects body temperature . Here we report that histamine... | [
"___MASK33___",
"___MASK38___",
"___MASK43___",
"___MASK54___",
"___MASK62___",
"___MASK63___",
"___MASK6___",
"___MASK72___",
"___MASK89___"
] | ___MASK89___ | MH_train_35 |
interacts_with DB08901? | [
"Progressive changes in the leukemogenic signaling in P11274 / P00519 - transformed cells . Our previous study indicated that P11274 / P00519 SH2 domain and P11274 / P00519 SH3 domain + SH2 domain complex are required for immediate activation of the phosphatidylinositol - 3 kinase PI - 3k ) --> Akt serine / threoni... | [
"___MASK13___",
"___MASK26___",
"___MASK28___",
"___MASK36___",
"___MASK41___",
"___MASK58___",
"___MASK77___",
"___MASK81___",
"___MASK92___"
] | ___MASK81___ | MH_train_36 |
interacts_with DB01184? | [
"P51787 , Q9Y6J6 , and Na +- coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability . Na (+)- coupled solute transport is crucial for the uptake of nutrients and metabolic precursors , such as myo - inositol , an important osmolyte and precursor for various cell signali... | [
"___MASK22___",
"___MASK23___",
"___MASK24___",
"___MASK42___",
"___MASK44___",
"___MASK71___",
"___MASK72___",
"___MASK83___",
"___MASK84___"
] | ___MASK42___ | MH_train_37 |
interacts_with DB09079? | [
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastro... | [
"___MASK20___",
"___MASK24___",
"___MASK42___",
"___MASK49___",
"___MASK54___",
"___MASK62___",
"___MASK77___",
"___MASK80___",
"___MASK94___"
] | ___MASK80___ | MH_train_38 |
interacts_with DB01269? | [
"Making sense of anti - P00533 plus oxaliplatin - based therapy in the first - line treatment of metastatic colorectal cancer . P01133 receptor ( P00533 ) targeting in patients with wild - type P01116 metastatic colorectal cancer has been associated with clinical activity in first - , second - and third - line ther... | [
"___MASK17___",
"___MASK28___",
"___MASK36___",
"___MASK47___",
"___MASK72___",
"___MASK90___",
"___MASK92___",
"___MASK93___",
"___MASK96___"
] | ___MASK36___ | MH_train_39 |
interacts_with DB05773? | [
"DB05773 is highly effective in preclinical models of P04626 - positive gastric cancer . BACKGROUND : A novel antibody - drug conjugate ( trastuzumab - DM1 , DB05773 ) is currently in clinical trials for patients with trastuzumab resistant P04626 - positive breast cancer . Since no clinical data is available from g... | [
"___MASK15___",
"___MASK16___",
"___MASK30___",
"___MASK35___",
"___MASK46___",
"___MASK65___",
"___MASK67___",
"___MASK73___",
"___MASK90___"
] | ___MASK67___ | MH_train_40 |
interacts_with DB00530? | [
"Erlotinib in non - small cell lung cancer : a review . Erlotinib ( Tarceva , DB00530 ; Pfizer , Inc . ) is an orally - active , targeted inhibitor of the epidermal growth factor receptor ( P00533 / P00533 ) , which is part of a key regulatory pathway in cancer . Patients with advanced , incurable non - small cell ... | [
"___MASK18___",
"___MASK30___",
"___MASK52___",
"___MASK55___",
"___MASK56___",
"___MASK77___",
"___MASK79___",
"___MASK90___",
"___MASK91___"
] | ___MASK30___ | MH_train_41 |
interacts_with DB01241? | [
"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subject... | [
"___MASK10___",
"___MASK16___",
"___MASK25___",
"___MASK55___",
"___MASK66___",
"___MASK70___",
"___MASK82___",
"___MASK95___",
"___MASK97___"
] | ___MASK66___ | MH_train_42 |
interacts_with DB01240? | [
"Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension . Inhaled DB01240 has been reported to elicit pulmonary vasodilation , but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain . We designed this study to address the in vivo effectiven... | [
"___MASK15___",
"___MASK6___",
"___MASK70___",
"___MASK76___",
"___MASK77___",
"___MASK79___",
"___MASK81___",
"___MASK86___",
"___MASK8___"
] | ___MASK79___ | MH_train_43 |
interacts_with DB08870? | [
"A comparative assessment of fracture resistance of endodontically treated and re - treated teeth : An in vitro study . AIM : To compare and assess the fracture resistance of endodontically treated teeth with those that have been subjected to endodontic retreatment . MATERIALS AND METHODS : 30 extracted mandibular ... | [
"___MASK23___",
"___MASK33___",
"___MASK35___",
"___MASK3___",
"___MASK5___",
"___MASK64___",
"___MASK78___",
"___MASK8___",
"___MASK90___"
] | ___MASK78___ | MH_train_44 |
interacts_with DB01278? | [
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS ... | [
"___MASK11___",
"___MASK13___",
"___MASK23___",
"___MASK24___",
"___MASK35___",
"___MASK48___",
"___MASK71___",
"___MASK74___",
"___MASK75___"
] | ___MASK48___ | MH_train_45 |
interacts_with DB00277? | [
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during f... | [
"___MASK28___",
"___MASK40___",
"___MASK5___",
"___MASK61___",
"___MASK63___",
"___MASK73___",
"___MASK74___",
"___MASK78___",
"___MASK98___"
] | ___MASK74___ | MH_train_46 |
interacts_with DB00315? | [
"The clinical effectiveness of DB00315 in the acute treatment of migraine . Efficacy with currently marketed antimigraine compounds is less than optimal . DB00315 is a novel and selective P28221 receptor agonist in development for the acute treatment of migraine . It shows evidence of both central and peripheral ac... | [
"___MASK18___",
"___MASK21___",
"___MASK26___",
"___MASK28___",
"___MASK32___",
"___MASK47___",
"___MASK82___",
"___MASK89___",
"___MASK96___"
] | ___MASK18___ | MH_train_47 |
interacts_with DB00862? | [
"O60674 - P40763 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells . P05231 - mediated P40763 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis . To investigate the molecular mec... | [
"___MASK11___",
"___MASK15___",
"___MASK16___",
"___MASK3___",
"___MASK55___",
"___MASK89___",
"___MASK91___",
"___MASK92___",
"___MASK94___"
] | ___MASK3___ | MH_train_48 |
interacts_with DB00216? | [
"___MASK60___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a ... | [
"___MASK19___",
"___MASK27___",
"___MASK35___",
"___MASK45___",
"___MASK60___",
"___MASK67___",
"___MASK68___",
"___MASK77___",
"___MASK85___"
] | ___MASK68___ | MH_train_49 |
interacts_with DB06813? | [
"Genome - wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome - wide transcriptiona... | [
"___MASK19___",
"___MASK24___",
"___MASK43___",
"___MASK80___",
"___MASK82___",
"___MASK87___",
"___MASK88___",
"___MASK96___",
"___MASK98___"
] | ___MASK87___ | MH_train_50 |
interacts_with DB00773? | [
"Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case - controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . ___MASK8___ , the addictive component of cigarettes , accelerates cell proliferation through nicotinic ace... | [
"___MASK14___",
"___MASK23___",
"___MASK49___",
"___MASK52___",
"___MASK55___",
"___MASK58___",
"___MASK59___",
"___MASK64___",
"___MASK8___"
] | ___MASK59___ | MH_train_51 |
interacts_with DB01235? | [
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytoto... | [
"___MASK10___",
"___MASK26___",
"___MASK28___",
"___MASK48___",
"___MASK59___",
"___MASK77___",
"___MASK79___",
"___MASK81___",
"___MASK99___"
] | ___MASK99___ | MH_train_52 |
interacts_with DB06699? | [
"DB06699 : a novel gonadotropin - releasing hormone blocker for the treatment of prostate cancer . Androgen deprivation therapy with gonadotropin releasing - hormone ( DB00644 ) receptor agonists provides the mainstay of endocrine treatment for advanced prostate cancer . Although effective , DB00644 agonists induce... | [
"___MASK23___",
"___MASK31___",
"___MASK45___",
"___MASK55___",
"___MASK73___",
"___MASK77___",
"___MASK80___",
"___MASK84___",
"___MASK91___"
] | ___MASK23___ | MH_train_53 |
interacts_with DB01088? | [
"P43119 - mediated DB00171 release from erythrocytes requires the voltage - dependent anion channel . Erythrocytes have been implicated as controllers of vascular caliber by virtue of their ability to release the vasodilator DB00171 in response to local physiological and pharmacological stimuli . The regulated rele... | [
"___MASK19___",
"___MASK21___",
"___MASK32___",
"___MASK38___",
"___MASK4___",
"___MASK52___",
"___MASK61___",
"___MASK71___",
"___MASK81___"
] | ___MASK4___ | MH_train_54 |
interacts_with DB06825? | [
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activ... | [
"___MASK10___",
"___MASK20___",
"___MASK28___",
"___MASK34___",
"___MASK41___",
"___MASK68___",
"___MASK6___",
"___MASK76___",
"___MASK94___"
] | ___MASK20___ | MH_train_55 |
interacts_with DB00921? | [
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theor... | [
"___MASK17___",
"___MASK29___",
"___MASK2___",
"___MASK38___",
"___MASK43___",
"___MASK50___",
"___MASK72___",
"___MASK78___",
"___MASK85___"
] | ___MASK43___ | MH_train_56 |
interacts_with DB00637? | [
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical... | [
"___MASK1___",
"___MASK40___",
"___MASK47___",
"___MASK62___",
"___MASK66___",
"___MASK79___",
"___MASK80___",
"___MASK95___",
"___MASK9___"
] | ___MASK9___ | MH_train_57 |
interacts_with DB01367? | [
"Q16552 stimulates the production of inflammatory mediators via Erk1 / 2 , p38 MAPK , PI3K / Akt , and NF - κB pathways in ARPE - 19 cells . PURPOSE : To investigate the signaling pathways involved in interleukin ( IL ) - 17A - mediated production of interleukin 8 ( P10145 ) , chemokine ( C - C motif ) ligand 2 ( P... | [
"___MASK2___",
"___MASK47___",
"___MASK60___",
"___MASK63___",
"___MASK65___",
"___MASK75___",
"___MASK84___",
"___MASK97___",
"___MASK99___"
] | ___MASK99___ | MH_train_58 |
interacts_with DB01229? | [
"Patient age and biological aggressiveness of endometrial carcinoma . BACKGROUND : Advanced age is associated with a significantly worse prognosis of endometrial carcinoma patients . The aim of this study was to test whether age is a poor - risk factor in endometrial carcinoma because tumors arising in older patien... | [
"___MASK17___",
"___MASK33___",
"___MASK36___",
"___MASK39___",
"___MASK40___",
"___MASK41___",
"___MASK61___",
"___MASK68___",
"___MASK93___"
] | ___MASK40___ | MH_train_59 |
interacts_with DB00005? | [
"Pharmacokinetics and brain uptake of an IgG - P01375 decoy receptor fusion protein following intravenous , intraperitoneal , and subcutaneous administration in mice . P01375 ( P01375 ) - α is a proinflammatory cytokine active in the brain . DB00005 , the P01375 decoy receptor ( TNFR ) , does not cross the blood - ... | [
"___MASK24___",
"___MASK33___",
"___MASK34___",
"___MASK40___",
"___MASK4___",
"___MASK50___",
"___MASK67___",
"___MASK71___",
"___MASK98___"
] | ___MASK40___ | MH_train_60 |
interacts_with DB01407? | [
"P10275 stimulates bone sialoprotein ( BSP ) gene transcription via DB02527 response element and activator protein 1 / glucocorticoid response elements . Bone sialoprotein ( BSP ) is an early marker of osteoblast differentiation . Androgens are steroid hormones that are essential for skeletal development . The andr... | [
"___MASK1___",
"___MASK22___",
"___MASK44___",
"___MASK45___",
"___MASK72___",
"___MASK75___",
"___MASK84___",
"___MASK89___",
"___MASK8___"
] | ___MASK45___ | MH_train_61 |
interacts_with DB01088? | [
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we inv... | [
"___MASK11___",
"___MASK30___",
"___MASK43___",
"___MASK44___",
"___MASK48___",
"___MASK74___",
"___MASK87___",
"___MASK88___",
"___MASK91___"
] | ___MASK30___ | MH_train_62 |
interacts_with DB00398? | [
"DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial fo... | [
"___MASK14___",
"___MASK30___",
"___MASK33___",
"___MASK41___",
"___MASK53___",
"___MASK5___",
"___MASK92___",
"___MASK94___",
"___MASK98___"
] | ___MASK53___ | MH_train_63 |
interacts_with DB00126? | [
"[ Low doses of sulphonyluria as a successful replacement for insulin therapy in a patient with neonatal diabetes due to a mutation of Q14654 gene encoding Kir6 . 2 ] . Neonatal diabetes mellitus is a rare metabolic disorder with an estimated incidence of 1 : 300 . 000 to 400 . 000 newborns , and less than 50 % of ... | [
"___MASK1___",
"___MASK37___",
"___MASK39___",
"___MASK64___",
"___MASK67___",
"___MASK76___",
"___MASK8___",
"___MASK90___",
"___MASK93___"
] | ___MASK1___ | MH_train_64 |
interacts_with DB00624? | [
"P10275 - immunoreactive cells in ram hypothalamus : distribution and co - localization patterns with gonadotropin - releasing hormone , somatostatin and tyrosine hydroxylase . DB00624 exerts important feedback effects on the hypothalamus of the ram to influence reproductive functioning . To provide a neuroanatomic... | [
"___MASK19___",
"___MASK44___",
"___MASK55___",
"___MASK68___",
"___MASK6___",
"___MASK71___",
"___MASK74___",
"___MASK80___",
"___MASK90___"
] | ___MASK80___ | MH_train_65 |
interacts_with DB00530? | [
"___MASK38___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK38___ , an oral tyrosine kinase inhibitor that targets the Ja... | [
"___MASK2___",
"___MASK38___",
"___MASK40___",
"___MASK52___",
"___MASK55___",
"___MASK5___",
"___MASK63___",
"___MASK91___",
"___MASK94___"
] | ___MASK63___ | MH_train_66 |
interacts_with DB01241? | [
"What future for combination therapies ? For most patients who require lipid - lowering treatment , statin monotherapy is the appropriate treatment . However , in those patients where statin monotherapy does not produce optimal lipid levels , the combination of a statin with niacin , a bile acid sequestrant , a fib... | [
"___MASK10___",
"___MASK13___",
"___MASK35___",
"___MASK3___",
"___MASK56___",
"___MASK64___",
"___MASK69___",
"___MASK8___",
"___MASK93___"
] | ___MASK3___ | MH_train_67 |
interacts_with DB00275? | [
"Blockade of P30556 reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation . Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease ( CKD ) associated with metabolic syndr... | [
"___MASK19___",
"___MASK31___",
"___MASK47___",
"___MASK58___",
"___MASK64___",
"___MASK80___",
"___MASK89___",
"___MASK92___",
"___MASK96___"
] | ___MASK92___ | MH_train_68 |
interacts_with DB00910? | [
"Examination of ceramic restorative material interfacial debonding using acoustic emission and optical coherence tomography . OBJECTIVE : CAD / P62158 ceramic restorative material is routinely bonded to tooth substrates using adhesive cement . This study investigates micro - crack growth and damage in the ceramic /... | [
"___MASK1___",
"___MASK32___",
"___MASK47___",
"___MASK48___",
"___MASK53___",
"___MASK56___",
"___MASK58___",
"___MASK96___",
"___MASK98___"
] | ___MASK1___ | MH_train_69 |
interacts_with DB03615? | [
"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . ... | [
"___MASK2___",
"___MASK3___",
"___MASK40___",
"___MASK49___",
"___MASK58___",
"___MASK68___",
"___MASK77___",
"___MASK84___",
"___MASK88___"
] | ___MASK84___ | MH_train_70 |
interacts_with DB01185? | [
"P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the co... | [
"___MASK11___",
"___MASK22___",
"___MASK34___",
"___MASK35___",
"___MASK44___",
"___MASK79___",
"___MASK87___",
"___MASK89___",
"___MASK97___"
] | ___MASK87___ | MH_train_71 |
interacts_with DB00700? | [
"Clathrin - dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to P35354 protein expression in rat aortic vascular smooth muscle cells . The major effects of Angiotensin II ( AngII ) in vascular tissue are mediated by AngII AT1A receptor activation . Certain effects initiat... | [
"___MASK14___",
"___MASK20___",
"___MASK35___",
"___MASK41___",
"___MASK42___",
"___MASK58___",
"___MASK60___",
"___MASK86___",
"___MASK91___"
] | ___MASK35___ | MH_train_72 |
interacts_with DB01427? | [
"Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast - mediated collagen gel degradation induced by tumor necrosis factor - alpha and neutrophil elastase . Tissue destruction , resulting in emphysema , can be a consequence of several pathologic processes . The current study evaluated the effects of the pho... | [
"___MASK10___",
"___MASK16___",
"___MASK20___",
"___MASK28___",
"___MASK36___",
"___MASK7___",
"___MASK80___",
"___MASK92___",
"___MASK96___"
] | ___MASK10___ | MH_train_73 |
interacts_with DB09078? | [
"___MASK90___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK90___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O147... | [
"___MASK27___",
"___MASK49___",
"___MASK60___",
"___MASK72___",
"___MASK75___",
"___MASK85___",
"___MASK87___",
"___MASK90___",
"___MASK91___"
] | ___MASK49___ | MH_train_74 |
interacts_with DB01012? | [
"New insights into the role of calcium - sensing receptor activation . The discovery of the calcium - sensing receptor ( P41180 ) prompted the identification of substances that affect its function . DB01012 , for example , is a drug that allosterically modifies the receptor so as to increase its sensitivity to circ... | [
"___MASK42___",
"___MASK45___",
"___MASK49___",
"___MASK53___",
"___MASK60___",
"___MASK68___",
"___MASK77___",
"___MASK79___",
"___MASK96___"
] | ___MASK79___ | MH_train_75 |
interacts_with DB00281? | [
"Combination effects of paclitaxel with signaling inhibitors in endometrial cancer cells . This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor ( P00533 ) or / and mammalian target of rapamycin ( P42345 ) inhibitors with ... | [
"___MASK18___",
"___MASK46___",
"___MASK55___",
"___MASK56___",
"___MASK58___",
"___MASK71___",
"___MASK74___",
"___MASK90___",
"___MASK9___"
] | ___MASK71___ | MH_train_76 |
interacts_with DB01257? | [
"Severe atypical HUS caused by P08603 S1191L -- case presentation and review of treatment options . Atypical hemolytic uremic syndrome ( aHUS ) has been associated with defective regulation of the alternative complement pathway . Although the use of plasma therapy is recommended , there is little consensus on the o... | [
"___MASK100___",
"___MASK11___",
"___MASK13___",
"___MASK20___",
"___MASK25___",
"___MASK46___",
"___MASK4___",
"___MASK69___",
"___MASK91___"
] | ___MASK100___ | MH_train_77 |
interacts_with DB00197? | [
"Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in th... | [
"___MASK20___",
"___MASK25___",
"___MASK2___",
"___MASK36___",
"___MASK37___",
"___MASK51___",
"___MASK57___",
"___MASK83___",
"___MASK93___"
] | ___MASK37___ | MH_train_78 |
interacts_with DB00169? | [
"The effect of 1 , 25 - dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma . 1 , 25 ( OH ) 2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system . alpha - Calcidol which is metabolised to 1 , 2... | [
"___MASK13___",
"___MASK27___",
"___MASK53___",
"___MASK56___",
"___MASK64___",
"___MASK66___",
"___MASK81___",
"___MASK91___",
"___MASK98___"
] | ___MASK91___ | MH_train_79 |
interacts_with DB08904? | [
"A review and expert opinion of the use of certolizumab for Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the las... | [
"___MASK21___",
"___MASK24___",
"___MASK32___",
"___MASK33___",
"___MASK43___",
"___MASK4___",
"___MASK54___",
"___MASK67___",
"___MASK93___"
] | ___MASK21___ | MH_train_80 |
interacts_with DB00136? | [
"( Pro ) renin promotes fibrosis gene expression in P29320 cells through a Nox4 - dependent mechanism . The ( pro ) renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this stu... | [
"___MASK26___",
"___MASK29___",
"___MASK30___",
"___MASK40___",
"___MASK52___",
"___MASK55___",
"___MASK58___",
"___MASK69___",
"___MASK99___"
] | ___MASK69___ | MH_train_81 |
interacts_with DB01276? | [
"___MASK31___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tiss... | [
"___MASK21___",
"___MASK28___",
"___MASK31___",
"___MASK32___",
"___MASK53___",
"___MASK60___",
"___MASK63___",
"___MASK79___",
"___MASK80___"
] | ___MASK32___ | MH_train_82 |
interacts_with DB01064? | [
"P25021 activation exacerbates myocardial ischemia / reperfusion injury by disturbing mitochondrial and endothelial function . There is evidence that P25021 blockade improves ischemia / reperfusion ( I / R ) injury , but the underlying cellular mechanisms remain unclear . DB11320 is known to increase vascular perme... | [
"___MASK12___",
"___MASK27___",
"___MASK35___",
"___MASK36___",
"___MASK58___",
"___MASK70___",
"___MASK84___",
"___MASK87___",
"___MASK90___"
] | ___MASK87___ | MH_train_83 |
interacts_with DB00669? | [
"How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside ... | [
"___MASK12___",
"___MASK13___",
"___MASK20___",
"___MASK26___",
"___MASK29___",
"___MASK43___",
"___MASK48___",
"___MASK62___",
"___MASK94___"
] | ___MASK20___ | MH_train_84 |
interacts_with DB00744? | [
"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK38___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical a... | [
"___MASK1___",
"___MASK23___",
"___MASK31___",
"___MASK38___",
"___MASK41___",
"___MASK49___",
"___MASK68___",
"___MASK6___",
"___MASK73___"
] | ___MASK38___ | MH_train_85 |
interacts_with DB00098? | [
"Upregulation of molecules associated with T - regulatory function by thymoglobulin pretreatment of human P01730 + cells . BACKGROUND : This study evaluated the immunologic effects of thymoglobulin in modulating human P01730 + cells . METHODS : Human P01730 + cells were purified from peripheral blood mononuclear ce... | [
"___MASK13___",
"___MASK20___",
"___MASK30___",
"___MASK37___",
"___MASK68___",
"___MASK73___",
"___MASK74___",
"___MASK80___",
"___MASK86___"
] | ___MASK86___ | MH_train_86 |
interacts_with DB06674? | [
"___MASK88___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) R... | [
"___MASK22___",
"___MASK23___",
"___MASK2___",
"___MASK30___",
"___MASK35___",
"___MASK56___",
"___MASK70___",
"___MASK88___",
"___MASK92___"
] | ___MASK23___ | MH_train_87 |
interacts_with DB00831? | [
"Suppressed Ca2 +/ P62158 / CaMKII - dependent K ( DB00171 ) channel activity in primary afferent neurons mediates hyperalgesia after axotomy . Painful axotomy decreases K ( DB00171 ) channel current ( IK ( DB00171 ) ) in primary afferent neurons . Because cytosolic Ca ( 2 +) signaling is depressed in injured dorsa... | [
"___MASK10___",
"___MASK13___",
"___MASK41___",
"___MASK57___",
"___MASK60___",
"___MASK69___",
"___MASK80___",
"___MASK8___",
"___MASK95___"
] | ___MASK80___ | MH_train_88 |
interacts_with DB01235? | [
"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatment... | [
"___MASK13___",
"___MASK29___",
"___MASK31___",
"___MASK47___",
"___MASK50___",
"___MASK52___",
"___MASK53___",
"___MASK76___",
"___MASK83___"
] | ___MASK52___ | MH_train_89 |
interacts_with DB08896? | [
"Determination of ancestral allele for possible human cancer - associated polymorphisms . To determine ancestral allele in possible cancer - associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 (... | [
"___MASK1___",
"___MASK36___",
"___MASK43___",
"___MASK45___",
"___MASK60___",
"___MASK69___",
"___MASK75___",
"___MASK82___",
"___MASK88___"
] | ___MASK88___ | MH_train_90 |
interacts_with DB01436? | [
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastro... | [
"___MASK12___",
"___MASK17___",
"___MASK32___",
"___MASK36___",
"___MASK46___",
"___MASK65___",
"___MASK68___",
"___MASK75___",
"___MASK95___"
] | ___MASK36___ | MH_train_91 |
interacts_with DB00216? | [
"Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine... | [
"___MASK100___",
"___MASK28___",
"___MASK39___",
"___MASK59___",
"___MASK5___",
"___MASK77___",
"___MASK80___",
"___MASK90___",
"___MASK97___"
] | ___MASK59___ | MH_train_92 |
interacts_with DB00973? | [
"Pathophysiological factors affecting CAR gene expression . The body defends itself against potentially harmful compounds , such as drugs and toxic endogenous compounds and their metabolites , by inducing the expression of enzymes and transporters involved in their metabolism and elimination . The orphan nuclear re... | [
"___MASK35___",
"___MASK39___",
"___MASK3___",
"___MASK42___",
"___MASK4___",
"___MASK52___",
"___MASK60___",
"___MASK71___",
"___MASK8___"
] | ___MASK4___ | MH_train_93 |
interacts_with DB06441? | [
"Activation of Gi - coupled receptors releases a tonic state of inhibited platelet aggregation . Single - receptor pharmacology does not satisfactorily explain the physiology of the ADP - induced platelet aggregation response . It has been shown that , in addition to Gq - coupled receptor activation , one Gi - coup... | [
"___MASK10___",
"___MASK32___",
"___MASK6___",
"___MASK72___",
"___MASK74___",
"___MASK88___",
"___MASK91___",
"___MASK98___",
"___MASK99___"
] | ___MASK10___ | MH_train_94 |
interacts_with DB00814? | [
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK75___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit... | [
"___MASK43___",
"___MASK49___",
"___MASK56___",
"___MASK60___",
"___MASK69___",
"___MASK75___",
"___MASK7___",
"___MASK98___",
"___MASK99___"
] | ___MASK56___ | MH_train_95 |
interacts_with DB00159? | [
"Curcumin : getting back to the roots . The use of turmeric , derived from the root of the plant Curcuma longa , for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years . The active component of turmeric responsible for this activity... | [
"___MASK14___",
"___MASK15___",
"___MASK18___",
"___MASK23___",
"___MASK46___",
"___MASK58___",
"___MASK5___",
"___MASK94___",
"___MASK95___"
] | ___MASK18___ | MH_train_96 |
interacts_with DB00181? | [
"Inhibition of mutant P15056 splice variant signaling by next - generation , selective RAF inhibitors . ___MASK4___ and dabrafenib block MEK - P27361 / 2 signaling and cause tumor regression in the majority of advanced - stage P15056 ( V600E ) melanoma patients ; however , acquired resistance and paradoxical signal... | [
"___MASK10___",
"___MASK12___",
"___MASK15___",
"___MASK4___",
"___MASK52___",
"___MASK54___",
"___MASK68___",
"___MASK7___",
"___MASK87___"
] | ___MASK68___ | MH_train_97 |
interacts_with DB00120? | [
"[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent ... | [
"___MASK100___",
"___MASK19___",
"___MASK20___",
"___MASK41___",
"___MASK49___",
"___MASK53___",
"___MASK59___",
"___MASK67___",
"___MASK72___"
] | ___MASK41___ | MH_train_98 |
interacts_with DB00051? | [
"[ The importance of biologicals in the treatment of SoJIA ] . Systemic onset juvenile idiopathic arthritis ( SoJIA ) remains difficult to treat . In addition to conventional antirheumatic therapy with non - steroidal antirheumatic drugs ( NSARDs ) , steroids or disease - modifying antirheumatic drugs ( DMARDs ) , ... | [
"___MASK24___",
"___MASK29___",
"___MASK46___",
"___MASK48___",
"___MASK55___",
"___MASK6___",
"___MASK73___",
"___MASK88___",
"___MASK89___"
] | ___MASK46___ | MH_train_99 |
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