interacts_with DB01238?
Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( DB01238 ) 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 . Gene expression and molecular changes in cerebral arteries following subarachnoid hemorrhage in the rat . OBJECT : The authors investigated early changes in the cerebral arteries of rats that occur after subarachnoid hemorrhage ( Q53FZ2 ) . METHODS : Messenger RNA was investigated by performing microarray and quantitative real-time polymerase chain reaction ( PCR ) analyses , and protein expression was shown by performing immunohistochemical studies . The array data indicated that the initial processes that occur after Q53FZ2 involve activation of genes involved in angiogenesis , inflammation , and extracellular matrix ( Q13201 ) remodeling . The real-time PCR investigation confirmed upregulation of genes that were observed using the microarray to be regulated , including P35228 , P45452 , and cxcl2 . The authors also verified the upregulation of previously implicated genes for G-protein-coupled receptors ( endothelin B [ ETB ] , angiotensin 1 [ AT1 ] , and P50052 ) and metalloproteinase 9 . The results of an immunohistochemical study confirmed that receptor genes that were seen to be regulated produced an increase in protein expression . Double immunostaining of rat cerebral arteries with endothelial cell- or smooth-muscle cell-specific antibodies verified that an increase in ETB , 5-hydrotryptamine ( P28222 ) , and P28221 receptor expression occurs in smooth-muscle cells . CONCLUSIONS : Processes occurring after Q53FZ2 lead to enhanced arterial contractility and Q13201 remodeling either directly or through angiogenesis and inflammation . These processes are active via an increase in metalloproteinase expression , the presence of proangiogenic factors , and the expression of proinflammatory genes . Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8-OH-DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p-chlorophenylalanine ( p- P15085 , 300 mg/kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0.5 mg/kg ) or 8-OH-DPAT ( 0.5 mg/kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5,7-dihydroxytryptamine ( 5,7- DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0.5 mg/kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5,7- DB02901 treated rats . In lesioned animals 8-OH-DPAT ( 0.5 mg/kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour . P01308 and adiponectin inhibit the TNFalpha-induced DB01686 accumulation in human endothelial cells : the role of DDAH . OBJECTIVE : P01308 and adiponectin exert important effects on the vasculature . We wanted to explore whether the P29474 inhibitor asymmetric dimethylarginine ( DB01686 ) contribute to their effects . METHODS : Human umbilical vein endothelial cells ( HUVECs ) and human coronary artery endothelial cells ( HCAECs ) were incubated with growth medium in the presence or absence of tumor necrosis factor-alpha ( TNFalpha ) , D-glucose , insulin or adiponectin . Further , cells exposed to TNFalpha for 24h were co-stimulated with insulin or adiponectin for additional 24h . Concentrations of DB01686 in conditioned media and activity of dimethylarginine dimethylaminohydrolase ( DDAH ) in cell lysates were determined . RESULTS : The dose-dependent TNFalpha-induced DB01686 accumulation was significantly inhibited when co-stimulated with insulin or adiponectin in both cell lines ( p < 0.01 for all ) , accompanied by significant increases in DDAH activity in all conditions . P01308 alone resulted in a significant , but inversely dose-dependent accumulation of DB01686 as compared to control cells in both cell lines , accompanied by increased DDAH activity . Q15848 alone tended , dose-dependently to decrease DB01686 , but without an increase of DDAH activity . CONCLUSION : The results indicate that DB01686 accumulation in human cultured endothelial cells is influenced by both insulin and adiponectin , and both mediators counteract the TNFalpha-induced accumulation of DB01686 through the DDAH pathway . DB08895 in kidney transplantation . INTRODUCTION : This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase ( JAK ) 3 inhibitor tofacitinib , formerly known as CP-690,550 and tasocitinib . AREAS COVERED : Successful kidney transplantation requires adequate immunosuppression . Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors . JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors , particularly members of the cytokine receptor common gamma ( cγ ) chain family . P52333 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis . Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control . Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival . There was also a lower rate of new onset diabetes after transplant . However , there was a trend toward more infections , including cytomegalovirus and BK virus nephritis . EXPERT OPINION : DB08895 may be a promising alternative to calcineurin inhibitors . The optimal therapeutic window is still being determined . DB00171 -sensitive potassium channel activation induces angiogenesis in vitro and in vivo . Intense research is conducted to identify new molecular mechanisms of angiogenesis . Previous studies have shown that the angiogenic effects of hydrogen sulfide ( H2S ) depend on the activation of DB00171 -sensitive potassium channels ( KATP ) and that P23582 ( P09543 ) , which can act through KATP , promotes endothelial cell growth . We therefore investigated whether direct KATP activation induces angiogenic responses and whether it is required for the endothelial responses to P09543 or vascular endothelial growth factor ( P15692 ) . Chick chorioallantoic membrane ( P62158 ) angiogenesis was similarly enhanced by the direct KATP channel activator 2-nicotinamidoethyl acetate ( SG-209 ) and by P09543 or P15692 . The KATP inhibitors glibenclamide and 5-hydroxydecanoate ( 5-HD ) reduced basal and abolished P09543 -induced P62158 angiogenesis . In vitro , the direct KATP openers nicorandil and SG-209 and the polypeptides P15692 and P09543 increased proliferation and migration in bEnd.3 mouse endothelial cells . In addition , P15692 and P09543 induced cord-like formation on Matrigel by human umbilical vein endothelial cells ( HUVECs ) . All these in vitro endothelial responses were effectively abrogated by glibenclamide or 5-HD . In HUVECs , a small-interfering RNA-mediated decrease in the expression of the inwardly rectifying potassium channel ( Kir ) 6.1 subunit impaired cell migration and network morphogenesis in response to either SG-209 or P09543 . We conclude that 1 ) direct pharmacologic activation of KATP induces angiogenic effects in vitro and in vivo , 2 ) angiogenic responses to P09543 and P15692 depend on KATP activation and require the expression of the Kir6.1 KATP subunit , and 3 ) KATP activation may underpin angiogenesis to a variety of vasoactive stimuli , including H2S , P15692 , and P09543 . Differential regulation of membrane guanylyl cyclases in congestive heart failure : natriuretic peptide receptor ( NPR ) -B , Not P16066 , is the predominant natriuretic peptide receptor in the failing heart . Atrial natriuretic peptide ( P01160 ) and B-type natriuretic peptide ( DB04899 ) bind natriuretic peptide receptor ( NPR ) -A and decrease blood pressure and cardiac hypertrophy by elevating cGMP concentrations . Physiological responses to P01160 and DB04899 are diminished in congestive heart failure ( CHF ) by an unknown mechanism . P23582 ( P09543 ) binding to P20594 decreases cardiac hypertrophy , but the effect of CHF on P20594 is unknown . Here , we measured P01160 / P16066 -dependent and P09543 / P20594 -dependent guanylyl cyclase activities in membranes from failing and nonfailing hearts . Transaortic banding of mice resulted in marked CHF as indicated by increased heart/body weight ratios , increased left ventricular diameters , and decreased ejection fractions . In nonfailed hearts , saturating P01160 concentrations increased particulate guanylyl cyclase activity almost 10-fold , whereas saturating P09543 concentrations increased activity 6.9-fold , or to about 70 % of the P01160 response . In contrast , in failed heart preparations , P09543 elicited twice as much activity as P01160 due to dramatic reductions in P16066 activity without changes in P20594 activity . For the first time , these data indicate that P20594 activity represents a significant and previously unappreciated portion of the natriuretic peptide-dependent guanylyl cyclase activity in the normal heart and that P20594 accounts for the majority of the natriuretic peptide-dependent activity in the failed heart . Based on these findings , we suggest that drugs that target both NPRs may be more beneficial than drugs like nesiritide ( Natrecor ) that target P16066 alone . Angiotensin II regulates vascular and endothelial dysfunction : recent topics of P30556 signaling in the vasculature . Accumulating evidence strongly implicates angiotensin II ( AngII ) intracellular signaling in mediating cardiovascular diseases such as hypertension , atherosclerosis and restenosis after vascular injury . In vascular smooth muscle cells ( VSMCs ) , through its G-protein-coupled AngII Type 1 receptor ( AT(1) ) , AngII activates various intracellular protein kinases , such as receptor or non-receptor tyrosine kinases , which includes epidermal growth factor receptor ( P00533 ) , platelet-derived growth factor receptor ( P09619 ) , c-Src , Q14289 , Q05397 , O60674 . In addition , AngII activates serine/threonine kinases such as mitogen-activated protein kinase ( MAPK ) family , P08133 S6 kinase , Akt/protein kinase B and various protein kinase C isoforms . In VSMCs , AngII also induces the generation of intracellular reactive oxygen species ( ROS ) , which play critical roles in activation and modulation of above signal transduction . Less is known about endothelial cell ( EC ) AngII signaling than VSMCs , however , recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide ( NO ) signaling pathway and thereby induces endothelial dysfunction . Moreover , in both VSMCs and ECs , AngII signaling cross-talk with insulin signaling might be involved in insulin resistance , an important risk factor in the development of cardiovascular diseases . In fact , clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity . In this review , we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes , such as activation of receptor or non-receptor tyrosine kinases and ROS , as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs . Agonist selectivity for three species of natriuretic peptide receptor-A . We determined the nucleotide sequence of mouse natriuretic peptide receptor-A ( P16066 ) cDNA and compared the revised deduced amino acid sequence with those of rat and human P16066 . The ligand selectivity of these three receptor/guanylyl cyclases was examined by whole-cell stimulation of cGMP production . The 28-amino acid atrial natriuretic peptide ( P01160 ) has only one difference among these three species , i.e. , human DB00134 -12 versus rat and mouse DB00167 -12 . However , despite the nearly invariant P01160 sequence among these species , P01160 analogs have marked differences in ED50 values and maximal cGMP responses among the three receptors . With the natriuretic peptide analogs we tested , human P16066 is less sensitive than rat or mouse P16066 to changes in the 17-amino acid , disulfide-bonded ring of P01160 and to the species differences in brain natriuretic peptide ( DB04899 ) but is more sensitive to deletions in the carboxyl tail of P01160 . The P01160 determinants of agonist potency have therefore changed for different species of P16066 . This is reflected in the amino acid sequence divergence in the receptor extracellular domains and in the divergence and specificity of DB04899 among species . Our results suggest that the coevolution of P16066 and DB04899 has thus been constrained within the context of the conserved P01160 sequence . O14965 regulates O60674 - P40763 activity in human gastric and esophageal cancers . O14965 is a frequently amplified and overexpressed gene in upper gastrointestinal adenocarcinomas ( UGCs ) . Using in vitro cell models of UGCs , we investigated whether O14965 can regulate Signal Transducer and Activator of Transcription 3 ( P40763 ) . Our data indicate that overexpression of O14965 in FLO-1 and AGS cells increase P40763 phosphorylation at the Tyr705 site , whereas O14965 genetic depletion by siRNA results in decreased phosphorylation levels of P40763 in FLO-1 and MKN45 cells . Immunofluorescence analysis showed that O14965 overexpression enhanced P40763 nuclear translocation while O14965 genetic knockdown reduced the nuclear translocation of P40763 in AGS and FLO-1 cells , respectively . Using a luciferase reporter assay , we demonstrated that O14965 expression induces transcriptional activity of P40763 . Pharmacological inhibition of O14965 by DB05220 reduced P40763 phosphorylation along with down-regulation of P40763 pro-survival targets , P10415 and Q07820 . Moreover , by using clonogenic cells survival assay , we showed that DB05220 single dose treatment reduced the ability of FLO-1 and AGS cells to form colonies . Additional experiments utilizing cell models of overexpression and knockdown of O14965 indicated that P40763 upstream non-receptor tyrosine kinase O60674 ( O60674 ) is mediating the effect of O14965 on P40763 . The inhibition of O60674 using O60674 -specific inhibitor AZD1480 or siRNA knockdown , in presence of O14965 overexpression , abrogated the O14965 -mediated P40763 activation . These results confirm that the O14965 - O60674 axis is the main mechanism by which O14965 regulates P40763 activity . In conclusion , we report , for the first time , that O14965 promotes P40763 activity through regulating the expression and phosphorylation levels of O60674 . This highlights the importance of targeting O14965 as a therapeutic approach to treat gastric and esophageal cancers . Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis . DB08895 is the first in a new class of nonbiologic disease-modifying antirheumatic drugs ( DMARDs ) , a targeted , synthetic DMARD , approved for the treatment of rheumatoid arthritis ( RA ) as monotherapy or in combination with methotrexate or other non-biologic DMARD . DB08895 , an orally administered Janus kinase ( JAK ) inhibitor , decreases T-cell activation , pro-inflammatory cytokine production , and cytokine signaling by inhibiting binding of type I cytokine receptors family and γ-chain cytokines to paired P23458 / P52333 receptors . The net effect of tofacitinb 's mechanism of action is decreased synovial inflammation and structural joint damage in RA patients . To date , six phase 3 trials have been conducted to evaluate the safety and efficacy of tofacitinib under the oral rheumatoid arthritis triaLs ( ORAL ) series . This review describes the pharmacology of the novel agent , tofacitinib , and details the safety and efficacy data of the ORAL trials . 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 , DB06271 ( 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 . Combination therapy for hepatocellular carcinoma : additive preclinical efficacy of the HDAC inhibitor DB06603 with sorafenib . BACKGROUND & AIMS : Hepatocellular carcinoma ( HCC ) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy . Histone deacetylases ( HDAC ) are commonly dysregulated in cancer and therefore represent promising targets for therapies , however their role in HCC pathogenesis is still unknown . We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor DB06603 alone and in combination with sorafenib in preclinical models of liver cancer . METHODS : Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs , while the effects of DB06603 and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model . RESULTS : Aberrant HDAC expression was identified and validated in 91 and 243 HCCs , respectively . Upregulation of O15379 and Q9UQL6 mRNAs was significantly correlated with DNA copy number gains . Inhibiting HDACs with DB06603 led to strong anti-tumoral effects in vitro and vivo , enhanced by the addition of sorafenib . Cell viability and proliferation declined , while apoptosis and autophagy increased . DB06603 increased histone H3 and HSP90 acetylation , downregulated O15392 ( survivin ) and upregulated CDH1 . Combination therapy with DB06603 and sorafenib significantly decreased vessel density , and most significantly decreased tumor volume and increased survival in HCC xenografts . CONCLUSIONS : Aberrant expression of several HDACs and copy number gains of O15379 and Q9UQL6 occur in HCC . Treatment with DB06603 combined with sorafenib demonstrated the highest preclinical efficacy in HCC models , providing the rationale for clinical studies with this novel combination . 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 . Risk variants in the P04271 gene predict elevated P04271 serum concentrations in healthy individuals . Several lines of evidence suggest an important role of the P04271 protein and its coding gene in different neuropathological and psychiatric disorders like dementia , bipolar affective disorders and schizophrenia . To clarify whether a direct link exists between gene and gene product , that is , whether P04271 variants directly modulate P04271 serum concentration , 196 healthy individuals were assessed for P04271 serum concentrations and genotyped for five potentially functional P04271 SNPs . Functional variants of the serotonergic genes P08908 and 5-HTT possibly modulating P04271 serum levels were also studied . Further , publicly available human postmortem gene expression data were re-analyzed to elucidate the impact of P04271 , P08908 and 5-HTT SNPs on frontal cortex P04271 mRNA expression . Several P04271 SNPs , particularly rs9722 , and the P04271 haplotype T-G-G-A ( including rs2186358-rs11542311-rs2300403-rs9722 ) were associated with elevated P04271 serum concentrations ( Bonferroni corrected P < 0.05 ) . Of these , rs11542311 was also associated with P04271 mRNA expression directly ( Bonferroni corrected P = 0.05 ) and within haplotype G-A-T-C ( rs11542311-rs2839356-rs9984765-rs881827 ; P = 0.004 ) , again with the G-allele increasing P04271 expression . Our results suggest an important role of P04271 SNPs on P04271 serum concentrations and P04271 mRNA expression . It hereby links recent evidence for both , the impact of P04271 gene variation on various neurological or psychiatric disorders like dementia , bipolar affective disorders and schizophrenia and the strong relation between P04271 serum levels and these disorders . High glucose-mediated imbalance of nitric oxide synthase and dimethylarginine dimethylaminohydrolase expression in endothelial cells . The mechanisms involved in endothelial dysfunction are multifactorial . A correlation between oxidative stress and derangements of nitric oxide synthase ( NOS ) pathways in altered endothelial homeostasis has been most studied and demonstrated in different pathophysiological conditions . NOS activities are regulated by endogenous inhibitors such as asymmetric DB01686 ( DB01686 ) that is metabolized by dimethylarginine dimethylaminohydrolase ( DDAH ) . Since recent data demonstrated that some endothelial dysfunction may be related to reduced expression and/or activity of DDAH , the aim of the present research was to investigate the expression of O95865 and NOS isoforms in high glucose-mediated oxidative stress . Endothelial cells were incubated with normal ( 7 mM ) and high concentrations ( 33 mM ) of D-glucose for 5 days ; mannose ( 26 mM ) plus D-glucose ( 7 mM ) was used as osmotic control . Data obtained in the present study show that the exposure for 5 days to high glucose increases oxidative stress , reduces O95865 and P29474 expression and increases P35228 expression . These results indicate that O95865 and P35228 / P29474 dysregulation may play a key role in high glucose-mediated oxidative stress , suggesting that selective modulation of DDAH isoforms may result in selective inhibition/activation of NOS isoforms , thereby providing a novel strategy of approach in vascular complications of several pathologies . Pyrrolo[1,2-f]triazines as O60674 inhibitors : achieving potency and selectivity for O60674 over P52333 . SAR studies of pyrrolo[1,2-f]triazines as O60674 inhibitors is presented . Achieving O60674 inhibition selectively over P52333 is discussed . Could treatment with arundic acid ( DB05343 ) increase vulnerability for depression ? Arundic acid ( DB05343 ) is believed to be neuroprotective because of its actions on glia cells ; i.e. , its inhibitory effects on the synthesis of a calcium-binding protein P04271 . DB05343 is undergoing clinical trials for the treatment of patients with stroke and Alzheimer 's disease . Recent clinical studies point to a pervasive comorbidity of depression with stroke and Alzheimer 's disease . Previously , P04271 has been implicated in the pathobiological mechanisms of depression . Preclinical studies have shown that antidepressant treatment significantly increases brain P04271 . Here we hypothesize that available data that link P04271 with depression , along with the proposed inhibitory action of DB05343 on P04271 synthesis , indicate that this compound could increase vulnerability for depression in patients at risk for this disorder , and we propose that evaluation of patients with stroke and Alzheimer 's disease for the presence of depression should be routine in clinical trials employing DB05343 . Although it may be open for discussion whether the neuroprotective effects of DB05343 are exclusively due to its inhibition of P04271 synthesis , the latter action of DB05343 warrants studies of the effects of this drug in the pathobiology of depression . DB06603 synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells . BACKGROUND : Inducing endoplasmic reticulum ( ER ) stress is a novel strategy used to treat malignancies . Inhibition of histone deacetylase ( HDAC ) 6 by the HDAC inhibitor DB06603 hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90 . We investigated whether combining DB06603 with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins , thereby causing ubiquitinated proteins to accumulate and induce ER stress . METHODS : Caki-1 , ACHN , and 769-P cells were treated with DB06603 and/or bortezomib . Cell viability , clonogenicity , and induction of apoptosis were evaluated . The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model . The combination-induced ER stress and ubiquitinated protein accumulation were assessed . RESULTS : The combination of DB06603 and bortezomib induced apoptosis and inhibited renal cancer growth synergistically ( combination indexes < 1 ) . It also suppressed colony formation significantly ( p < 0.05 ) . In a murine subcutaneous tumor model , a 10-day treatment was well tolerated and inhibited tumor growth significantly ( p < 0.05 ) . Enhanced acetylation of the Q9UBN7 substrate alpha-tubulin was consistent with the suppression of Q9UBN7 activity by DB06603 , and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically . CONCLUSIONS : DB06603 inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation . The current study provides a basis for testing the combination in patients with advanced renal cancer . Aripiprazole : a review of its use in the treatment of manic episodes in adolescents with bipolar I disorder . Aripiprazole ( DB01238 (®) ) is an atypical antipsychotic that is widely used in the treatment of psychiatric conditions . Unlike other currently available atypical antipsychotics that primarily have varying degrees of dopamine D2 receptor antagonism , aripiprazole is a partial agonist at D2 and serotonin P08908 receptors , which may explain differences in tolerability profiles . Recently in the EU , oral aripiprazole 10 mg once daily for 12 weeks was approved for the treatment of moderate to severe manic episodes in adolescents ( aged ≥13 years ) with bipolar I disorder . Approval was based on a phase 3 , 30-week US trial in children and adolescents with bipolar I disorder experiencing manic or mixed episodes . Using trial data together with ancillary analyses , the European Medicines Agency concluded that aripiprazole 10 mg once daily for 12 weeks was effective in reducing symptoms of mania , but because of the high drop-out rate , efficacy over 30 weeks of treatment was not proven . Aripiprazole was generally well tolerated in the phase 3 trial . Ancillary analyses indicated that tolerability was less favourable in younger ( 10-12 years ) than in older ( ≥13 years ) subjects , and less favourable with the higher ( 30 mg/day ) than the lower dosage ( 10 mg/day ) . The drug is associated with sedation , weight gain and extrapyramidal symptoms ( EPS ) , although the incidence of EPS over 12 weeks was not significantly different between aripiprazole 10 mg/day and placebo . Data comparing the use of atypical antipsychotics in the treatment of mania in adolescents with bipolar I disorder are limited , but evidence shows that aripiprazole provides a valuable additional therapeutic option for use in this population . Cyclic guanosine monophosphate responses to atrial natriuretic factor , brain natriuretic peptide , but not P23582 , and the characterization of their receptors in rat medullary thick ascending limb . The effects of atrial natriuretic factor ( ANF ) , brain natriuretic peptide ( DB04899 ) , and P23582 ( P09543 ) on renal medullary thick ascending limb ( mTAL ) have not been fully understood . The aim of this study is to examine the second-messenger responses of rat mTAL to ANF , DB04899 , and P09543 . Characterizations of the ANF , DB04899 , and P09543 receptors in mTAL were also performed by radioligand studies . Results showed that ANF and DB04899 were both capable of eliciting cyclic guanosine monophosphate ( cGMP ) responses in mTAL . Conversely , no cGMP response was observed upon stimulation by P09543 in mTAL . The presence of ANF receptors was demonstrated by radioligand studies . One receptor site was found , and the Kd and maximum binding capacity were 4.0 +/- 0.45 nmol/L and 277.8 +/- 47.7 fmol/mg protein , respectively . DB04899 receptors were also found in mTAL , and ANF and DB04899 were sharing the same receptor . On the contrary , no P09543 receptor could be shown by radioligand studies . These results suggest that guanylyl cyclase-coupled receptors ( atrial natriuretic peptide receptor-A [ P16066 ] ) specific for ANF and DB04899 are present in rat mTAL , while those for P09543 ( P20594 ) are absent . ANF and DB04899 but not P09543 act on mTAL to control water excretion . The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid ( CD437 ) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases . The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid ( CD437 ) , which was originally developed as an retinoic acid receptor ( RAR ) -gamma agonist , induces rapid apoptosis in all-trans retinoic acid ( DB00755 ) -sensitive and DB00755 -resistant clones of the NB4 cell line , a widely used experimental model of acute promyelocytic leukemia ( APL ) . In addition , the compound is apoptogenic in primary cultures of freshly isolated APL blasts obtained from a newly diagnosed case and an DB00755 -resistant relapsed patient . NB4 cells in the S-phase of the cycle are most sensitive to CD437-triggered apoptosis . CD437-dependent apoptosis does not require de novo protein synthesis and activation of P13631 or any of the other nuclear retinoic acid receptors . The process is preceded by rapid activation of a caspase-like enzymatic activity capable of cleaving the fluorogenic DEVD but not the fluorogenic YVAD tetrapeptide . Increased caspase activity correlates with caspase-3 and caspase-7 activation . Inhibition of caspases by z-VAD suppresses the nuclear DNA degradation observed in NB4 cells treated with CD437 , as well as the degradation of pro-caspase-3 and pro-caspase-7 . CD437-dependent activation of caspases is preceded by release of cytochrome c from the mitochondria into the cytosol of treated cells . Leakage of cytochrome c lays upstream of caspase activation , because the phenomenon is left unaffected by pretreatment of NB4 cells with z-VAD . Treatment of APL cells with CD437 is associated with a caspase-dependent degradation of promyelocytic leukemia- P10276 , which can be completely inhibited by z-VAD . Neuronal ablation of p-Akt at Ser473 leads to altered P08908 /2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5-HT ) signaling . To explore how impairment in Akt function regulates 5-HT homeostasis , we used a brain-specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5- Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin ( 8-OH-DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head-twitch response ( HTR ) to the 5- Q13049 /C agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , with evidence of impaired 5- Q13049 /C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI-induced 5- Q13049 receptor signaling , thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation . These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function . Arundic acid ( DB05343 ) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of P04271 . After focal cerebral ischemia , the infarct volume increases rapidly within acute infarct expansion ( initial 12 to 24 h ) and continues slowly during delayed infarct expansion ( 25 to 168 h ) . While acute infarct expansion represents progressive necrosis within the ischemic core , delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border , which gradually coalesces to form a larger infarct . Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events . Specifically , the calcium binding protein P04271 exerts detrimental effects on cell survival through activation of various intracellular signaling pathways , resulting in altered protein expression . Arundic acid [ ( R ) -(-)-2-propyloctanoic acid , DB05343 ] is a novel agent that inhibits P04271 synthesis in cultured astrocytes . In the rodent ischemia model , this agent was shown to inhibit both the astrocytic overexpression of P04271 and the subsequent activation of signaling pathways in the peri-infarct area . Concurrently , delayed infarct expansion was prevented , and neurologic deficits were promptly ameliorated . The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression . Pulmonary arterial dysfunction in insulin resistant obese Zucker rats . BACKGROUND : P01308 resistance and obesity are strongly associated with systemic cardiovascular diseases . Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension . The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat . METHODS : Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording . mRNA and protein expression was measured by RT-PCR or Western blot , respectively . KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique . RESULTS : Right ventricular wall thickness was similar in obese and lean Zucker rats . Lung Q13873 , KV1.5 and 5- Q13049 receptor mRNA and protein expression and KV current density were also similar in the two rat strains . In conductance and resistance pulmonary arteries , the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung P29474 expression revealed a preserved endothelial function . However , in resistance ( but not in conductance ) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents ( hypoxia , phenylephrine and 5-HT ) was observed . The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the P35228 inhibitor 1400W . CONCLUSIONS : In contrast to rat models of type 1 diabetes or other mice models of insulin resistance , the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of P35228 . Investigation of the hub genes and related mechanism in ovarian cancer via bioinformatics analysis . BACKGROUND : Ovarian cancer is a cancerous growth arising from the ovary . OBJECTIVE : This study was aimed to explore the molecular mechanism of the development and progression of the ovarian cancer . METHODS : We first identified the differentially expressed genes ( DEGs ) between the ovarian cancer samples and the healthy controls by analyzing the GSE14407 affymetrix microarray data , and then the functional enrichments of the DEGs were investigated . Furthermore , we constructed the protein-protein interaction network of the DEGs using the STRING online tools to find the genes which might play important roles in the progression of ovarian cancer . In addition , we performed the enrichment analysis to the PPI network . RESULTS : Our study screened 659 DEGs , including 77 up- and 582 down-regulated genes . These DEGs were enriched in pathways such as Cell cycle , p53 signaling pathway , Pathways in cancer and Drug metabolism . P24864 , O95067 and P20815 were the significant genes identified from these pathways . Protein-protein interaction ( PPI ) network was constructed and network Module A was found closely associated with ovarian cancer . Hub nodes such as P15692 , P62158 , O15392 and P28340 were found in the PPI network . Module A was related to biological processes such as mitotic cell cycle , cell cycle , nuclear division , and pathways namely Cell cycle , Oocyte meiosis and p53 signaling pathway . CONCLUSIONS : It indicated that ovarian cancer was closely associated to the dysregulation of p53 signaling pathway , drug metabolism , tyrosine metabolism and cell cycle . Besides , we also predicted genes such as P24864 , O95067 , P20815 and P15692 might be target genes for diagnosing the ovarian cancer . Regulation of P40763 by histone deacetylase-3 in diffuse large B-cell lymphoma : implications for therapy . Diffuse large B-cell lymphoma ( DLBCL ) with an activated B-cell ( DB01048 ) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type . ABC cell lines have constitutive activation of P40763 ; however , the mechanisms regulating P40763 signaling in lymphoma are unknown . In studies of class-I histone deacetylase ( HDAC ) expression , we found overexpression of O15379 in phospho P40763 -positive DLBCL and the O15379 was found to be complexed with P40763 . Inhibition of HDAC activity by DB06603 ( LBH589 ) increased p300-mediated P40763 (Lys685) acetylation with increased nuclear export of P40763 to the cytoplasm . HDAC inhibition abolished P40763 (Tyr705) phosphorylation with minimal effect on P40763 (Ser727) and O60674 tyrosine activity . pSTAT3(Tyr705)-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3(Tyr705)-negative DLBCLs . This cytotoxicity was associated with downregulation of the direct P40763 target Mcl-1 . O15379 knockdown upregulated P40763 (Lys685) acetylation but prevented P40763 (Tyr705) phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells . These studies provide the rationale for targeting P40763 -positive DLBCL tumors with HDAC inhibitors . Genome-wide association studies identify P30532 /3 and Q13639 in the development of airflow obstruction . RATIONALE : Genome-wide association studies ( GWAS ) have identified loci influencing lung function , but fewer genes influencing chronic obstructive pulmonary disease ( P48444 ) are known . OBJECTIVES : Perform meta-analyses of GWAS for airflow obstruction , a key pathophysiologic characteristic of P48444 assessed by spirometry , in population-based cohorts examining all participants , ever smokers , never smokers , asthma-free participants , and more severe cases . METHODS : Fifteen cohorts were studied for discovery ( 3,368 affected ; 29,507 unaffected ) , and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up ( 3,837 cases ; 4,479 control subjects ) . Airflow obstruction was defined as Q99581 (1) and its ratio to FVC ( Q99581 (1)/FVC ) both less than their respective lower limits of normal as determined by published reference equations . MEASUREMENTS AND MAIN RESULTS : The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes A2RU49 , P48200 , and P30532 / P32297 genes . The region was also modestly associated among never smokers . Gene expression studies confirmed the presence of P30532 /3 in lung , airway smooth muscle , and bronchial epithelial cells . A single-nucleotide polymorphism in Q13639 , a gene previously related to Q99581 (1)/FVC , achieved genome-wide statistical significance in combined meta-analysis . Top single-nucleotide polymorphisms in Q9H013 , P10826 , O14495 , and Q8TE59 were nominally replicated in the P48444 meta-analysis . CONCLUSIONS : These results suggest an important role for the P30532 /3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the Q13639 gene in the etiology of airflow obstruction . Combined treatment with DB02546 , bortezomib , and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells . The ubiquitin-proteasome pathway and the autophagy-lysosome pathway are two major intracellular protein degradation systems . We previously reported that clarithromycin ( P62158 ) blocks autophagy flux , and that combined treatment with P62158 and proteasome inhibitor bortezomib ( BZ ) enhances ER-stress-mediated apoptosis in breast cancer cells , whereas treatment with P62158 alone results in almost no cytotoxicity . Since Q9UBN7 is involved in aggresome formation , which is recognized as a cytoprotective response serving to sequester misfolded proteins and facilitate their clearance by autophagy , we further investigated the combined effect of vorinostat ( suberoylanilide hydroxamic acid ( DB02546 ) ) , which has a potent inhibitory effect for Q9UBN7 , with P62158 and BZ in breast cancer cell lines . DB02546 exhibited some cytotoxicity along with an increased acetylation level of α-tubulin , a substrate of Q9UBN7 . Combined treatment of DB02546 , P62158 , and BZ potently enhanced the apoptosis-inducing effect compared with treatment using each reagent alone or a combination of two of the three . Expression levels of ER-stress-related genes , including the pro-apoptotic transcription factor P35638 ( P35638 ) , were maximally induced by the simultaneous combination of three reagents . Like breast cancer cell lines , a wild-type murine embryonic fibroblast ( MEF ) cell line exhibited enhanced cytotoxicity and maximally up-regulated Chop after combined treatment with DB02546 , P62158 , and BZ ; however , a Chop knockout MEF cell line almost completely canceled this enhanced effect . The specific Q9UBN7 inhibitor tubacin also exhibited a pronounced cytocidal effect with a combination of P62158 plus BZ . These data suggest that simultaneous targeting of intracellular proteolytic pathways and Q9UBN7 enhances ER-stress-mediated apoptosis in breast cancer cells . 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 . Characterization of a novel Q13639 receptor antagonist of the azabicycloalkyl benzimidazolone class : DAU 6285 . Three chemical classes of serotonin Q13639 receptor agonists have been identified so far : 5-substituted indoles ( e.g. 5-HT ) , benzamides ( e.g. renzapride ) and benzimidazolones ( e.g. BIMU 8 ) . In a search for Q13639 receptor antagonists , we have discovered that the benzimidazolone derivative DAU 6285 ( for structure see text ) , is 3-5 times more potent than tropisetron in blocking 5-HT , renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons . Schild plot analysis yielded Ki values of 220 , 181 and 255 nmol/l , respectively . In addition , DAU 6285 showed poor activity as a 5- Q9H205 receptor ligand with respect to tropisetron , as demonstrated by in vitro binding studies ( Ki , 322 vs 2.8 nmol/l ) and by its antagonistic activity in the Bezold-Jarisch reflex test ( ID50 , 231 vs 0.5 micrograms/kg , i.v. ) . No significant binding ( Ki greater than 10 mumol/l ) of DAU 6285 to serotonergic P08908 , P28222 , P28335 , P28221 , and 5-HT2 receptors as well as to adrenergic alpha 1 , alpha 2 , dopaminergic D1 , D2 or muscarinic M1-M3 receptor subtypes was found . The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for Q13639 receptors , a property confirmed in functional tests , and much lower affinity than tropisetron for 5- Q9H205 receptors . The compound represents a new interesting tool for investigating the pharmacological and physiological properties of Q13639 receptors . 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 syndrome . The aim of this study was to determine the effects of treatment with angiotensin II ( Ang II ) type-1 receptor blocker ( ARB ) on the regulation of adipocytokines . DB00275 , an ARB , significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice , without affecting body weight , but had no effect on plasma adiponectin levels in lean mice . DB00275 also ameliorated dysregulation of adipocytokines in obesity , such as tumor necrosis factor-alpha , plasminogen activator inhibitor-1 , monocyte chemotactic protein-1 , and serum amyloid A3 . DB00275 significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue . In cultured adipocytes , olmesartan acted as an antioxidant and improved adipocytokine dysregulation . Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated , at least in part , by targeting oxidative stress in obese adipose tissue . Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD . [ Leukemia- and lymphoma-associated flow cytometric , cytogenetic , and molecular genetic aberrations in healthy individuals ] . Most leukemia and lymphoma cases are characterized by specific flow cytometric , cytogenetic and molecular genetic aberrations , which can also be detected in healthy individuals in some cases . The authors review the literature concerning monoclonal B-cell lymphocytosis , and the occurrence of chromosomal translocations t(14;18) and t(11;14) , P06748 - Q9UM73 fusion gene , O60674 V617F mutation , P11274 - P00519 fusion gene , P41212 - Q01196 ( P41212 - Q01196 ) , Q03164 - P51825 and P29590 - P10276 fusion gene in healthy individuals . At present , we do not know the importance of these aberrations . From the authors review it is evident that this phenomenon has both theoretical and practical ( diagnostic , prognostic , and therapeutic ) significance . Expression of renin-angiotensin system components in the early bovine embryo . The renin-angiotensin system ( DB01367 ) , mainly associated with the regulation of blood pressure , has been recently investigated in female reproductive organs and the developing foetus . Angiotensin II ( Ang II ) influences oviductal gamete movements and foetal development , but there is no information about DB01367 in the early embryo . The aim of this study was to determine whether DB01367 components are present in the pre-implantation embryo , to determine how early they are expressed and to investigate their putative role at this stage of development . Bovine embryos produced in vitro were used for analysis of DB01367 transcripts ( RT-PCR ) and localisation of the receptors P30556 and P50052 ( immunofluorescent labelling ) . We also investigated the effects of Ang II , DB00275 ( P30556 antagonist ) and PD123319 ( P50052 antagonist ) on oocyte cleavage , embryo expansion and hatching . Pre-implanted embryos possessed P30556 and P50052 but not the other DB01367 components . Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst . P30556 was mainly localised in granular-like structures in the cytoplasm , suggesting its internalisation into clathrin-coated vesicles , and P50052 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells . Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control . These results , the first on DB01367 in the early embryo , suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself . This may be a route by which the maternal DB01367 influences blastocyst hatching and early embryonic development . Preclinical to clinical translation of tofacitinib , a Janus kinase inhibitor , in rheumatoid arthritis . A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity . The preclinical pharmacokinetic ( PK ) /pharmacodynamic ( PD ) profile of tofacitinib , an oral Janus kinase ( JAK ) inhibitor , in a mouse collagen-induced arthritis ( mCIA ) model was compared with clinical PK/PD data from patients with rheumatoid arthritis ( RA ) . Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice-daily ( P55957 ) dosing paradigms in mice . The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA , and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment ( 1-15 mg P55957 ) . In mCIA , the main driver of efficacy was inhibition of cytokine receptor signaling mediated by P23458 heterodimers , but not O60674 homodimers , and continuous daily inhibition was not required to maintain efficacy . Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm , with a total steady-state plasma concentration achieving 50 % of the maximal response ( Cave50 ) of ~100 nM . DB08895 potency ( ED50 ) in clinical studies was ~3.5 mg P55957 ( 90 % confidence interval : 2.3 , 5.5 ) or total Cave50 of ~40 nM , derived using Disease Activity Scores from patients with RA . The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy , rather than maximum or minimum plasma concentration ( Cmax or Cmin ) , where Cave50 values were within ~2-fold of each other . Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 D2- and Serotonin- P08908 -receptors as well as an antagonism at Serotonin-5- Q13049 -receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein . 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 . DB01686 and oxidative stress . Elevated plasma concentrations of the endogenous nitric oxide synthase ( P29474 ) inhibitor asymmetric dimethylarginine ( DB01686 ) represent a novel risk factor for the development of endothelial dysfunction and a predictor for all-cause and cardiovascular mortality . However , it is unknown whether elevated DB01686 plasma concentrations may be considered simply as a marker for cardiovascular disease or whether increased DB01686 levels per se may predispose to the development of vascular disease . There is experimental and clinical evidence linking endothelial dysfunction to increased production of oxygen-derived free radicals such as superoxide anion . Oxidative stress has been shown to increase the activity of arginine methylating and DB01686 degrading enzymes leading to increased DB01686 concentrations . Interestingly , the endothelial nitric oxide synthase may become uncoupled in the presence of high DB01686 levels further contributing to the vascular oxidative stress burden . It remains to be established to what extent DB01686 is able to interact with P29474 in vivo . Possible mechanisms underlying increased oxidative stress in the setting of elevated DB01686 concentrations and therapeutic implications will be discussed . P51955 mediates P00352 -dependent drug resistance in multiple myeloma . We reported previously that increased expression of aldehyde dehydrogenase 1 ( P00352 ) in multiple myeloma ( MM ) is a marker of tumor-initiating cells ( TICs ) that is further associated with chromosomal instability ( Q96GD0 ) . Here we demonstrate that member A1 of the P00352 family of proteins , P00352 , is most abundantly expressed in myeloma . Enforced expression of P00352 in myeloma cells led to increased clonogenicity , tumor formation in mice , and resistance to myeloma drugs in vitro and in vivo . The mechanism underlying these phenotypes included the P00352 -dependent activation of drug-efflux pump , P08183 , and survival proteins , AKT and P10415 . Over expression of P00352 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 ( P51955 ) , whereas shRNA-mediated knock down of P51955 decreased drug efflux pump activity and drug resistance . The activation of P51955 in myeloma cells relied on the P00352 -dependent generation of the retinoid X receptor α ( RXRα ) ligand , 9-cis retinoic acid ( 9CRA ) - not the retinoic acid receptor α ( RARα ) ligand , all-trans retinoic acid ( DB00755 ) . These findings implicate the P00352 -RXRα- P51955 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of P00352 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma . 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 . Agonist-promoted down-regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO- P04264 cells . WT , Ser22 , and Val28 displayed similar high-affinity binding to [ 3H ] -8-OH-DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist-promoted down-regulation was tested by exposure to 100 mumol/L 8-OH-DPAT . After 24-h exposure , WT and Val28 underwent 59.3 +/- 3.9 % and 59.5 +/- 1.4 % reduction in receptor density respectively , whereas the degree of down-regulation was significantly lower for Ser22 ( 21.4 +/- 4.2 % ) . Cell treatment for 24 h with 100 mumol/L 8-OH-DPAT reduced the 5-HT-induced inhibition of DB02527 accumulation by 24.9 +/- 5.1 % for WT and 16.4 +/- 0.8 % for Val28 , but only by 4.8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist-mediated receptor down-regulation and desensitization . Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors . Retinoids have great promise in the area of cancer therapy and chemoprevention . These natural and synthetic derivatives of vitamin A have been shown to play an important role in regulating cell differentiation and proliferation . While all-trans-retinoic acid ( DB00755 ) has been demonstrated to inhibit the growth of several ovarian tumor cell lines , other ovarian carcinoma cell lines have been found to be resistant to retinoid dependent growth suppression . Interestingly , a novel synthetic retinoid , CD437 or AHPN , has been demonstrated to inhibit the growth of both DB00755 -sensitive ( CA-OV3 ) and DB00755 -resistant ( SK-OV3 ) ovarian tumor cell lines as well as to induce apoptosis . The overall goal of this research was to understand the mechanism by which AHPN/CD437 induces apoptosis in ovarian tumor cell lines . Since a number of studies have demonstrated the importance of nuclear receptors ( RARs and RXRs ) in mediating cellular responses to retinoids , we wished to determine the role of RARs in mediating the AHPN/CD437 response . We modulated RAR level and function by overexpressing either wild type P13631 or a pan dominant negative mutant of all RAR subtypes called P10826 ( R269Q ) , or through the use of an P13631 antagonist , MM11253 . We found that inhibition of RAR function reduced but did not eliminate induction of apoptosis in both CA-OV3 and SK-OV3 cells by AHPN/CD437 . Likewise , overexpression of wild type P13631 was found to increase apoptosis after treatment with AHPN/CD437 . Our results suggest that in ovarian carcinomas , AHPN/CD437 induced apoptosis is mediated at least in part via an RAR pathway . Growth rates of hprt and tk mutant CHO cell lines . The growth rates of 31 X-ray-induced hypoxanthine phosphoribosyl transferase ( hprt ) deficient mutants of CHO- P04264 cells were measured . Mutants had been classified as ( 1 ) full-deletion , ( 2 ) partial deletion or rearrangement , or ( 3 ) unchanged by Southern blot analyses . No relationship between growth rate and deletion type was observed . Even where all hprt-specific bands were missing , proliferation rates in culture were normal . Additionally , in CHO- P01008 -2 cells , which are heterozygous at the tk locus , no difference in growth rates between a spontaneous hprt mutant and its parent was observed , although double hprt-tk-/- mutants grew more slowly . Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8-hydroxy-DPAT ( 8-OH-DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3-10 , 10-17 or 17-24 ) were injected daily with 1 mg/kg 8-OH-DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye-opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10-17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin 's influence in brain development . Activation of the JAK/ P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5-hydroxytryptamine , 5-HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5- Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK/ P35610 pathway in VSMCs and resultant potential alterations in 5-HT signaling in diabetes . Therefore , we tested the hypothesis that 5-HT differentially activates the JAK/ P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5-HT ( 10(-6) M ) resulted in time-dependent activation ( approximately 2-fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10(-9)-10(-5) M , 5-min stimulation ) did not activate the JAK/ P35610 pathway . Treatment with the 5- Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5-HT . Treatment of streptozotocin-induced diabetic rats with ketanserin ( 5 mg.kg-1.day-1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium-denuded thoracic aorta in vivo . 5-HT ( 10(-6) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK/ P35610 pathway by 5-HT . Therefore , we conclude that 5-HT activates O60674 , P23458 , and P42224 via the 5- Q13049 receptors in a reactive oxygen species-independent manner under both normal and high glucose conditions . Immunohistochemical analysis of brain lesions using P04271 and glial fibrillary acidic protein antibodies in arundic acid- ( DB05343 ) treated stroke-prone spontaneously hypertensive rats . Stroke-prone spontaneously hypertensive rats ( SHRSP ) used as a model of essential hypertension cause a high incidence of brain stroke on the course of hypertension . Incidences and sizes of brain lesions are known to relate to the astrocyte activities . Therefore , relation between brain damage and the expression profile of the astrocytes was investigated with morphometric and immunohistochemical analyses using astrocyte marker antibodies of P04271 and glial fibrillary acidic protein ( P14136 ) with or without arundic acid administration , a suppressor on the activation of astrocytes . Arundic acid extended the average life span of SHRSP . An increase in brain tissue weight was inhibited concomitant with a lower rate of gliosis/hemosiderin deposit/scarring in brain lesions . P04271 - or P14136 -positive dot and filamentous structures were decreased in arundic acid-treated SHRSP , and this effect was most pronounced in the cerebral cortex , white matter , and pons , and less so in the hippocampus , diencephalon , midbrain , and cerebellum . Blood pressure decreased after administration of arundic acid in the high-dose group ( 100 mg/kg/day arundic acid ) , but not in the low-dose group ( 30 mg/kg/day ) . These data indicate that arundic acid can prevent hypertension-induced stroke , and may inhibit the enlargement of the stroke lesion by preventing the inflammatory changes caused by overproduction of the P04271 protein in the astrocytes . Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension . P30556 blockers ( ARBs ) are regarded as first-line treatments for type-2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open-label prospective crossover study , we compared the effects of olmesartan ( 20 mg/day ) and telmisartan ( 40 mg/day ) . Twenty Japanese early-stage type-2 diabetes patients with hypertension treated with valsartan ( 80 mg/day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg/day ) or telmisartan ( 40 mg/day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24-h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . DB00275 lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA1c and adiponectin , the decreases in serum interleukin-6 and highly sensitive P02741 were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan .