interacts_with DB00834?
P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53-dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p-Src ) , P04049 , and P29323 . The levels of p-Src and p-Src-progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 . The P4-induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4-induced increases of the levels of p53 mRNA and protein . These data suggest that P4-induced up-regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4-induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant-negative P28482 prevented the P4-induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor-κB ( NF-κB ) nuclear translocation and NF-κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4-induced up-regulation of the p53 promoter activity was prevented by preadministration with dominant-negative P28482 or NF-κB inhibitors . Taken together , our data suggest that the cSrc/Kras/ P04049 / P28482 /NF-κB signaling pathway contributes to the P4-induced up-regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs . Phosphodiesterase inhibitors control A172 human glioblastoma cell death through DB02527 -mediated activation of protein kinase A and Epac1/Rap1 pathways . AIMS : We investigated whether DB02527 -mediated protein kinase A(PKA) and Epac1/Rap1 pathways differentially affect brain tumor cell death using 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone(rolipram) , specific phosphodiesterase type IV ( PDE IV ) inhibitor . MAIN METHODS : A172 and U87MG human glioblastoma cells were used . Percentage of cell survival was determined by MTT assay . PKA and Epac1/Rap1 activation was determined by western blotting and pull-down assay , respectively . Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis . KEY FINDINGS : Non-specific PDE inhibitors , isobutylmethylxanthine( DB07954 ) and theophylline reduce survival percentage of A172 and U87MG cells . The expression of P27815 and Q07343 was detected in A172 and U87MG cells . DB01954 -treated A172 or U87MG cell survival was lower in the presence of forskolin , adenylate cyclase activator , than that in its absence . Co-treatment with rolipram and forskolin also enhanced CREB phosphorylation on serine 133 that was inhibited by H-89 , PKA inhibitor and DB02527 -responsive guanine nucleotide exchange factor 1(Epac1) , a Rap GDP exchange factor-mediated Rap1 activity in A172 cells . When A172 cells were treated with cell-permeable dibutyryl- DB02527 (dbcAMP) , PKA activator or 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate(CPT) , Epac1 activator , basal level of cell death was increased and cell cycle was arrested at the phase of G2/M . DB01954 -induced A172 cell death was also increased by the co-treatment with dbcAMP or CPT , but it was inhibited by the pre-treatment with H-89 . SIGNIFICANCE : These findings demonstrate that PKA and Epac1/Rap1 pathways could cooperatively play a role in rolipram-induced brain tumor cell death . It suggests that rolipram might regulate glioblastoma cell density through dual pathways of PKA- and Epac1/Rap1-mediated cell death and cell cycle arrest . Targeted deletion of ER chaperone P14625 in the liver results in injury , repopulation of P14625 -positive hepatocytes , and spontaneous hepatocellular carcinoma development in aged mice . Hepatocellular carcinoma ( HCC ) often results from chronic liver injury and severe fibrosis or cirrhosis , but the underlying molecular pathogenesis is unclear . We previously reported that deletion of glucose regulated protein 94 ( P14625 ) , a major endoplasmic reticulum chaperone , in the bone marrow and liver leads to progenitor/stem cell expansion . Since liver progenitor cell ( Q16549 ) proliferation can contribute to liver tumor formation , here we examined the effect of P14625 deficiency on spontaneous liver tumorigenesis . Utilizing liver-specific Grp94 knockout mice driven by Albumin-Cre ( cGrp94(f/f) ) , we discovered that while wild-type livers are tumor free up to 24 months , cGrp94(f/f) livers showed abnormal small nodules at 15 months and developed HCC and ductular reactions ( DRs ) by 21 months of age , associating with increased liver injury , apoptosis and fibrosis . cGrp94(f/f) livers were progressively repopulated by P14625 -positive hepatocytes . At 15 months , we observed expansion of LPCs and mild DRs , as well as increase in cell proliferation . In examining the underlying mechanisms for HCC development in cGrp94(f/f) livers , we detected increase in TGF-β1 , activation of Q15796 /3 , P29323 , and JNK , and cyclin D1 upregulation at the premalignant stage . While epithelial-mesenchymal transition ( EMT ) was not evident , P12830 expression was elevated . Correlating with the recurrence of P14625 positive-hepatocytes , the HCC was found to be P14625 -positive , whereas the expanded LPCs and DRs remained P14625 -negative . Collectively , this study uncovers that P14625 deficiency in the liver led to injury , Q16549 expansion , increased proliferation , activation of oncogenic signaling , progressive repopulation of P14625 -positive hepatocytes and HCC development in aged mice . The use of a cyclooxygenase-2 inhibitor ( DB06802 ) in an ocular and metastatic animal model of uveal melanoma . The expression of cyclooxygenase-2 ( P35354 ) has been reported as an indicator of poor prognosis in a wide variety of human tumors , including colon , breast and uveal melanoma ( UM ) . P35354 inhibitors have shown promise in controlling the malignancy of several types of tumors . Previous studies have demonstrated the efficacy of a P35354 inhibitor on the proliferation rates of human UM cells . The goal of this experiment was to investigate the efficiency of DB06802 , a topically administered P35354 inhibitor , in a rabbit model of UM . The animals were divided into two groups of 14 animals for the duration of the 12-week experiment . One animal per group was killed each week to evaluate disease progression and for histopathological studies . The experimental group received drops containing 0.3 % DB06802 solution . Intraocular tumor growth was evaluated weekly by fundoscopic examination and each animal was weighed prior to examination . Blood samples were taken weekly from all rabbits to detect circulating malignant cells ( CMCs ) throughout the experiment . After the second week of inoculation , the experimental group weighed significantly more than the control group . The control group developed more intraocular tumors and presented with metastases and higher detectable levels of CMCs before the treated group . These results indicate that the topical administration of a P35354 inhibitor delayed the progression of this malignancy in our animal model . A clinical trail using an anti- P35354 inhibitor for patients with UM should be considered . Pharmacogenetics of antipsychotic-induced weight gain : review and clinical implications . Second-generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first-generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application . Hyperecho-turbo spin-echo sequences at 3T : clinical application in neuroradiology . BACKGROUND AND PURPOSE : Hyperecho-turbo spin-echo ( hyperTSE ) sequences were developed to reduce the specific absorption rate ( SAR ) , especially at high fields such as 3T and above . The purpose of this study was to quantitatively and qualitatively assess the detection of neuroradiologic pathologies by hyperTSE in comparison with standard turbo spin-echo ( TSE180 degrees ) sequences . MATERIALS AND METHODS : TSE180 degrees and hyperTSE images with parameters adapted for equal P24752 contrast were acquired on a 3T whole-body system in 51 patients with 54 cerebral pathologies . Region-of-interest analysis was performed of signal intensities of pathologies , normal white and gray matter , P04141 , and the SD of noise . Signal intensity-to-noise ratios ( SNRs ) and contrast-to-noise ratios ( CNRs ) for healthy tissues and pathologies were determined . A qualitative rating concerning artifacts , lesion conspicuity , and image quality was performed by 2 experienced neuroradiologists . RESULTS : HyperTSE sequences were equivalent to standard TSE180 degrees sequences for the P21554 of pathologies and of the contrast between gray and white matter . The SNR of gray and white matter and P04141 were also the same . The CNRs of the pathologies in hyperTSE and TSE180 degrees images were strongly correlated with each other ( r = 0.93 , P = .001 ) . The visual rating of images revealed no significant differences between hyperTSE and TSE180 degrees . CONCLUSION : HyperTSE sequences proved to be qualitatively and quantitatively equivalent to TSE180 degrees sequences in the detection of high- and low-signal-intensity lesions . They provide equal P21554 of pathologies and of gray minus white matter and reduce the imaging restrictions of conventional TSE180 degrees imposed by SAR limitations at 3T . DB00502 , but not clozapine , produces dramatic catalepsy in delta9-THC-treated rats : possible clinical implications . The effect on rat catalepsy induced by Delta9-tetrahydrocannabinol ( Delta9-THC ) in association with haloperidol ( HP ) or clozapine ( CLOZ ) administration was investigated . Delta9-THC dose-dependently increased HP ( 0.05-1 mg kg-1 , s.c. ) -induced rat catalepsy , while no catalepsy was observed after CLOZ ( 1-20 mg kg-1 , s.c. ) or Delta9-THC+CLOZ administration . The P21554 antagonist SR141716A ( 0.5-5 mg kg-1 , i.p. ) reversed the increase mediated by Delta9-THC on HP-induced catalepsy . The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP+Delta9-THC ; however , higher doses of quinpirole were needed in the presence of Delta9-THC . The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP+Delta9-THC in a similar manner . CLOZ and the 5- Q13049 /2C antagonists ritanserin , RS102221 and SB242084 were more effective in antagonizing HP than HP+Delta9-THC-induced catalepsy.7 HP and CLOZ failed to inhibit in vitro [3H]CP-55,940 binding , while Delta9-THC and SR141716A did not show an appreciable affinity for the D2 receptor . It was suggested that the different effects on rat catalepsy induced by Delta9-THC following HP or CLOZ administration may depend on the receptor-binding profiles of the two antipsychotics . The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed . CREB-Dependent Regulation of Q05329 Transcription by P23560 /TrkB in Cortical Interneurons . In the cerebral cortex , the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network , which use γ-aminobutyric acid ( GABA ) as their main neurotransmitter . Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme , Q05329 , depend on brain derived neurotrophic factor ( P23560 ) /TrkB activation . However , the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown . Here , we show a direct regulation of the Q05329 gene by P23560 -TrkB signaling via CREB in cortical interneurons . Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched Q05329 protein and its transcripts levels , suggesting that transcriptional regulation of the Q05329 gene is altered . Dissection of the intracellular pathway that underlies this process revealed that P23560 /TrkB signaling controls the transcription of Q05329 in a Ras- P29323 -CREB-dependent manner . Our study reveals a novel molecular mechanism through which P23560 /TrkB signaling may modulate the maturation and function of cortical inhibitory circuits . The P28222 receptor mediates the effect of d-fenfluramine on eating caused by intra-hypothalamic injection of neuropeptide Y . d- DB00574 ( 0.63 mg/kg i.p. ) , a serotonin ( 5-hydroxytryptamine , 5-HT ) releaser and re-uptake inhibitor , reduced the eating caused by neuropeptide Y ( 235 pmol ) injected into the paraventricular nucleus of the hypothalamus . The 5-HT1 and 5-HT2 receptor antagonist metergoline ( 1.0 and 2.0 mg/kg i.p. ) and the P08908 and P28222 receptor antagonist (+/-)-cyanopindolol ( 3.0 and 8.0 mg/kg s.c. ) significantly antagonized the effect of d-fenfluramine . The 5- Q13049 and P28335 receptor antagonist mesulergine ( 0.1 and 0.3 mg/kg s.c. ) and the 5- Q13049 receptor antagonist ketanserin ( 2.5 and 5.0 mg/kg i.p. ) did not significantly modify the effect , nor did the P08908 and P28222 receptor antagonist (-)-propranolol ( 20-40 nmol ) , injected bilaterally into the paraventricular nucleus of the hypothalamus . The results suggest that d-fenfluramine reduces neuropeptide Y 's hyperphagia by indirectly stimulating P28222 receptors outside the paraventricular nucleus of the hypothalamus . 5-HT manipulation and dietary choice : variable carbohydrate ( Polycose ) suppression demonstrated only under specific experimental conditions . The effects of six 5-HT anorectic agents , d-fenfluramine ( 5-HT releaser and reuptake inhibitor ) , fluoxetine ( 5-HT reuptake inhibitor ) , mCPP ( P28222 / P28335 receptor agonist ) , RU24969 ( P08908 / P28222 receptor agonist ) , MK212 ( P28335 receptor agonist ) and DOI ( 5-HT2/ P28335 receptor agonist ) , and two non-5-HT anorectic agents , salbutamol ( beta 2-adrenergic agonist ) and DB01576 ( catecholaminergic agonist ) , were examined in an experimental procedure designed to disclose selective effects on carbohydrate consumption . In this procedure , a revised version of what we have termed " The Classic Sclafani Paradigm " , animals are presented with powdered Polycose as an optional carbohydrate supplement to hydrated chow ( nutritionally complete diet ) . All drugs produced significant reductions in total ( hydrated chow plus powdered Polycose ) intake . However , only the 5-HT drugs DOI and fluoxetine exerted significantly stronger anorectic effects on intake of powdered Polycose than on intake of hydrated chow . d- DB00574 also showed a tendency to selectively suppress Polycose intake but this effect marginally failed to reach significance . These results suggest that when experimental conditions are favourable , what appears to be selective carbohydrate ( Polycose ) suppression can be demonstrated with certain 5-HT drugs . They also suggest that a selective effect on carbohydrate intake is not the most prominent feeding response to 5-HT drugs . DB00114 ( PLP ) deficiency might contribute to the onset of type I diabetes . The incidence of type I diabetes is rising worldwide , particularly in young children . Type I diabetes is considered a multifactorial disease with genetic predisposition and environmental factors participating . Currently , despite years of research , there is no consensus regarding the factors that initiate the autoimmune response . Type I diabetes is preceded by autoimmunity to islet antigens , among them the protein glutamic acid decarboxylase , Q05329 . DB00114 ( PLP ) is formed from vitamin B6 by the action of pyridoxal kinase . Interaction of Q05329 with PLP is necessary for Q05329 -mediated synthesis of the neurotransmitter γ-aminobutyric acid ( GABA ) . PLP is also a required cofactor for dopamine synthesis by L-aromatic decarboxylase ( L- P20711 ) . Both Q05329 and L- P20711 are expressed in pancreatic islets . Here it is proposed that lack of the vitamin B6 derivative pyridoxal 5'-phosphate might contribute to the appearance of pancreatic islet autoimmunity and type I diabetes onset . Mediation by 5-hydroxytryptamine2B receptors of endothelium-dependent relaxation in rat jugular vein . 1. An ' atypical ' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described . In the present study we have further defined the nature of the 5-HT2 receptor subtype present in this preparation . 2 . In experiments conducted in the presence of ketanserin to preclude involvement of 5-HT2 receptors , the mixed P41595 /2C antagonist , SB 200646 , acted as an antagonist of 5-HT at the endothelial 5-HT receptor ( pA2 = 7.2 ) . Yohimbine , which exhibits negligible affinity for rat P28335 receptors but has high P41595 receptor affinity , acted as a potent but non-surmountable antagonist ( pA2 > or = 7.3 ) in rat jugular vein . Neither yohimbine nor SB 200646 affected endothelium-dependent relaxations induced by carbachol . 3 . DB06148 also acted as a surmountable antagonist ( pA2 = 7.3 ) and the P41595 agonist , BW 723C86 , acted as a potent partial agonist ( pEC50 [ 95 % C L ] , intrinsic activity +/- s.e. mean = 7.9 [ 7.6-8.3 ] , 0.84 +/- 0.04 ) . Responses to BW 723C86 were antagonized by SB 200646 ( 0.3 microM ) yielding an ' apparent ' pA2 [ 95 % CL ] of 7.03 [ 6.76-7.32 ] . 4 . These data are consistent with the presence of P41595 receptors mediating endothelium-dependent relaxation of rat jugular vein . 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 . DB08885 . Metastatic colorectal cancer : at least as poorly tolerated as bevacizumab . The Folfiri protocol is often proposed to patients with metastatic colorectal cancer in relapse or treatment failure after the Folfox protocol . The benefit of adding a monoclonal antibody is far from certain . In two trials , addition of bevacizumab , a P15692 inhibitor , to a second-line regimen prolonged survival by about two months , at a cost of many additional serious or even life-threatening adverse effects . DB08885 ( Zaltrap , Sanofi Aventis ) , another P15692 inhibitor , has been authorised in the European Union as an adjunct to the Folfiri protocol in patients with metastatic colorectal cancer in treatment failure or relapse after a first-line regimen including oxaliplatin ( Folfox protocol , for example ) . DB08885 has not been compared with bevacizumab in this setting . In a double-blind , randomised , placebo-controlled trial including 1226 patients , adding aflibercept to the Folfiri protocol prolonged median overall survival by about 1.5 months . In this trial , 83 % of patients in the aflibercept group experienced at least one serious adverse event , versus 62 % of patients in the placebo group . DB08885 had the typical adverse effect profile of P15692 inhibitors , which includes arterial hypertension , arterial thrombosis , pulmonary embolism , bleeding , fistulae , bowel perforation , leukoencephalopathy , and delayed wound healing . Adding aflibercept also increased the frequency of certain adverse effects of the Folfiri protocol , including diarrhoea , dehydration , mucositis , infections and palmoplantar erythrodysesthesia . The adverse effects of aflibercept were fatal in some patients . In practice , patients with metastatic colorectal cancer in treatment failure or relapse after first-line therapy should not expect too much from the addition of aflibercept or bevacizumab to a second-line protocol . Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol-mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol 's ( 400mg/kg , oral ) antinociceptive activity was assessed through formalin-induced nociception . Serotonin content and gene expression of P08908 , 5- Q13049 and P21554 receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol-mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol-mediated increase in serotonin level . DB00316 did not alter P08908 expression , but caused down-regulation of 5- Q13049 and up-regulation of P21554 receptors . Arsenic down-regulated these receptors . However , paracetamol-mediated down-regulation of 5- Q13049 was more pronounced . Arsenic did not modify paracetamol 's effect on P08908 expression , but reduced paracetamol-mediated down-regulation of 5- Q13049 and reversed up-regulation of P21554 receptors . Results suggest arsenic reduced paracetamol-induced analgesia possibly by interfering with pronociceptive 5- Q13049 and antinociceptive P21554 receptors . The effects of a cyclooxygenase-2 ( P35354 ) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production . BACKGROUND : P35354 ( P35354 ) expression has previously been identified in uveal melanoma although the biological role of P35354 in this intraocular malignancy has not been elucidated . This study aimed to investigate the effect of a P35354 inhibitor on the proliferation rate of human uveal melanoma cells , as well as its effect on the cytotoxic response of macrophages . METHODS : Human uveal melanoma cell lines were transfected to constitutively express P35354 and the proliferative rate of these cells using two different methods , with and without the addition of Amfenac , was measured . DB00435 production by macrophages was measured after exposure to melanoma-conditioned medium from both groups of cells as well as with and without Amfenac , the active metabolite of DB06802 . RESULTS : Cells transfected to express P35354 had a higher proliferation rate than those that did not . The addition of Amfenac significantly decreased the proliferation rate of all cell lines . DB00435 production by macrophages was inhibited by the addition of melanoma conditioned medium , the addition of Amfenac partially overcame this inhibition . CONCLUSION : Amfenac affected both P35354 transfected and non-transfected uveal melanoma cells in terms of their proliferation rates as well as their suppressive effects on macrophage cytotoxic activity . Endothelin receptor antagonists as disease modifiers in systemic sclerosis . Systemic sclerosis ( SSc ) is a multisystem connective tissue disease of unknown etiology that is characterized by inflammation , vascular dysfunction and fibrosis of the skin and visceral organs . SSc is clinically diverse both in terms of the burden of skin and organ involvement and the rate of progression of the disease . Recent studies indicate that the endothelin system , especially ET-1 and the P25101 and ETB receptors may play a key role in the pathogenesis of SSc . A new class of drugs , endothelin receptor antagonists has been introduced for treatment of patients with pulmonary arterial hypertension ( PAH ) . DB00559 , a dual endothelin receptor antagonist as well as DB06268 and DB06403 , selective blockers of the P25101 receptor have proven effective in SSc-PAH . This effect may be mediated through both a vasodilatory and antifibrotic effect , thus making these agents attractive as potential disease modifying agents for SSc . Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours . BACKGROUND : This phase I cohort study investigated aflibercept ( vascular endothelial growth factor ( P15692 ) trap ) plus docetaxel and cisplatin in patients with advanced solid tumours . METHODS : Patients received intravenous aflibercept 4 , 5 , or 6 mg kg(-1) with docetaxel and cisplatin ( 75 mg m(-2) each ) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity . Primary objectives were determining cycle 1 dose-limiting toxicities ( DLTs ) and the aflibercept recommended phase II trial dose ( RP2D ) for this combination . RESULTS : During the dose-escalation phase ( n=16 ) , there were two DLTs of febrile neutropenia ( at 4 and 5 mg kg(-1) ) . P09919 prophylaxis was subsequently recommended . The RP2D of aflibercept was established at 6 mg kg(-1) and administered to 14 additional patients . The most frequent grade 3/4 adverse events ( AEs ) were neutropenia ( 43.3 % ) , stomatitis ( 20.0 % ) , asthenia/fatigue ( 20.0 % ) , and hypertension ( 16.7 % ) . All-grade AEs associated with P15692 blockade included epistaxis ( 83.3 % ) , dysphonia ( 70.0 % ) , proteinuria ( 53.3 % ) , and hypertension ( 50.0 % ) . There were five partial responses ( 16.7 % ) and 18 cases of stable disease ( 60.0 % ) ( lasting > 3 months in 10 patients ) . There were no pharmacokinetic ( PK ) interactions between the three drugs . CONCLUSION : DB08885 6 mg kg(-1) with docetaxel and cisplatin 75 mg m(-2) every 3 weeks is the RP2D based on tolerability , antitumour activity , and PKs . Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib-pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation . Downregulation of phosphodiesterase 4B ( Q07343 ) activates protein kinase A and contributes to the progression of prostate cancer . BACKGROUND : Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men . Unfortunately , few successful therapies for castration-resistant prostate cancer ( CRPC ) exist . The protein kinase A ( PKA ) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells . However , the PKA activity and the mechanism of regulation in CRPC remain unclear . Then , in this study , we intended to reveal the PKA activity and the mechanism of regulation in CRPC . METHODS : Western blotting , quantitative real-time polymerase chain reaction , cytotoxicity analysis , and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line , LNCaP and their derivatives . RESULTS : DB02527 -specific phosphodiesterase 4B ( Q07343 ) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives ( CxR cells ) . DB01954 activated the PKA pathway via inhibition of Q07343 , resulting in AR transactivation while the PKA inhibitor , H89 reduced AR transactivation . In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives ( HPR50 cells ) Q07343 was decreased and as a result PKA activity was increased . Moreover , Q07343 expression was reduced in advanced prostate cancer and Q07343 knockdown promoted castration-resistant growth of LNCaP cells . CONCLUSIONS : Oxidative stress may suppress Q07343 expression and activate the PKA pathway . The Q07343 /PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC . This pathway may represent an attractive therapeutic molecular target . 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 ( DB02901 ) 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 DB02901 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 . P04150 and histone deacetylase-2 mediate dexamethasone-induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up-regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose-dependent and time-dependent manner , and that the DB00514 -induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre-exposure of cells to DB00834 , a GR antagonist , and mutations in either the GRE3 or GRE5 cis-sites abolished the DB00514 -induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis-elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase-2 ( Q92769 ) in P98088 -expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis-elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 -specific short interfering RNA prevented the DB00514 -induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis-sites in the P98088 promoter and mediate the DB00514 -induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases . Antiinflammatory steroid action in human ovarian surface epithelial cells . The human ovarian surface epithelium ( OSE ) is subject to serial injury and repair during ovulation , which is a natural inflammatory event . We asked whether there is a compensatory antiinflammatory component to this process , involving steroid hormones produced locally at the time of ovulation . Quantitative RT-PCR analysis of total RNA from cultured human OSE cell monolayers showed that exposure to proinflammatory IL1alpha ( 500 pg/ml ) increased mRNA levels of cyclooxygenase-2 ( P35354 ) ( P < 0.01 ) at 48 h . The P35354 mRNA response to IL1alpha was associated with an approximate 18-fold ( P < 0.01 ) increase in mRNA levels of 11beta-hydroxysteroid dehydrogenase type 1 ( 11betaHSD1 ) , encoding the steroid dehydrogenase that reversibly reduces cortisone to antiinflammatory cortisol . Addition of cortisol to OSE cell culture medium dose-dependently suppressed the P35354 mRNA response to IL1alpha ( P < 0.01 ) but reciprocally enhanced the 11betaHSD1 mRNA response ( P < 0.05 ) , with both effects strongest at 1 microm cortisol . Presence of glucocorticoid receptor-alpha mRNA and protein was established in OSE cell monolayers and treatment with IL1alpha shown to significantly up-regulate the glucocorticoid receptor-alpha mRNA level ( P < 0.05 ) . P04150 antagonist ( DB00834 , 10 microm ) fully reversed the inhibitory effect of 1 microm cortisol on IL1alpha-stimulated P35354 mRNA expression . Progesterone also suppressed IL1alpha-induced P35354 mRNA expression but had no significant effect on IL1alpha-stimulated 11betaHSD1 expression . These data provide direct evidence for antiinflammatory actions of cortisol and progesterone in human OSE cells . Cholecystokinin-induced satiety depends on activation of P28335 receptors . To investigate the dependence of the satiating action of cholecystokinin on serotonergic function in rats , we examined the effects of systemic pretreatment with serotonin ( 5-HT ) antagonists of varying selectivity for 5-HT receptor subtypes on suppression of food intake induced by systemic administration of cholecystokinin octapeptide ( CCK-8 ) . DB06148 , a P28335 /2-selective antagonist , significantly attenuated the satiating action of CCK-8 . Ketanserin , a 5-HT2 antagonist , and three 5- Q9H205 antagonists , MDL-72222 , ICS 205-930 , and ondansetron , however , had no effect on the satiating action of CCK-8 . These results demonstrate that the satiating action of exogenous CCK depends on activation of 5-HT1 ( probably P28335 ) receptors and that activation of 5-HT2 or 5- Q9H205 receptors is not required . Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge-induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester-polyurethane sponges were implanted in C57Bl/6j mice . Animals received doses ( 3 and 10 mg/kg/daily , s.c. ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N-acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 -α , P15692 , P09341 /KC , P13500 /JE , and P10147 /MIP-1α levels , with increase in P13501 /RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge-induced inflammatory angiogenesis both via P21554 and CB2 receptors . Ameliorative Effect of a Selective Endothelin P25101 Receptor Antagonist in Rat Model of L- DB00134 -induced Vascular Dementia . The present study was designed to investigate the efficacy of selective P25101 receptor antagonist , ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia . L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats . DB06403 was administered to L-methionine-treated effect rats for 4 weeks ( starting from 5(th) to 8(th) week of L-methionine treatment ) . On 52(nd) day onward , the animals were exposed to the Morris water maze ( MWM ) for testing their learning and memory abilities . Vascular endothelial function , serum nitrite/nitrate levels , brain thiobarbituric acid reactive species ( TBARS ) , brain reduced glutathione ( DB00143 ) levels , and brain acetylcholinesterase ( P22303 ) activity were also measured . L-methionine-treated animals showed significant learning and memory impairment , endothelial dysfunction , decrease in/serum nitrite/nitrate and brain DB00143 levels along with an increase in brain TBARS levels and P22303 activity . DB06403 significantly improved hyperhomocysteinemia-induced impairment of learning , memory , endothelial dysfunction , and changes in various biochemical parameters . These effects were comparable to that of donepezil serving as positive control . It is concluded that ambrisentan , a selective P25101 receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia . DB03758 -sensitive peptide binding to the N-terminal portion of P14625 . P14625 is a molecular chaperone that carries immunologically relevant peptides from cell to cell , transferring them to major histocompatibility proteins for presentation to T cells . Here we examine the binding of several peptides to recombinant P14625 and study the regulation and site of peptide binding . We show that P14625 contains a peptide-binding site in its N-terminal 355 amino acids . A number of peptides bind to this site with low on- and off-rates and with specificity that is distinct from that of another endoplasmic reticulum chaperone , P11021 / P11021 . Binding to the N-terminal fragment is sufficient to account for the peptide binding activity of the entire molecule . Peptide binding is inhibited by radicicol , a known inhibitor of the chaperone activities of HSP90-family proteins . However , the peptide-binding site is distinct from the radicicol-binding pocket , because both can bind to the N-terminal fragment simultaneously . Furthermore , peptide binding does not cause the same conformational change as does binding of radicicol . When the latter binds to the N-terminal domain , it induces a conformational change in the downstream , acidic domain of P14625 , as measured by altered gel mobility and loss of an antibody epitope . These results relate the peptide-binding activity of P14625 to its other function as a chaperone . P04150 signaling in a bronchial epithelial cell line . Glucocorticoids are an effective anti-inflammatory therapy for the treatment of asthma . The anti-inflammatory effects of glucocorticoids may be due to the inhibition of transcription factors that regulate cytokine synthesis . Because of the potential role of the bronchial epithelium in asthmatic inflammation and the possibility that this cell may be the main target of inhaled glucocorticoids , we have characterized glucocorticoid receptors ( GR ) and GR signaling in the human bronchial epithelial cell line BEAS-2B . Western blot analysis and radioligand binding studies demonstrated that BEAS-2B cells have functional GR that bind to dexamethasone ( DB00514 ) ( dissociation constant = 5.6 nM and maximal density of binding sites = 228 +/- 3.3 fmol/mg protein ) . GR were activated by DB00514 as assessed using a glucocorticoid-responsive reporter plasmid . Transfection of BEAS-2B cells with an activator protein-1 ( AP-1 ) reporter construct followed by 12-O-tetradecanoylphorbol-13-acetate ( TPA ) treatment resulted in a fivefold induction of reporter gene activity . Transfection with a nuclear factor ( NF ) -kappa B reporter construct followed by tumor necrosis factor-alpha ( P01375 ) treatment resulted in a 10-fold induction of reporter gene activity . DB00514 ( 10(-7) M ) markedly repressed both the induced AP-1 and NF-kappa B activity . The GR antagonist DB00834 inhibited the repressive effect of DB00514 on P01375 -induced NF-kappa B activity by 81 % but only counteracted the repressive effect of DB00514 on TPA-induced AP-1 activity by 43 % . These studies demonstrate that cross-signaling between AP-1 and NF-kappa B with GR may explain the anti-inflammatory properties of glucocorticoids in airway epithelial cells . A transcriptional repressor co-regulatory network governing androgen response in prostate cancers . Transcriptional corepressors are frequently aberrantly over-expressed in prostate cancers . However , their crosstalk with the P10275 ( AR ) , a key player in prostate cancer development , is unclear . Using ChIP-Seq , we generated extensive global binding maps of AR , ERG , and commonly over-expressed transcriptional corepressors including Q13547 , Q92769 , O15379 , and Q15910 in prostate cancer cells . Surprisingly , our results revealed that ERG , HDACs , and Q15910 are directly involved in androgen-regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters . Moreover , we showed that similar to ERG , these corepressors function to mediate repression of AR-induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis . Specifically , we demonstrated that the direct suppression of P18206 expression by ERG , Q15910 , and HDACs leads to enhanced invasiveness of prostate cancer cells . Taken together , our results highlight a novel mechanism by which , ERG working together with oncogenic corepressors including HDACs and the polycomb protein , Q15910 , could impede epithelial differentiation and contribute to prostate cancer progression , through directly modulating the transcriptional output of AR . DB00114 values in cerebrospinal fluid : reference values and diagnosis of Q9NVS9 deficiency in paediatric patients . Our aim was to establish reference values for cerebrospinal fluid ( P04141 ) pyridoxal 5'-phosphate ( PLP ) in a paediatric population for the diagnosis of pyridox(am)ine 5'-phosphate oxidase ( Q9NVS9 ) deficiency . For reference values , P04141 samples from 113 paediatric controls ( age range : 1 day-18 years ) from Barcelona and London were analysed . Cerebrospinal fluid PLP and biogenic amine concentrations were analysed by HPLC with fluorescence and electrochemical detection . DB00114 concentrations in 4 patients with Q9NVS9 deficiency were determined . A negative correlation between P04141 PLP values and age of controls was observed in both populations ( r=-0.503 ; p < 0.0001 and r=-0.542 ; p=0.002 ) . Reference values were stratified into 4 ( Barcelona ) and 3 age groups ( London ) . For the newborn period , P04141 PLP reference intervals were 32-78 and 44-89 nmol/L for the Barcelona and London centers , respectively ) . No correlation was observed in the different age groups between PLP values and biogenic amines metabolites . PLP values in neonates with Q9NVS9 deficiency were clearly decreased ( PLP=3.6 , 12.0 , 14.0 and 18.0 nmol/L ) compared with our reference ranges . In conclusion , reference values for P04141 PLP should be stratified according to age . No association was observed between PLP values and biogenic amines metabolites . In our 4 cases with Q9NVS9 deficiency , P04141 PLP values were clearly below the reference values . Heat-shock factor 1 controls genome-wide acetylation in heat-shocked cells . A major regulatory function has been evidenced here for Q00613 , the key transcription factor of the heat-shock response , in a large-scale remodeling of the cell epigenome . Indeed , upon heat shock , Q00613 , in addition to its well-known transactivating activities , mediates a genome-wide and massive histone deacetylation . Investigating the underlying mechanisms , we show that Q00613 specifically associates with and uses Q13547 and Q92769 to trigger this heat-shock-dependent histone deacetylation . This work therefore identifies Q00613 as a master regulator of global chromatin acetylation and reveals a cross-talk between Q00613 and histone deacetylases in the general control of genome organization in response to heat shock . Fibroblast androgen receptors in patients with genitourinary anomalies . The etiology of certain disorders of sexual differentiation is unclear . The authors have examined the hypothesis that hypospadias and other disorders compatible with a defect in androgen action , such as cryptorchidism , micropenis , chordee/penile torsion , and ectopic testis , might be explained by androgen receptor abnormalities . Therefore , 25 subjects were studied who were selected only because they had one of these developmental defects , together with a predominantly male phenotype , and no readily ascertainable explanation for the defect . Four of these subjects had mixed gonadal dysgenesis with multiple genito-urinary anomalies . They were included for comparative purposes , since there is no evidence for androgen resistance in this disorder . Patients with testicular regression syndrome ( gross testosterone deficiency ) , impaired testosterone biosynthesis ( relative testosterone deficiency ) , 5 alpha-reductase deficiency ( altered T/ DB02901 ratio ) , and a family history or endocrine profile suggestive of androgen resistance , were all excluded from evaluation . P10275 content ( R0 ) and binding affinity ( Kd ) were measured in 26 genital or pubic skin fibroblast strains cultured from 25 affected patients using a dispersed , whole cell assay at 22 C . There was no difference in the mean androgen receptor content ( approximately 10,000 sites/cell ) or binding affinity ( approximately 1 nM ) between the patients ' fibroblasts and those from 26 fibroblast strains established from 26 normal males . Moreover , there were no differences in the nuclear uptake of [3H]dihydro-testosterone into dispersed , intact fibroblasts incubated at 37 C when 11 patient and seven normal male fibroblast strains were compared. ( ABSTRACT TRUNCATED AT 250 WORDS ) Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin P98088 protein by Streptococcus pneumoniae by inhibiting DB02527 -protein kinase A-dependent P28562 phosphatase pathway . Otitis media ( OM ) is the most common childhood bacterial infection and the major cause of conductive hearing loss in children . Mucus overproduction is a hallmark of OM . Streptococcus pneumoniae is the most common gram-positive bacterial pathogen causing OM . Among many mucin genes , P98088 has been found to be greatly up-regulated in the middle ear mucosa of human patients with OM . We previously reported that S. pneumoniae up-regulates P98088 expression in a MAPK P29323 -dependent manner . We also found that MAPK phosphatase-1 ( P28562 ) negatively regulates S. pneumoniae-induced P29323 -dependent P98088 up-regulation . Therapeutic strategies for up-regulating the expression of negative regulators such as P28562 may have significant therapeutic potential for treating mucus overproduction in OM . However , the underlying molecular mechanism by which P28562 expression is negatively regulated during S. pneumoniae infection is unknown . In this study we show that phosphodiesterase 4B ( Q07343 ) mediates S. pneumoniae-induced P98088 up-regulation by inhibiting the expression of a negative regulator P28562 , which in turn leads to enhanced MAPK P29323 activation and subsequent up-regulation of P98088 . Q07343 inhibits P28562 expression in a DB02527 -PKA-dependent manner . DB05876 -specific inhibitor rolipram inhibits S. pneumoniae-induced P98088 up-regulation both in vitro and in vivo . Moreover , we show that Q07343 plays a critical role in P98088 induction . Finally , topical and post-infection administration of rolipram into the middle ear potently inhibited S. pneumoniae-induced P98088 up-regulation . Collectively , these data demonstrate that Q07343 mediates P29323 -dependent up-regulation of mucin P98088 by S. pneumoniae by inhibiting DB02527 -PKA-dependent P28562 pathway . This study may lead to novel therapeutic strategy for inhibiting mucus overproduction . Dexamethasone inhibits interleukin-1β-induced matrix metalloproteinase-9 expression in cochlear cells . OBJECTIVES : To investigate the effect of interleukin ( IL ) -1β on matrix metalloproteinase ( MMP ) -9 expression in cochlea and regulation of IL-1β-mediated P14780 expression by dexamethasone and the molecular and signaling mechanisms involved . METHODS : House ear institute-organ of Corti 1 ( HEI-OC1 ) cells were used and exposed to IL-1β with/without dexamethasone . P04150 antagonist , DB00834 , was used to see the role of dexamethasone . PD98059 ( an extracellular signal-regulated kinases [ ERKs ] inhibitor ) , SB203580 ( a p38 mitogen-activated protein kinases [ MAPK ] inhibitor ) , SP600125 ( a c-Jun N-terminal kinase [ JNK ] inhibitor ) were also used to see the role of MAPKs signaling pathway(s) in IL-1β-induced P14780 expression in HEI-OC1 cells . Reverse transcription-polymerase chain reaction and gelatin zymography were used to measure mRNA expression level of P14780 and activity of P14780 , respectively . RESULTS : Treatment with IL-1β-induced the expression of P14780 in a dose- and time-dependent manner . IL-1β ( 1 ng/mL ) -induced P14780 expression was inhibited by dexamethasone . Interestingly , p38 MAPK inhibitor , SB203580 , significantly inhibited IL-1β-induced P14780 mRNA and P14780 activity . However , inhibition of JNKs and ERKs had no effect on the IL-1β-induced P14780 expression . CONCLUSION : These results suggest that the pro-inflammatory cytokine IL-1β strongly induces P14780 expression via activation of p38 MAPK signaling pathway in HEI-OC1 cells and the induction was inhibited by dexamethasone . DB03758 activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes . Heat shock proteins ( HSPs ) constitute an endogenous cellular defense mechanism against environmental stresses . In the past few years , studies have shown that overexpression of HSPs can protect cardiac myocytes against ischemia-reperfusion injury . In an attempt to increase the HSPs in cardiac tissue , we used the compound radicicol that activates HSP expression by binding to the P08238 kDa ( HSP90 ) . HSP90 is the main component of the cytosolic molecular chaperone complex , which has been implicated in the regulation of the heat shock factor 1 ( Q00613 ) . Q00613 is responsible for the transcriptional activation of the heat shock genes . In the present study , we show that radicicol induces HSP expression in neonatal rat cardiomyocytes , and this increase in HSPs confers cardioprotection to these cardiomyocytes . We also show that radicicol induction of the HSP and cardioprotection is dependent on the inhibition of HSP90 in cardiomyocytes . These results indicate that modulation of the active HSP90 protein level plays an important role in cardioprotection . Therefore , compounds , such as radicicol and its possible derivatives that inhibit the function of HSP90 in the cell may represent potentially useful cardioprotective agents . P04150 antagonism disrupts the reconsolidation of social reward-related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play-induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play-induced CPP . DB00834 did not affect social play-induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP . However , the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories .