MH_dev_175

The use of a cyclooxygenase - 2 inhibitor ( DB06802 MEN ) in an ocular and metastatic animal model of uveal melanoma . The expression of cyclooxygenase - 2 ( P35354 REA ) has been reported as an indicator of poor prognosis in a wide variety of human tumors , including colon , breast and uveal melanoma ( UM ) . P35354 REA inhibitors have shown promise in controlling the malignancy of several types of tumors . Previous studies have demonstrated the efficacy of a P35354 REA inhibitor on the proliferation rates of human UM cells . The goal of this experiment was to investigate the efficiency of DB06802 MEN , a topically administered P35354 REA 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 MEN 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 REA inhibitor delayed the progression of this malignancy in our animal model . A clinical trail using an anti - P35354 REA inhibitor for patients with UM should be considered .

DB08875 ( DB05153 MEN ) , a novel MET and P35968 REA inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 REA ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 REA , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 REA axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 MEN ) is a small-molecule kinase inhibitor with potent activity toward MET and P15692 REA receptor 2 ( P35968 REA ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 REA , P10721 REA , P30530 REA , and P36888 REA . Treatment with cabozantinib inhibited MET and P35968 REA phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 REA signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .

Natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild-type mice ; untreated UUO in P16066 REA KO mice ; and P01160 REA treated ( 0.05 microg / kg / min ) UUO in wild-type mice . We measured histological and immunohistochemical findings ( alpha-SMA and F4 /8 0 ) , tissue cGMP levels , various mRNA expression levels by real-time PCR analysis , and transcription factor levels ( AP - 1 and NF-kappaB ) in renal tissue . RESULTS : Compared with wild-type UUO mice , NPRA-KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha-SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta , collagen I , collagen III , P05121 REA , renin and angiotensinogen , whereas there were no differences in F4 /8 0 positive cells or the mRNA expression levels of P05362 REA , osteopontin , or P13500 REA between the two groups . In contrast , P01160 REA pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta , collagen I , collagen III , P05121 REA , P05362 REA , osteopontin , P13500 REA , renin , and angiotensinogen . NPRA-KO UUO mice had higher AP - 1 levels than wild-type UUO mice and P01160 REA pre-treatment reduced AP - 1 and NF-kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 REA system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF-beta / collagen pathway and exogenous P01160 REA pre-treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF-beta / collagen and NF-kappaB / inflammatory pathways .

Current status of antibody therapy in ALL . Despite the significant advances in modern chemotherapy , it remains challenging to treat adult patients with acute lymphoblastic leukaemia ( ALL ) . The relapse rate remains high , and the outcome at the time of relapse is dismal . Antibody-based therapies have demonstrated promising results in this patient group . Variable mechanisms have been applied to target surface antigens ( P11836 [ also termed P11836 ] , P20273 REA , P31358 REA and P15391 REA ) that are commonly expressed on malignant leukaemia cells . In this review , we will focus on the clinical application of such therapies in adult ALL , including the naked antibodies : DB00073 , Ofatumumab , DB04958 and DB00087 ; the immunotoxins : BL22 and Combotox ; the immunoconjugates : inotuzumab and SAR 3419 ; as well as the Bi-specific T cell engaging ( BiTE ) - specific antibody , DB09052 MEN .

Block of Q12809 REA channels by berberine : mechanisms of voltage - and state-dependence probed with site-directed mutant channels . DB04115 prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude . Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current , I ( Kr ) and I ( Ks ) . Here we have studied the effects of berberine on hERG ( I ( Kr ) ) and P51787 REA / P15382 REA ( I ( Ks ) ) channels expressed in P29320 REA - 293 cells and Xenopus oocytes . In P29320 REA - 293 cells , the IC50 for berberine was 3.1 + / - 0.5 microM on hERG compared with 11 + / - 4 % decreases on P51787 REA / P15382 REA channels by 100 microM berberine . Likewise in oocytes , hERG channels were more sensitive to block by berberine ( IC50 = 80 + / - 5 microM ) compared with P51787 REA / P15382 REA channels ( approximately 20 % block at 300 microM ) . hERG block was markedly increased by membrane depolarization . Mutation to Ala of Y652 or F656 located on the S6 domain , or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine . An inactivation-deficient mutant hERG channel ( G628C / S631C ) was also blocked by berberine . Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists .

Acute effects of acamprosate and MPEP on ethanol Drinking-in-the-Dark in male C57BL / 6J mice . BACKGROUND : Recently , a simple procedure in mice , Drinking-in-the-Dark ( DID ) , was hypothesized to have value for medication development for human alcoholism . In DID , mice are offered intermittent , limited access to ethanol over a series of days during the dark phase that results in rapid drinking to intoxication in predisposed genotypes . METHODS : We measured the effects of acamprosate or MPEP , metabotropic glutamate 5 receptor ( P41594 REA ) antagonist , on intake of 20 % ethanol , plain tap water or 10 % sugar water using the DID procedure in male C57BL / 6J mice . RESULTS : DB00659 MEN ( 100 , 200 , 300 , or 400 mg / kg ) dose dependently decreased ethanol drinking with 300 mg / kg reducing ethanol intake by approximately 20 % without affecting intake of plain water or 10 % sugar water . MPEP ( 1 , 3 , 5 , 10 , 20 , or 40 mg / kg ) was more potent than acamprosate with 20 mg / kg reducing ethanol intake by approximately 20 % and for longer duration without affecting intake of plain water or 10 % sugar water . CONCLUSIONS : These results support the hypothesis that P41594 REA signaling plays a role in excessive ethanol intake in DID and suggest DID may have value for screening novel compounds that reduce overactive glutamate signaling for potential pharmaceutical treatment of excessive ethanol drinking behavior .

The low-potency , voltage-dependent Q12809 REA blocker propafenone - - molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 REA ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe 656 and Tyr 652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 REA blockers may be different . In this study , alanine-substituted Q12809 REA channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 REA channel binding site of the antiarrhythmic propafenone . DB01182 SUB ' s blockade of Q12809 REA was strongly dependent on residue Phe 656 but was insensitive or weakly sensitive to mutation of Tyr 652 , Thr 623 , Ser 624 , Val 625 , Gly 648 , or Val 659 and did not require functional inactivation . Homology models of Q12809 REA based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe 656 in the closed state ( whereas exclusive interactions between propafenone and Phe 656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 REA channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe 656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe 656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe 656 side chains .

DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post-stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell ( NFAT ) signaling ] and increased P15692 REA gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col 1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 REA and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild-type European brown trout , Salmo trutta . A positive correlation between post-stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post-stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well-known from mammalian cardiology .

Aripiprazole : a review of its use in the treatment of manic episodes in adolescents with bipolar I disorder . Aripiprazole ( DB01238 MENMAX DB01238 MEN ( ® ) ) 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 REA 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 .

Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 REA , Q12809 REA , Q14524 REA , P22460 REA , Q9UK17 , P15382 REA , 2 , 5 , P63252 REA , P35498 REA - 3B , P01160 REA , and P36382 REA from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .

Differential expression of urokinase-type plasminogen activator and plasminogen activator inhibitor - 1 in early and late gestational mouse skin and skin wounds . Early gestation fetal mouse skin heals without scars . P00747 REA activator inhibitor - 1 ( P05121 REA ) has been associated with postnatal organ fibrosis . We hypothesized that the relative balance between urokinase-type plasminogen activator ( uPA ) and P05121 REA expression in favor of uPA prevents scarring in early fetal skin wounds , whereas a change in favor of P05121 REA in late gestation results in wound scarring . To evaluate uPA and P05121 REA expression , 1 - mm skin wounds were made in Q14207 . 5 and E18 mice and harvested 24 , 48 , or 96 hours postwounding . DB06692 MEN ( 2 mg / ml ) - coated beads were injected into selected Q14207 . 5 wounds . Normal skin and skin wounds were evaluated for uPA , P05121 REA , and collagen expression . We showed that in normal skin uPA level is higher in Q14207 . 5 than in E18 mice , while P05121 REA is lower in Q14207 . 5 than in E18 mice . After wounding , Q14207 . 5 wounds show a moderate increase in uPA and a minimal increase in P05121 REA . E18 wounds show a transient increase in uPA but a significant , sustained increase in P05121 REA . Addition of aprotinin to Q14207 . 5 wounds causes an increase in collagen deposition . We conclude that the differential expression of uPA and P05121 REA in the skin of early vs . late gestation mice may contribute to the degree of scar formation seen after cutaneous injury .

Role of the P08908 REA 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 REA 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 REA receptor interactions with epidermal growth factor ( P01133 REA ) . Behaviorally , the animals were more anxious . Animals treated from P01160 REA 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 REA 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .

Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 REA gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 REA gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 REA gene activity is DB00136 itself , which down-regulates the gene . The down-regulation of the O15528 REA gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 REA - binding regions in the distal promoter , 2.6 and 3.2 kb upstream from the TSS , that bind vitamin D receptor-retinoid X receptor complexes . Since the down regulation of the O15528 REA gene is tissue - and cell-type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 REA - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non-permissive to the phenomenon of DB00136 - mediated down-regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 REA promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 REA gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 REA gene is repressed in P29320 REA - 293 but not in MCF - 7 cells .

Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 REA ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 REA plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 REA / 2 - P27361 REA / 2 with the result of inhibition of DNA synthesis . P01160 REA , as well as its receptors ( P16066 REA and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 REA . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 REA / 2 - P27361 REA / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 REA markedly . Nevertheless , the role of P01160 REA in MM is unclear . Based on these results above , we raise the hypothesis that P01160 REA is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 REA may be a potential agent to treat MM .

Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 REA victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44.1 ± 72.1 days ) were genetically analyzed for P51787 REA , Q12809 REA , P15382 REA - 5 , P63252 REA , Q14524 REA , P36382 REA , and P62158 by using denaturing high-performance liquid chromatography and direct sequencing . Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 REA and Q12809 REA cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 REA , and 1 mutation ( p . G628D ) in Q12809 REA . N1774D , F1486del , and N406K in Q14524 REA displayed tetrodotoxin-sensitive persistent late Na ( + ) currents . By contrast , Q14524 REA - T290fsX53 was nonfunctional . Q12809 REA - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 REA mutations , as well as loss of function associated with the Q12809 REA mutation .

DB01780 MEN signaling reveals 14-3- 3 protein function as a novel step in left-right patterning during amphibian embryogenesis . To gain insight into the molecular mechanisms underlying the control of morphogenetic signals by H + flux during embryogenesis , we tested DB01780 MEN - A ( FC ) , a compound produced by the fungus Fusicoccum amygdali Del . In plant cells , FC complexes with 14-3- 3 proteins to activate H + pumping across the plasma membrane . It has long been thought that FC acts on higher plants only ; here , we show that exposing frog embryos to FC during early development specifically results in randomization of the asymmetry of the left-right ( LR ) axis ( heterotaxia ) . Biochemical and molecular-genetic evidence is presented that 14-3- 3 - family proteins are an obligate component of Xenopus FC receptors and that perturbation of 14-3- 3 protein function results in heterotaxia . The subcellular localization of 14-3- 3 mRNAs and proteins reveals novel cytoplasmic destinations , and a left-right asymmetry at the first cell division . Using gain-of-function and loss-of-function experiments , we show that P62258 REA protein is likely to be an endogenous and extremely early aspect of LR patterning . These data highlight a striking conservation of signaling pathways across kingdoms , suggest common mechanisms of polarity establishment between C . elegans and vertebrate embryos , and uncover a novel entry point into the pathway of left-right asymmetry determination .

Competitive interaction of seven in absentia homolog - 1A and Ca2 + / calmodulin with the cytoplasmic tail of group 1 metabotropic glutamate receptors . BACKGROUND : Group 1 metabotropic glutamate receptors ( Q13255 REA and P41594 REA ) are coupled to inositol trisphosphate / Ca2 + signaling via G proteins and play an important role in excitatory synaptic transmission . To explore the regulation of group 1 mGluR function , we applied the yeast two-hybrid system using the intracellular carboxy-terminal domain of group 1 mGluRs ( group 1 ct-mGluRs ) and attempted to identify novel protein-protein interactions of group 1 mGluRs . RESULTS : The two-hybrid screening revealed a specific interaction between group 1 ct-mGluRs and Siah - 1A , the mammalian homolog of Drosophila seven in absentia which is involved in photoreceptor cell differentiation via the ubiquitin / proteasome-dependent mechanism . This interaction occurs within a homologous 27-28 amino acid stretch within group 1 ct-mGluRs and requires the latter two-thirds of Siah - 1A . Following coexpression in COS - 7 cells , myc-tagged Siah - 1A was coimmunoprecipitated with the flag-tagged ct - Q13255 REA by anti-flag antibody . Furthermore , in vitro binding revealed that Siah - 1A and Ca2 + / calmodulin ( P62158 ) binding sites overlap , such that Siah - 1A binding is competitively inhibited by P62158 in a Ca2 + - dependent manner . CONCLUSIONS : The results demonstrate a direct interaction between group 1 mGluRs and Siah - 1A and suggest a novel modulatory mechanism mediated by a competitive interaction between Ca2 + / P62158 and Siah - 1A .

Inhibition of aldehyde dehydrogenase 2 activity enhances antimycin-induced rat cardiomyocytes apoptosis through activation of MAPK signaling pathway . Aldehyde dehydrogenase 2 ( P05091 REA ) , a mitochondrial-specific enzyme , has been proved to be involved in oxidative stress-induced cell apoptosis , while little is known in cardiomyocytes . This study was aimed at investigating the role of P05091 REA in antimycin A-induced cardiomyocytes apoptosis by suppressing P05091 REA activity with a specific P05091 REA inhibitor DB02115 MEN . Antimycin A ( 40μg / ml ) was used to induce neonatal cardiomyocytes apoptosis . DB02115 MEN ( 60μM ) effectively inhibited P05091 REA activity by 50 % without own effect on cell apoptosis , and significantly enhanced antimycin A-induced cardiomyocytes apoptosis from 33.5 ± 4.4 to 56.5 ± 6.4 % ( Hochest method , p < 0.05 ) , and from 57.9 ± 1.9 to 74.0 ± 11.9 % ( FACS , p < 0.05 ) . Phosphorylation of activated MAPK signaling pathway , including extracellular signal-regulated kinase ( P27361 REA / 2 ) , c-Jun NH2 - terminal kinase ( JNK ) and p38 was also increased in antimycin A and daidzin treated cardiomyocytes compared to the cells treated with antimycin A alone . These findings indicated that modifying mitochondrial P05091 REA activity / expression might be a potential therapeutic option on reducing oxidative insults induced cardiomyocytes apoptosis .

Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 MEN ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1,25- dihydroxyvitamin D ( 1,25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 REA is the key 1 - hydroxylase . Both 25OHD and 1,25 ( OH ) 2D are catabolized by Q07973 REA . 1,25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 REA ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell-specific fashion . P11473 REA - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1,25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .

Immunophenotypic profile and role of adhesion molecules in splenic marginal zone lymphoma with bone marrow involvement . Splenic Marginal Zone Lymphoma ( SMZL ) , with or without villous lymphocytes ( VL + / - ) , is a low-grade lymphoproliferative disorder with constant involvement of the bone marrow ( BM ) . Different BM infiltration patterns , mainly intra-sinusoidal , interstitial and nodular , have been described . Adhesion molecules ( AMs ) constitute a heterogeneous group of antigenic receptors playing a major role in leukocyte recruitment , in lymphocyte homing and in cellular-mediated immune response . Evolution and pattern of the BM infiltrate could be influenced by a variable expression of AM on SMZL lymphocytes . The degree and pattern of BM infiltration and the immunohistochemical expression of AM ( H - P62158 , P20273 REA , P14151 REA , Q14242 REA , P16581 REA , P05362 REA , P19320 REA and Beta - 1 integrin ) among the different infiltration patterns were evaluated in BM biopsies of 38 patients with SMZL and graded according to a semi-quantitative score ranging from 0-4 and based on the percentage of positive cells . An intra-sinusoidal infiltration was constantly observed , alone or in conjunction with other patterns . H - P62158 and P20273 REA showed a moderate-to-high degree of positivity in the intra-sinusoidal infiltrate ( median expression grade - 3 ) and were expressed in the neoplastic lymphocytes independently from the pattern . Q14242 REA was mostly expressed in the perisinusoidal region and in case of interstitial infiltration ( grade - 2 ) . P05362 REA and P19320 REA were selectively expressed in the nodules as a reticular meshwork located in the core region ( grade - 2 ) ; P19320 REA was also expressed in the perinodular endothelia . P16581 REA , P14151 REA and beta - 1 integrin proved constantly negative . These data suggest that different expression of AM can influence the modality of BM infiltration in SMZL .

Potential opposite roles of the extracellular signal-regulated kinase ( P29323 REA ) pathway in autism spectrum and bipolar disorders . Signal transduction from the synapse to the nucleus subsequently involves transient increases in synaptic Ca2 + , activation of P62158 kinases , activation of the GTPase Ras , activation of the P29323 REA mitogen-activated protein kinase pathway , and finally GSK 3 inhibition and CREB-activation . Genetic studies in autism have identified mutations and copy number variations in a number of genes involved in this synapse to nucleus signaling path . In particular , a gain of function mutation in the Q13936 REA gene , deletions and disruption of the Q96PV0 gene , a copy number variation encompassing the P27361 REA gene and a duplication of P62258 REA indicate that in a subset of autism patients the P29323 REA cascade is inappropriately activated . Predicted functional consequences of this hyperactivation would be an increase in complexity of the dendritic tree , and via inhibition of GSK 3 , a delayed circadian phase . The latter effect indeed fits the frequent sleep disturbances observed in autistic patients . Interestingly , the sleep disturbances in bipolar disorder patients are frequently characterized as phase advanced . A selective evaluation of genetic mutations in bipolar patients indicates that the activity of the P29323 REA cascade , at least in a subset of patients , presumably is hypoactive . Thus , with respect to the P29323 REA pathway , autism and bipolar disorder seem each other ' s counter pole .

Celecoxib blocks cardiac Kv1 . 5 , Kv4 . 3 and Kv7 . 1 ( P51787 REA ) channels : effects on cardiac action potentials . Celecoxib is a P35354 REA inhibitor that has been related to an increased cardiovascular risk and that exerts several actions on different targets . The aim of this study was to analyze the effects of this drug on human cardiac voltage-gated potassium channels ( Kv ) involved on cardiac repolarization Kv1 . 5 ( I ( Kur ) ) , Kv4 . 3 + Q9NS61 ( I ( to1 ) ) and Kv7 . 1 + P15382 REA ( I ( Ks ) ) and to compare with another P35354 REA inhibitor , rofecoxib . Currents were recorded in transfected mammalian cells by whole-cell patch-clamp . Celecoxib blocked all the Kv channels analyzed and rofecoxib was always less potent , except on Kv4 . 3 + Q9NS61 channels . Kv1 . 5 block increased in the voltage range of channel activation , decreasing at potentials positive to 0 mV . The drug modified the activation curve of the channels that became biphasic . Block was frequency-dependent , increasing at fastest frequencies . Celecoxib effects were not altered by DB08837 ( out ) in R487Y mutant Kv1 . 5 channels but the kinetics of block were slower and the degree of block was smaller with DB08837 ( in ) , indicating that celecoxib acts from the cytosolic side . We confirmed the blocking properties of celecoxib on native Kv currents from rat vascular cells , where Kv1 . 5 are the main contributors ( IC ( 50 ) ≈ 7 μM ) . Finally , we demonstrate that celecoxib prolongs the action potential duration in mouse cardiac myocytes and shortens it in guinea pig cardiac myocytes , suggesting that Kv block induced by celecoxib may be of clinical relevance .