interacts_with DB00422?
DB05387 ( AEterna ) . AEterna is developing DB05387 , an angiogenesis inhibitor derived from the ultrafiltration of liquid shark cartilage , with matrix metalloprotease ( MMP ) -2 , P14780 and vascular endothelial growth factor inhibitory properties , for the potential treatment of non-small-cell lung cancer . Effects of phenacetin and its metabolite p-phenetidine on P23219 and P35354 activities and expression in vitro . The present study was aimed to test the possible cyclooxygenase ( P36551 ) -1/ P35354 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine , which exhibits high renal toxicity . DB00316 ( acetaminophen ) , the main metabolite of phenacetin with low renal toxicity , and indomethacin were selected as reference compounds . Collagen-stimulated platelet thromboxane B2 ( TxB2 ) production and phorbol 12-myristate-13-acetate ( PMA ) -induced neutrophil prostaglandin E2 ( DB00917 ) synthesis were used as indicators for P23219 and P35354 activity , respectively . DB03783 was even less potent than paracetamol to reduce the production of both TxB2 and DB00917 , and no clear preference for either of the P36551 -enzymes was seen . P-phenetidine was a more potent inhibitor , already at nanomolar level , of the synthesis of these prostanoids than indomethacin and showed some preference to P35354 inhibition . Somewhat higher , micromolar , concentrations of p-phenetidine also reduced P35354 expression in neutrophils . We suggest that the very potent inhibitory activity of p-phenetidine on DB00917 synthesis combined with the reduction of P35354 expression could explain the renal papillary necrosis in phenacetin kidney . Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit/hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR≥2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1.73 ; CI 1.15-2.59 ; P=0.008 ) and the P35372 risk genotypes ( rs1799971 : OR 1.71 ; CI 1.17-2.50 ; P=0.006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted . [ Pharma-clinics. The drug of the month. Celecoxib ( DB00482 ) ] . Celecoxib ( DB00482 , Pharmacia ) is a potent and selective inhibitor of the P35354 isoform of cyclooxygenase which is used as nonsteroidal anti-inflammatory drug ( NSAID ) . Its current indications are osteoarthritis and rheumatoid arthritis . The usual recommended daily dosage of celecoxib is 200 mg ( in one or two intakes per day ) , to be increased up to 400 mg ( two intakes per day ) if necessary . Its clinical efficacy seems to be similar to that of other NSAIDs . However , its safety profile , especially gastro-intestinal tolerance and perhaps renal safety , is much better because of the P35354 selectivity . Serotonin and vasopressin interact in the hypothalamus to control communicative behavior . The present study investigated whether serotonin ( 5-HT ) agonists could inhibit the ability of arginine-vasopressin ( AVP ) to induce a form of scent marking called flank marking by their actions in the medial preoptic-anterior hypothalamus ( MPOA-AH ) . DOI , a 5- Q13049 ,2B,2C receptor agonist , did not inhibit AVP-induced flank marking , but mCPP a 5- Q13049 antagonist and P41595 ,2C agonist inhibited AVP-induced flank marking . In addition , the finding that 8-OH-DPAT , CGS-12066A and SC53116 also inhibited AVP-induced flank marking suggests that 5-HT could also inhibit flank marking by acting through P08908 , P34969 , P28222 and/or Q13639 receptor subtypes . These data support the hypothesis that 5-HT acts within the MPOA-AH to inhibit the ability of AVP to induce flank marking . DB06288 is a potent P34969 antagonist : relevance for antidepressant actions in vivo . RATIONALE : DB06288 is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia , a mild form of depression , in Italy . DB06288 has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials . In part because of the selective D(2)/D(3) receptor antagonist properties of amisulpride , it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties . OBJECTIVES : The purpose of these studies was to determine if amisulpride 's antidepressant actions are mediated by off-target interactions with other receptors . MATERIALS AND METHODS : We performed experiments that : ( 1 ) examined the pharmacological profile of amisulpride at a large number of central nervous system ( CNS ) molecular targets and , ( 2 ) after finding high potency antagonist affinity for human 5-HT(7a) serotonin receptors , characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT(7) receptor knockout mice . RESULTS : We discovered that amisulpride was a potent competitive antagonist at 5-HT(7a) receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo . Significantly , and in contrast to their wild-type littermates , 5-HT(7) receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression , the tail suspension test and the forced swim test . CONCLUSIONS : These results indicate that 5-HT(7a) receptor antagonism , and not D(2)/D(3) receptor antagonism , likely underlies the antidepressant actions of amisulpride . Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic-pituitary-gonadal axis , including gonadotrophin-releasing hormone-I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor-1 ( VIPR-1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker-trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR-1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR-1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T-C1715301T haplotypes of VIPR-1 and EN300 . H1H3 had the highest EN300 . Four PCR-RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C-G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3-domain P62993 -like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR-1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 . Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus-encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3'-untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial-encoded transcripts , such as P35354 , a 3'-UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial-encoded tRNAs , appending the 3'-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders . P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist-induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D-Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l-alpha-acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta-endorphin(1-31) , enkephalins , and dynorphin A(1-17) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist-induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies . Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy . A number of candidate genes for lithium prophylactic efficacy have been proposed , some of them being also associated with a predisposition to bipolar illness . The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder , in relation to the putative role of these genes in the pathogenesis of this disorder . Some association with lithium prophylactic efficacy was found for the polymorphisms of P31645 , P21728 , P21964 , P23560 and P06241 genes , but not for 5HT2A , 5HT2C , P14416 , P35462 , P21917 , GSK-3 , Q16620 , Q13224 and P14780 . Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene ( P17752 A779C ) , but not with polymorphisms in five other serotonergic genes . BACKGROUND : There is a heritable component to suicidal behaviour , encouraging the search for the associated risk alleles . Given the putative role of the 5-HT ( 5-hydroxytryptamine ; serotonin ) system in suicidal behaviour , serotonergic genes are leading candidates . In particular , several studies have reported an association with variants in the tryptophan hydroxylase ( P17752 ) gene . METHOD : We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects . The polymorphisms were P17752 ( A779C ) , 5-HT transporter ( 5-HTT , LPR S/L ) , monoamine oxidase A ( P21397 G941T ) , P28222 receptor ( P28222 G861C ) , 5- Q13049 receptor ( P28223 T102C ) , and P28335 receptor ( P28335 Cys23Ser ) . Genotyping was done using polymerase chain reaction ( PCR ) -based assays . The primary analyses compared allele and genotype frequencies between cases and controls . There were a limited number of planned secondary analyses within the deliberate self-harm group . RESULTS : The P17752 A779 allele was more common in deliberate self-harm subjects than in controls ( OR 1.38 , 95 % CI 1.02-1.88 ; P = 0.03 ) . None of the other polymorphisms was associated with deliberate self-harm . Within the deliberate self-harm group there were no associations with impulsivity , suicide risk , lifetime history of depression , or family history of deliberate self-harm . CONCLUSIONS : Our data extend the evidence that allelic variation in the P17752 gene is a risk factor for deliberate self-harm . No evidence was found to implicate the other polymorphisms . Effects of gonadoliberin analogue triptorelin on the pituitary-testicular complex in neonatal rats . DB06825 , a synthetic analogue of neurohormone gonadoliberin ( gonadotropin-releasing hormone , DB00644 ) administered daily to rats on postnatal days 5-7 suppressed the expression of P30968 in the pituitary gland , but did not change functioning of the pituitary-testicular complex . Administration of triptorelin on postnatal days 12-14 ( i.e. during the formation of pulsatile pattern of DB00644 secretion and increasing levels of its mRNA receptor in the pituitary gland ) had no effect on receptor expression , but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes . At that time , blood levels of testosterone were lowered , which indicated disturbed pulsatile pattern of DB00644 secretion . Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes . BACKGROUND : Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders . Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex . DB06594 , a new antidepressant endowed with MT1/ P02795 agonist and P28335 serotonergic antagonist properties , has shown efficacy at both preclinical and clinical levels . RESULTS : Chronic treatment with agomelatine , or with the reference drug venlafaxine , induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion . No changes were observed in GABA release . This effect was accompanied by reduced accumulation of SNARE protein complexes , the key molecular effector of vesicle docking , priming and fusion at presynaptic membranes . CONCLUSIONS : Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus . Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release . Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( DB00422 ) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate DB00422 effects in P51689 , as in typically developing children with attention-deficit/hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to DB00422 during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of DB00422 during a 4-week blinded , crossover study . Outcome measures included the Clinical Global Impression-Improvement ( CGI-I ) scale and the Aberrant Behavior Checklist ( ABC-hyperactivity index ) . A total of 14 subjects discontinued the study because of DB00422 side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty-nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P=0.006 ) , P08913 ( P < 0.02 ) , P21964 ( P < 0.04 ) , P35462 ( P < 0.05 ) , P21917 ( P < 0.05 ) , Q01959 ( P < 0.05 ) and P31645 ( P < 0.05 ) genotypes were found for responders versus non-responders . Variants in P14416 ( P < 0.001 ) and P35462 ( P < 0.04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first DB00422 pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in DB00422 's efficacy and tolerability . P08183 , Q9UNQ0 , and P60484 determine the response of glioblastoma to temozolomide and ABT-888 therapy . PURPOSE : Little is known about the optimal clinical use of ABT-888 ( veliparib ) for treatment of glioblastoma . ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma , because it may synergize with the standard-of-care temozolomide ( DB00853 ) . We have elucidated important factors controlling ABT-888 efficacy in glioblastoma . EXPERIMENTAL DESIGN : We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type ( WT ) and Abcb1/Abcg2-deficient ( KO ) recipients . RESULTS : ABT-888/ DB00853 is not efficacious against p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR allografts in wild-type recipients , indicating inherent resistance . Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier ( BBB ) causes a 5-fold reduction of ABT-888 brain penetration ( P < 0.0001 ) that was fully reversible by elacridar . Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/Abcg2 at the BBB and in tumor cells impair DB00853 /ABT-888 combination treatment efficacy . DB04881 also markedly improved DB00853 /ABT-888 combination treatment in the spontaneous p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR glioblastoma model . Importantly , ABT-888 does enhance DB00853 efficacy in Pten deficient glioblastoma allografts and spontaneous tumors , even in Abcb1/Abcg2 proficient wild-type mice . Loss of P60484 occurs frequently in glioblastoma ( 36 % ) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival ( 310 days vs. 620 days , n = 117 ) . CONCLUSIONS : The potential of ABT-888 in glioblastoma can best be demonstrated in patients with P60484 null tumors . Therefore , clinical trials with ABT-888 should evaluate these patients as a separate group . Importantly , inhibition of P08183 and Q9UNQ0 ( by elacridar ) may improve the efficacy of DB00853 /ABT-888 therapy in all glioblastoma patients . Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non-steroidal anti-inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti-inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non-selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta-analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs . Redox regulation of P60484 by S-nitrosothiols . P60484 ( phosphatase with sequence homology to tensin ) is a phosphatidylinositol 3,4,5-trisphosphate phosphatase that regulates many cellular processes . Activity of the enzyme is dependent on the redox state of the active site cysteine such that oxidation by H2O2 leads to inhibition . Because S-nitrosothiols are known to modify enzymes containing reactive cysteines , we hypothesized that S-nitrosothiols would oxidize P60484 and inhibit its phosphatase activity . In the present study , we show that S-nitrosocysteine ( CSNO ) , S-nitrosoglutathione ( GSNO ) , and S-nitroso-N-acetylpenicillamine ( P60880 ) reversibly oxidized recombinant P60484 . In addition , CSNO led to concentration- and time-dependent oxidation of endogenous cellular P60484 . However , in contrast , GSNO and P60880 were effective only when coincubated with cysteine , suggesting that these nitrosothiols must react with cysteine to form CSNO , which can be transferred across cell membranes . Oxidation of cellular P60484 resulted from thiol modification and led to reversible inhibition of phosphatase activity . Although oxidation of P60484 by H2O2 led to formation of an intramolecular disulfide , oxidation of P60484 by CSNO seemed to lead to formation of a mixed disulfide . Glutathionylation of cellular proteins by incubating cells with diamide or incubating cellular extracts with GSSG oxidized P60484 in a manner similar to that of CSNO . Overall , these data demonstrate for the first time that S-nitrosothiols oxidatively modify P60484 , leading to reversible inhibition of its phosphatase activity , and suggest that the oxidized species is a mixed disulfide .