MH_dev_69

DB01393 MEN restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor-alpha through peroxisome proliferator-activated receptor-gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid-lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC-resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 REA resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor-alpha ( P01375 REA ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 REA significantly inhibited follicle-stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose-dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 REA . DB01393 MEN treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 REA . We examined the expression of peroxisome proliferator-activated receptor ( Q07869 REA ) subtypes in mouse preantral follicles . As the protein expression of only P37231 REA was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 REA pathways . Treatment with GW1929 , a selective P37231 REA agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 REA , whereas treatment with GW9662 , a selective P37231 REA antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 REA through the P37231 REA pathway .

A novel mechanism of autophagic cell death in dystrophic muscle regulated by Q99572 REA receptor large-pore formation and HSP 90 . Q99572 REA is an DB00171 - gated ion channel , which can also exhibit an open state with a considerably wider permeation . However , the functional significance of the movement of molecules through the large pore ( LP ) and the intracellular signaling events involved are not known . Here , analyzing the consequences of Q99572 REA activation in primary myoblasts and myotubes from the Dmd ( mdx ) mouse model of Duchenne muscular dystrophy , we found DB00171 - induced Q99572 REA - dependent autophagic flux , leading to P42574 REA - P55210 REA - independent cell death . Q99572 REA - evoked autophagy was triggered by LP formation but not Ca ( 2 + ) influx or P28482 REA - P27361 REA phosphorylation , 2 canonical Q99572 REA - evoked signals . Phosphoproteomics , protein expression inference and signaling pathway prediction analysis of Q99572 REA signaling mediators pointed to P54652 REA and HSP 90 proteins . Indeed , specific HSP 90 inhibitors prevented LP formation , LC3 - II accumulation , and cell death in myoblasts and myotubes but not in macrophages . Pharmacological blockade or genetic ablation of p2rx7 also proved protective against DB00171 - induced death of muscle cells , as did inhibition of autophagy with 3 - MA . The functional significance of the Q99572 REA LP is one of the great unknowns of purinergic signaling . Our data demonstrate a novel outcome - - autophagy - - and show that molecules entering through the LP can be targeted to phagophores . Moreover , we show that in muscles but not in macrophages , autophagy is needed for the formation of this LP . Given that Q99572 REA - dependent LP and HSP 90 are critically interacting in the DB00171 - evoked autophagic death of dystrophic muscles , treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy .

P21728 REA behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally-lesioned rats exhibited self-biting behavior following treatment with the DA precursor L-dihydroxyphenylalanine ( DB01235 SUB ) . In response to treatment with the selective D1 agonist SKF 38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH 23390 and the D2 antagonist haloperidol were also studied . Neonatally-lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40-50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long-term effects on a D1 receptor system .

Glycogen synthase kinase 3B in bovine oocytes and granulosa cells : possible involvement in meiosis during in vitro maturation . Glycogen synthase kinase 3 ( GSK 3 ) regulates cellular metabolism and cell cycle via different signalling pathways . In response to insulin and growth factors GSK 3 is serine-phosphorylated and inactivated . We analysed P49841 REA expression and activation in bovine cumulus cells ( CC ) and oocytes at different meiotic stages in vitro in parallel with Q96HU1 kinases P29323 REA ( P27361 REA / P28482 REA ) and p38 ( Q16539 REA ) . P49841 REA localised to cytoplasm in granulosa cells and in oocytes throughout folliculogenesis . In mature metaphase-II ( MII ) oocytes , P49841 REA was concentrated to the region of midzone between the oocyte and the first polar body , as well as active phospho - DB00156 Aurora A kinase ( O14965 REA ) . During in vitro maturation ( IVM ) , in oocytes , phospho - DB00133 ( 9 ) - P49841 REA level increased as well as phospho - P27361 REA / P28482 REA , while phospho - Q16539 REA decreased . In CC , phospho - Q16539 REA increased upon germinal vesicle breakdown ( GVBD ) / metaphase-I ( MI ) and then decreased during transition to MII . Administration of inhibitors of GSK 3 activity ( lithium chloride or 2 ' Z , 3 ' E - 6 - bromoindirubin - 3 ' - oxime ) rapidly increased phospho - DB00133 ( 9 ) - P49841 REA , and led to transient decrease of phospho - P27361 REA / P28482 REA and to durable enhancing of phospho - Q16539 REA in granulosa primary cell culture . GSK 3 inhibitors during IVM diminished cumulus expansion and delayed meiotic progression . In cumulus , phospho - Q16539 REA level was significantly higher in the presence of inhibitors , comparing with control , through the time of MI / MII transition . In oocytes , phospho - P49841 REA was increased and phospho - P27361 REA / P28482 REA was decreased before GVBD and oocytes were mainly arrested at MI . Therefore , P49841 REA might regulate oocyte meiosis , notably MI / MII transition being the part of P27361 REA / 1 and Q16539 REA pathways in oocytes and CC . P49841 REA might be also involved in the local activation of O14965 REA that controls this transition .

Mammalian Q99572 REA receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 REA receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 REA receptors rapidly opens a non-selective cation channel . Sustained Q99572 REA receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single-nucleotide polymorphism-mediated differences in Q99572 REA receptor activation have been reported that complicate understanding of the physiological role of Q99572 REA receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 REA receptors . EXPERIMENTAL APPROACH : Receptor-mediated changes in calcium influx and Yo-Pro uptake were compared between recombinant mouse , rat and human Q99572 REA receptors . For mouse Q99572 REA receptors , wild-type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 REA receptor were also compared . KEY RESULTS : BzATP [ 2,3- O - ( 4 - benzoylbenzoyl ) - DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo-Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 REA receptors . Two selective Q99572 REA receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 REA receptor activation across mammalian species . Several reported P51575 REA receptor antagonists [ e . g . P59665 REA 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 REA receptors . NF279 fully blocked human Q99572 REA receptors , but only partially blocked BALB / c Q99572 REA receptors and was inactive at C57BL / 6 Q99572 REA receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 REA receptor antagonist pharmacology across mammalian species . Q99572 REA receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild-type mouse Q99572 REA receptors . Several structurally novel , selective and competitive Q99572 REA receptor antagonists show less species differences compared with earlier non-selective antagonists .

p38 mitogen-activated protein kinase mediates signal integration of TCR / P10747 REA costimulation in primary murine T cells . Optimal T cell activation requires two signals , one generated by TCR and another by the P10747 REA costimulatory receptor . In this study , we investigated the regulation of costimulation-induced mitogen-activated protein kinase ( MAPK ) activation in primary mouse T cells . In contrast to that reported for human Jurkat T cells , we found that p38 MAPK , but not Jun NH2 - terminal kinase ( JNK ) , is weakly activated upon stimulation with either anti-CD 3 or anti - P10747 REA in murine thymocytes and splenic T cells . However , p38 MAPK is activated strongly and synergistically by either CD3 / P10747 REA coligation or PMA / Ca2 + ionophore stimulation , which mimics TCR-CD 3 / P10747 REA - mediated signaling . Activation of p38 MAPK correlates closely with the stimulation of T cell proliferation . In contrast , PMA-induced JNK activation is inhibited by Ca2 + ionophore . T cell proliferation and production of P60568 REA , P05112 REA , and P01579 REA induced by both CD3 and CD3 / P10747 REA ligation and the nuclear expression of the c-Jun and P39905 REA - 2 proteins are each blocked by the p38 MAPK inhibitor SB203580 . Our findings demonstrate that p38 P28482 REA ) plays an important role in signal integration during costimulation of primary mouse T cells , 2 ) may be involved in the induction of c-Jun activation and augmentation of AP - 1 transcriptional activity , and 3 ) regulates whether T cells enter a state of functional unresponsiveness .

Targetting esophageal and gastric cancers with monoclonal antibodies . Target therapies and notably monoclonal antibodies are currently being considered for esophageal , gastric , and gastroesophageal junction cancers . P00533 REA was found to be overexpressed in 60-86 % of gastric or gastroesophageal tumors and in 50-70 % of esophageal cancers . Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia . These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers . Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported . These promising results are still to be confirmed by the ongoing phase III trials . Several studies reported P04626 REA overexpression in gastric cancer ( 7-34 % ) , which appeared to be associated with poorer prognosis . DB00072 MEN is a monoclonal antibody directed against the extracellular P04626 REA domain . The international phase III trial known as ToGA ( DB00072 MEN for Gastric Cancer ) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first-line chemotherapy in P04626 REA - overexpressing gastric or gastroesophageal cancer . Angiogenesis is an essential step in the initial phase of tumorigenesis , and it is normally absent from healthy tissues except for particular physiological situations , such as wound healing . P15692 REA plays a role in endothelial growth and angiogenesis . DB00112 , a humanized monoclonal anti - P15692 REA antibody , is currently being studied for gastric cancer . The phase III AVAGAST study , evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma , did not achieve its primary aim of improved OS in bevacizumab-treated patients .

Selective deletion of P60484 REA in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons . The widespread distribution of the tumor suppressor P60484 REA in the nervous system suggests a role in a broad range of brain functions . P60484 REA negatively regulates the signaling pathways initiated by protein kinase B ( Akt ) thereby regulating signals for growth , proliferation and cell survival . Pten deletion in the mouse brain has revealed its role in controlling cell size and number . In this study , we used Cre-loxP technology to specifically inactivate Pten in dopamine ( DA ) neurons ( Pten KO mice ) . The resulting mutant mice showed neuronal hypertrophy , and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon . Interestingly , quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum , despite a significant increase in total DA tissue levels . Striatal dopamine receptor D1 ( P21728 REA ) and prodynorphin ( PDyn ) mRNA levels were significantly elevated in KO animals , suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway , while dopamine receptor D2 ( P14416 REA ) and preproenkephalin ( PPE ) mRNA levels remained unchanged . In addition , P60484 REA inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion . These results provide further evidence about the role of P60484 REA in the brain and suggest that manipulation of the P60484 REA / Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson ' s disease , and other neurodegenerative disorders .

Shed P04626 REA extracellular domain in P04626 REA - mediated tumor growth and in trastuzumab susceptibility . The question of the serum P04626 REA extracellular domain ( P04626 REA / O95905 ) measurement for prediction of response to the anti - P04626 REA antibody DB00072 MEN is still an open and current matter of clinical debate . To elucidate the involvement of shed P04626 REA / O95905 in P04626 REA - driven tumor progression and in guiding therapy of individual patients , we examined biological effects exerted by elevated P04626 REA / O95905 in cancer growth and in response to DB00072 MEN . To this purpose SKOV 3 tumor cells were stably transfected to release a recombinant P04626 REA / O95905 molecule ( rECD ) . Transfectants releasing high levels of 110 - kDa rECD , identical in size to native P04626 REA / O95905 ( nECD ) , grew significantly slower than did controls , which constitutively released only basal levels of nECD . While transmembrane P04626 REA and P00533 REA were expressed at equal levels by both controls and transfected cells , activation of these molecules and of downstream P28482 REA and Akt was significantly reduced only in rECD transfectants . Surface plasmon resonance analysis revealed heterodimerization of the rECD with P00533 REA , - 2 , and - 3 . In cell growth bioassays in vitro , shed P04626 REA significantly blocked P04626 REA - driven tumor cell proliferation . In mice , high levels of circulating rECD significantly impaired P04626 REA - driven SKOV 3 tumor growth but not that of P04626 REA - negative tumor cells . In vitro and in mice , DB00072 MEN significantly inhibited tumor growth due to the rECD-facilitated accumulation of the antibody on tumor cells . Globally our findings sustain the biological relevance of elevated P04626 REA / O95905 levels in the outcome of P04626 REA - disease and in the susceptibility to DB00072 MEN - based therapy .

Possible association of beta-arrestin 2 gene with methamphetamine use disorder , but not schizophrenia . Recent investigations suggest that the AKT / glycogen synthase kinase 3 ( GSK 3 ) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine ( METH ) use disorder . One important molecule related to this cascade is beta-arrestin 2 ( P32121 REA ) . We therefore conducted a genetic case-control association analysis of the gene for P32121 REA with schizophrenia and METH use disorder in a Japanese population ( 547 people with schizophrenia , 177 with METH use disorder and 546 controls ) . A possible association of ' tag single nucleotide polymorphisms ( SNPs ) ' was found in METH use disorder ( rs1045280 : P ( genotype ) = 0.0118 , P ( allele ) = 0.00351 ; rs2036657 : P ( allele ) = 0.0431 ; rs4790694 : P ( genotype ) = 0.0167 , P ( allele ) = 0.0202 ) , but no association was found with schizophrenia . We also evaluated the gene-gene interactions among P32121 REA , P31749 REA , and P49841 REA , which we previously reported for each of these diseases . However , no interaction was seen in our samples . This is the first association analysis of P32121 REA , and our results indicate that P32121 REA may play a role in the pathophysiology of METH use disorder .

A common variant in P35462 REA gene is associated with risperidone-induced extrapyramidal symptoms . We present a pharmacogenetic study of acute antipsychotic ( AP ) - induced extrapyramidal symptoms ( EPS ) using an extensive linkage disequilibrium mapping approach in seven-candidate genes with a well-established link to dopamine ( P14416 REA , P35462 REA , P12821 REA , P21964 REA , Q01959 REA , P21397 REA , P27338 REA ) . From a cohort of 321 psychiatric inpatients , 81 cases presenting with EPS ( Simpson-Angus > 3 ) and 189 controls presenting without EPS ( Simpson-Angus < or = 3 ) took part . Eighty-four-tag single nucleotide polymorphisms ( SNPs ) in candidate genes were genotyped . After extensive data cleaning , 70 SNPs were analyzed for association of single markers and haplotypes . AP dosage , AP - P14416 REA blockade potency and age were identified as susceptibility factors for AP-induced EPS . One SNP of the P35462 REA gene , rs167771 , achieved significant association with EPS risk after Bonferroni correction ( nominal P-value 1.3 x 10 ( - 4 ) ) in the patients treated with risperidone ( 132 patients ) . AP-induced EPS remains a serious public health problem . Our finding of a common SNP ( rs167771 ) in the P35462 REA gene provides a strong new candidate gene for risperidone-induced EPS .

Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 REA , P05177 REA , P10632 REA , P11712 REA - arg 144 , P11712 REA - cys 144 , P33261 REA , P10635 REA , P08684 REA and P20815 REA supplemented with an NADPH-generating system . DB01267 MEN was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol ( - 1 ) CYP min ( - 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 REA and 3A activities . Thus , both P10635 REA and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 REA ) and ketoconazole ( inhibitor of P08684 REA ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP 3A contributes significantly to the metabolism of risperidone in rat .

Gα ( olf ) mutation allows parsing the role of DB02527 - dependent and extracellular signal-regulated kinase-dependent signaling in DB01235 SUB - induced dyskinesia . Although DB01235 SUB ( DB01235 SUB ) remains the reference treatment of Parkinson ' s disease , its long-term beneficial effects are hindered by DB01235 SUB - induced dyskinesia ( LID ) . In the dopamine ( DA ) - denervated striatum , DB01235 SUB activates DA D₁ receptor ( D₁R ) signaling , including DB02527 - dependent protein kinase A ( PKA ) and extracellular signal-regulated kinase ( P29323 REA ) , two responses associated with LID . However , the cause of PKA and P29323 REA activation , their respective contribution to LID , and their relationship are not known . In striatal neurons , D₁R activates adenylyl-cyclase through Gα ( olf ) , a protein upregulated after lesion of DA neurons in rats and inpatients . We report here that increased Gα ( olf ) levels in hemiparkinsonian mice are correlated with LID after chronic DB01235 SUB treatment . To determine the role of this upregulation , we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα ( olf ) ( Gnal ⁺ / ⁻ ) . Despite an increase in the lesioned striatum , Gα ( olf ) levels remained below those of unlesioned wild-type mice . In Gnal ⁺ / ⁻ mice , the lesion-induced DB01235 SUB stimulation of DB02527 / PKA-mediated phosphorylation of P42261 REA Ser 845 and Q9UD71 ( 32 kDa DA - and DB02527 - regulated phosphoprotein ) Thr 34 was dramatically reduced , whereas P29323 REA activation was preserved . LID occurrence was similar in Gnal ⁺ / ⁺ and Gnal ⁺ / ⁻ mice after a 10 - d DB01235 SUB ( 20 mg / kg ) treatment . Thus , in lesioned animals , Gα ( olf ) upregulation is critical for the activation by DB01235 SUB of D₁R-stimulated DB02527 / PKA but not P29323 REA signaling . Although the DB02527 / PKA pathway appears to be required for LID development , our results indicate that its activation is unlikely to be the main source of LID . In contrast , the persistence of DB01235 SUB - induced P29323 REA activation in Gnal ⁺ / ⁻ mice supports its causal role in LID development .

Identification of tyrosine hydroxylase as a physiological substrate for Cdk 5 . P12004 REA - dependent kinase 5 ( Cdk 5 ) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post - and presynaptic compartments . Within the reward / motor circuitry of the basal ganglia , Cdk 5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator , Q9UD71 ( dopamine - and cyclic AMP-regulated phosphoprotein , M ( r ) 32,000 ) . Cdk 5 has also been implicated in regulating various steps in the presynaptic vesicle cycle . Here we report that Cdk 5 phosphorylates tyrosine hydroxylase ( TH ) , the key enzyme for synthesis of dopamine . Using phosphopeptide mapping , site-directed mutagenesis , and phosphorylation state-specific antibodies , the site was identified as Ser 31 , a previously defined extracellular signal-regulated kinases 1/2 ( P27361 REA / 2 ) site . The phosphorylation of Ser 31 by Cdk 5 versus P27361 REA / 2 was investigated in intact mouse striatal tissue using a pharmacological approach . The results indicated that Cdk 5 phosphorylates TH directly and also regulates P27361 REA / 2 - dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 ( Q02750 REA ) . Finally , phospho-Ser 31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine . These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk 5 / P27361 REA / 2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure .

P21917 REA signaling in the rat paraventricular hypothalamic nucleus : Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation . The dopamine D4 receptor has been investigated for its potential role in several CNS disorders , notably schizophrenia and more recently , erectile dysfunction . Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro , there have been few , if any , attempts to identify dopamine D4 receptor signal transduction pathways in vivo . In the present studies , the selective dopamine D4 agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase ( P29323 REA ) phosphorylation in the hypothalamic paraventricular nucleus ( PVN ) , a site known to regulate proerectile activity . The selective dopamine D4 receptor antagonist A - 381393 blocked both c-Fos expression and P27361 REA / 2 phosphorylation produced by PD168077 . In addition , PD168077 - induced P27361 REA / 2 phosphorylation was prevented by SL327 , an inhibitor of P27361 REA / 2 phosphorylation . Interestingly , treatment with A - 381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls . P21917 REA and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling , suggesting that PD168077 - induced signaling may result from direct dopamine D4 receptor activation . Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and Q96HU1 kinase activation . Further , the ability of the selective dopamine D4 antagonist A - 381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo . These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity .

DB01356 MEN inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment-polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen-activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 REA and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule-associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta-catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .

DB01032 MEN reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 REA receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .

DB01235 SUB - treatment in primates disrupts the expression of A ( 2A ) adenosine-CB ( 1 ) cannabinoid - P14416 REA heteromers in the caudate nucleus . The molecular basis of priming for DB01235 SUB - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 SUB treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A ) / CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 ) - mediated neurotransmission in the caudate-putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP-treated monkeys , DB01235 SUB treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A ) - CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 SUB - induced side effects .

Polymorphisms of dopamine receptor / transporter genes and risk of non-small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non-small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 REA / P15692 REA ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 REA ) , D4 ( P21917 REA ) and dopamine transporter 1 ( Q01959 REA / Q01959 REA ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 REA , P21917 REA and Q01959 REA / Q01959 REA genes in relation to lung cancer risk in a case-control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 REA polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 REA - 521C > T and Q01959 REA / Q01959 REA - 1476T > G are associated with a two - to five-fold increased NSCLC risk . The variant alleles of P14416 REA 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .

Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 REA status . A feasible approach for women with less aggressive , estrogen receptor / P04626 REA - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann-La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 REA - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . DB00072 MEN adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann-La Roche ) , gemcitabine , and vinorelbine . DB00072 MEN is also being investigated as part of triplet drug regimens . DB00072 MEN has good single-agent activity in first-line therapy . This is of relevance to women with P04626 REA - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 REA ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 REA polymorphisms , C957 T and - - 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and - - 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 SUB . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and - - 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 REA gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine ( e . g . beta-phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .

Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine-lesioned rats treated with D ( 1 ) or P14416 REA agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 SUB in 6 - hydroxydopamine-lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water-soluble A ( 2A ) antagonist P35240 REA BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 REA BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1.5 mg / kg ) as well as quinpirole ( 0.05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 REA BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .

P21728 REA , but not dopamine D2 receptor , is a critical regulator for acute cocaine-enhanced gene expression . OBJECTIVE : The aim of present study is to investigate the roles of dopamine receptor subfamilies and their subsequent molecular events in cocaine-enhanced gene expression in striatum . METHODS : Acute cocaine-treated mice models were build to address this issue . Specific antagonists for dopamine D1 and D2 receptors ( P35240 REA 23390 and raclopride , respectively ) and specific inhibitor for extracellular signal-regulated protein kinase 1/2 ( P27361 REA / 2 ) kinase were pretreated . Immunofluorescence was used to detect the expressions of c-Fos , phosphorylated DB02527 response element binding ( p-CREB ) and phosphorylated Elk - 1 ( p-Elk - 1 ) in striatum . RESULTS : Acute cocaine injection significantly enhanced expressions of c-Fos , p-CREB and p-Elk - 1 in the striatum . Notably , these enhancements were totally blocked to normal level by P35240 REA 23390 pre-treatment , while no changes occurred in the presence of raclopride . Moreover , we found that dopamine D1 receptor was involved in acute cocaine-induced activation of P27361 REA / 2 in the striatum . Blockade of this dopamine D1 receptor-dependent P27361 REA / 2 activation by SL 327 could reduce cocaine-enhanced expressions of c-Fos , p-CREB and p-Elk - 1 in the striatum . DISCUSSION : These results suggest that dopamine D1 receptor , but not dopamine D2 receptor , plays a critical role in regulating acute cocaine-enhanced gene expression in the striatum , and P27361 REA / 2 pathway may contribute to this regulation .

Estrogen-dependent regulation of P37231 REA signaling on collagen biosynthesis in adenocarcinoma endometrial cells . The link between estrogen and metabolic developmental factors of endometrial carcinoma is well established . Q07869 REA - gamma , ( an important modulator of metabolism ) and estrogen receptor belong to a family of nuclear hormone receptors that were shown to interact with each other . The interaction may affect transcriptional activity of these transcription factors . The anti-diabetic troglitazone ( Q96PF1 ) is well known Q07869 REA - gamma ligand . The effect of troglitazone-induced Q07869 REA - gamma activation on estrogen-dependent stimulation of collagen biosynthesis was studied in the Ishikawa endometrial adenocarcinoma cell line . We have found that the presence of estrogen activity in growth medium ( 1nM ) augmented collagen biosynthesis in the cells . An addition of Q07869 REA - gamma agonists , as troglitazone or clofibrat to the growth medium induced inhibition of collagen biosynthesis . The inhibition was effective only when estrogen receptor was stimulated , since removal of estrogen receptor by ICI 182 - 780 - dependent degradation did not affect collagen biosynthesis . The mechanism of the inhibition was found at the level of NF-kB ( known inhibitor of collagen gene expression ) and MAPK signaling . Q07869 REA - gamma ligands stimulated expression of NF-kB , while they inhibited expression of p - 38 but not P27361 REA / P28482 REA . The data document for the first time that inhibitory effect of Q07869 REA - gamma ligands on collagen biosynthesis in endometrial adenocarcinoma cells requires functional estrogen receptor .

Dopamine receptor D4 polymorphism predicts the effect of DB01235 SUB on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 REA ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L-dihydroxyphenylalanine ( DB01235 SUB ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 REA polymorphism . Subjects played a gambling task 60 minutes after DB01235 SUB administration . RESULTS : Without considering genetic information , DB01235 SUB administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 REA polymorphism accounted for variation in gambling behavior after the administration of DB01235 SUB . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 REA gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .

Opposed effects of lithium on the MEK - P29323 REA pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK 3 independent mechanisms . DB01356 MEN is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 REA cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose-dependently the phosphorylation of MEK and P29323 REA , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 REA and MEK , respectively , after a 7 - day exposure . DB01356 MEN also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum-deprived , quiescent astrocytes , pre-exposure to lithium resulted in the inhibition of cell cycle re-entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3-5 min , but was effective in inhibiting the long-term , sustained phosphorylation of MEK . DB01356 MEN inhibition of the astrocyte MEK / P29323 REA pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser 396 and stabilized cytosolic beta-catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 REA ) , but failed to reproduce lithium effects on MEK and P29323 REA phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 REA phosphorylation in a concentration-dependent manner , again through an inositol and P49841 REA independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .

LG839 : anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self-identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi-square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0.01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0.05 ) , and increased energy ( P < 0.001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 REA , Q07869 REA - gamma 2 , P42898 REA , 5 - Q13049 REA , and P14416 REA genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 REA gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0.42 , P= 0.045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA-directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .

Synergism between bosutinib ( DB06616 MEN ) and the Chk 1 inhibitor ( PF - 00477736 ) in highly imatinib-resistant P11274 REA / ABL ⁺ leukemia cells . Interactions between the dual P11274 REA / P00519 REA and Src inhibitor bosutinib and the Chk 1 inhibitor PF - 00477736 were examined in P11274 REA / P00519 REA ( + ) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 REA / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc 2 ) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph ( + ) ALL cell lines . Inhibition of Src or Q02750 REA by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co-treatment also potentiated cell death in P28906 REA ( + ) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 REA ( + ) cells . Finally , combined in vivo treatment significantly suppressed BaF 3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph ( + ) ALL .

P14416 REA - mediated epidermal growth factor receptor transactivation through a disintegrin and metalloprotease regulates dopaminergic neuron development via extracellular signal-related kinase activation . P14416 REA ( D2R ) - mediated extracellular signal-regulated kinase ( P29323 REA ) activation plays an important role in the development of dopaminergic mesencephalic neurons . Here , we demonstrate that D2R induces the shedding of heparin-binding epidermal growth factor ( P01133 REA ) through the activation of a disintegrin and metalloprotease ( ADAM ) 10 or 17 , leading to P01133 REA receptor transactivation , downstream P29323 REA activation , and ultimately an increase in the number of dopaminergic neurons and their neurite length in primary mesencephalic cultures from wild-type mice . These outcomes , however , were not observed in cultures from D2R knock-out mice . Our findings show that D2R - mediated P29323 REA activation regulates mesencephalic dopaminergic neuron development via P01133 REA receptor transactivation through O14672 REA / 17 .

Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow-derived macrophages ( BMDM ) with size-defined latex beads ( LxB ) . Although both nano-sized ( 20 nm ) and micro-sized ( 1,000 nm ) LxB induced IL - 1β production , only the nano-sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K ( + ) efflux and Q96P20 REA activation in BMDM were crucial in response to both 20 and 1,000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 REA , a receptor for DB00171 . The response by 1,000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 REA ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 REA and in BMDM deficient in thioredoxin-binding protein - 2 ( P20226 REA - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .

Dopamine receptor agonists reverse behavioral abnormalities of alpha-synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha-synuclein . We had previously generated transgenic mice termed Syn 130m that express truncated human alpha-synuclein ( amino acid residues 1-130 ) in DAergic neurons . Syn 130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn 130m mice to DB01235 SUB and DA receptor agonists . Administration of DB01235 SUB dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn 130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn 130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn 130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 ) - like receptors ( P14416 REA ) in the striatum was not increased in Syn 130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 REA . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn 130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .

Biochemical markers and genetic research of ADHD . ADHD ( attention hyperactivity disorder ) is a polygenetic disorder with various candidate genes . At this time , more than thirty dopaminergic , noradrenergic , serotonergic and GABA-ergic genes are known . The research of only some candidate genes ( P21917 REA , Q01959 REA , P21918 REA , P09172 REA , P31645 REA , P28222 REA and P60880 REA ) brought relatively consistent results confirming the heredity of ADHD syndromes . The results of research of other genes ( P14416 REA , P35462 REA , MAO , ADR 2A , GABA A3 , GABA B3 ) are not clear yet . This paper summarizes the most important genetic data in correlations with biochemical periphery parameters ( especially for P09172 REA , HVA , MHPG , serotonin ) . Hypothetically , certain subgroups of ADHD may be identified by correlation of biochemical characteristics and some candidate genes . The paper discusses some implications for future research . Review .

Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 REA ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2,5- dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL - 1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 REA - positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10 ( - 5 ) mol / l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 REA production . DB00215 MEN at 10 ( - 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .

P35462 REA stimulation underlies the development of DB01235 SUB - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 SUB - induced dyskinesia ( LID ) remains a major problem in the long-term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 SUB correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of DB01235 SUB . Furthermore , following a 14 day washout , when challenged with DB01235 SUB in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA-lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 SUB . Additionally , DB01235 SUB - induced elevations in striatal pre-proenkephalin-A ( PPE-A ) ( but not PPE-B , phospho [ DB00156 ( 34 ) ] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 SUB treatment with a D3 antagonist may reduce the development of LID in PD .

N-Acetylaspartate and Q9UD71 levels decrease in the corpus striatum of Huntington ' s disease mice . Huntington ' s disease ( HD ) is an autosomal dominant condition involving progressive neurodegeneration , primarily the corpus striatum and cerebral cortex . We have used in vivo magnetic resonance spectroscopy ( P59665 REA ) to assess specific neuronal markers in transgenic mice ( R6 / 1 line ) expressing exon I of the human huntingtin gene with an expanded CAG repeat . Levels of N-acetylaspartate ( NAA ) , an indicator of healthy neuronal function , were significantly reduced ( 26 % ) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age . However , levels of cholines and creatine-phosphocreatine were not altered in the HD mice . Expression of dopamine - and DB02527 - regulated phosphoprotein , 32 kDa ( Q9UD71 ) , was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and , even more dramatically , at 11 months of age . In contrast , expression of calbindin was not significantly decreased in HD mice . Our results suggest that the observed decreases in Q9UD71 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD .

Candidate gene studies of ADHD : a meta-analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 REA , P21917 REA , P21918 REA , P31645 REA , P28222 REA , and P60880 REA . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 REA , P21917 REA , P21918 REA , P09172 REA , P08913 REA , P31645 REA , Q8IWU9 , P21397 REA , and P60880 REA , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .

Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 REA ) at 11p15 , tyrosinase ( P14679 REA ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 REA ) at 11q22 - q23 , as well as with the c-Harvey-ras oncogene ( P01112 REA ) and insulin gene ( P01308 REA ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected-sib-pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two-point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 REA and P01308 REA excluded the 11p15 region encompassing both P21917 REA and TH . In agreement with the negative linkage results , affected-sib-pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 REA , TH , P14679 REA , and P14416 REA in the pathogenesis of bipolar illness .

Interaction of early environment , gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort . Objectives Depression is a worldwide leading cause of morbidity and disability . Genetic studies have recently begun to elucidate its molecular aetiology . The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 ( 12 058 live births ) . Design The authors ascertained and subdivided the study sample ( n = 5225 ) based on measures of early development and of social environment , and examined candidate genes of monoamine neurotransmission , many of which have shown prior evidence of a gene-environment interaction for affective disorders , namely P31645 REA , Q8IWU9 , P21964 REA , P21397 REA and the dopamine receptor genes P21728 REA - P21918 REA . Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness . However , when measures of early development and of social environment were considered , some evidence of interaction was observed . Allelic variants of P21964 REA interacted with high early developmental risk ( p= 0.005 for rs2239393 and p= 0.02 for rs4680 ) so that the association with depression was detected only in individuals at high developmental risk group ( p= 0.0046 and β = 0.056 for rs5993883 - rs2239393 - rs4680 risk haplotype CGG including Val 158 ) , particularly in males ( p= 0.0053 and β = 0.083 for the haplotype CGG ) . Rs4274224 from P14416 REA interacted with gender ( p= 0.017 ) showing a significant association with depressiveness in males ( p= 0.0006 and β = 0.0023 ; p= 0.00005 and β = 0.069 for rs4648318 - rs4274224 haplotype GG ) . The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex , but not direct major effects of monoaminergic genes in this unselected population .

Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes ( P21728 REA - P21918 REA , P31749 REA and GSK 3beta ) and serotonin receptor genes ( P08908 REA , P28222 REA , P28221 REA , P28223 REA , P28335 REA , P50406 REA and P34969 REA ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 REA ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 REA ( P31749 REA - SNP 1 [ rs3803300 ] and P31749 REA - SNP 5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 REA and P31749 REA may influence the treatment response to risperidone in schizophrenia patients .

Dopamine controls systemic inflammation through inhibition of Q96P20 REA inflammasome . Inflammasomes are involved in diverse inflammatory diseases , so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation . However , the endogenous regulatory mechanisms of inflammasome activation are still unclear . Here , we report that the neurotransmitter dopamine ( DA ) inhibits Q96P20 REA inflammasome activation via dopamine D1 receptor ( P21728 REA ) . P21728 REA signaling negatively regulates Q96P20 REA inflammasome via a second messenger cyclic adenosine monophosphate ( DB02527 ) , which binds to Q96P20 REA and promotes its ubiquitination and degradation via the E3 ubiquitin ligase Q9H992 . Importantly , in vivo data show that DA and P21728 REA signaling prevent Q96P20 REA inflammasome-dependent inflammation , including neurotoxin-induced neuroinflammation , LPS-induced systemic inflammation , and monosodium urate crystal ( MSU ) - induced peritoneal inflammation . Taken together , our results reveal an endogenous mechanism of inflammasome regulation and suggest P21728 REA as a potential target for the treatment of Q96P20 REA inflammasome-driven diseases .

Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 REA , Q01959 REA , Q13639 REA , P21917 REA , P14416 REA , P28223 REA , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 REA , P21397 REA and P23560 REA . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .

Task-dependent interactions between dopamine D2 receptor polymorphisms and DB01235 SUB in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 SUB during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty-five PD patients were genotyped for the P14416 REA polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 SUB states . For motor sequence learning , P14416 REA genotype mediated DB01235 SUB effects such that DB01235 SUB associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 = -2.71 , p= 0.022 ) , whereas G homozygotes showed no performance change with DB01235 SUB . For the grooved pegboard test , performance improved with DB01235 SUB independent of patients ' P14416 REA genotype . Collectively these results demonstrate that common P14416 REA allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .

Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration-dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 ) / P14416 REA antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L-beta -3,4- dihydroxyphenylalanine ( DB01235 SUB ) , which is metabolically transformed into DA . The DA-induced depression of the IPSPs was partially antagonised by the alpha 2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A ) - mediated IPSP . The DA-induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT-induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 SUB and antipsychotics and could be also involved in drug abuse .

[ Moclobemide ( DB01171 MEN ) , the first P21397 REA - inhibitor : really something new ? ] .

P28482 REA , but not P27361 REA , mediates acquired and " de novo " resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 REA / P00519 REA . However , other types of resistance that do not imply mutations in P11274 REA / P00519 REA have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 REA / P00519 REA mutations . Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 REA / P00519 REA mutations . Here we demonstrate that Erk 5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk 2 , but not Erk 1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk 2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk 2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk 2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk 2 activation .

The role of the subthalamic nucleus in DB01235 SUB induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 SUB is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 REA ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 REA in dyskinesia , using single-unit extracellular recording , behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic DB01235 SUB administration . Our results show that chronic DB01235 SUB treatment does not modify the abnormal Q05639 REA activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 REA responsiveness to a single DB01235 SUB dose both in lesioned and sham animals that received daily DB01235 SUB treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 REA neurons recorded 24 h or 20-120 min after the last DB01235 SUB injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 REA with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia . In addition , Q05639 REA lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 REA / P21728 REA ratio . The Q05639 REA lesion attenuated the striatal molecular changes and normalized the P14416 REA / P21728 REA ratio . Taken together , our results show that the Q05639 REA plays a role , if modest , in the physiopathology of dyskinesias .

Effects of peroxisome proliferator-activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 REA is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator-activated receptor ( Q07869 REA ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The DB01393 MEN Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild-type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha-deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .

Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization . Growth factor-induced receptor dimerization and cross-phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases ( RTKs ) . G protein-coupled receptors ( GPCRs ) can activate RTKs through a process known as transactivation . The prototypical model of RTK transactivation involves ligand-mediated RTK dimerization and cross-phosphorylation . Here , we show that the platelet-derived growth factor receptor beta ( PDGFRbeta ) transactivation by the dopamine receptor D4 ( P21917 REA ) is not dependent on ligands for PDGFRbeta . Furthermore , when PDGFRbeta dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels , the receptor maintains its ability to be transactivated and is still effective in signaling to P27361 REA / 2 . Hence , the P21917 REA - PDGFRbeta - P27361 REA / 2 pathway can occur independently of a PDGF-like ligand , PDGFRbeta cross-phosphorylation and dimerization , which is distinct from other known forms of transactivation of RTKs by GPCRs .

P14416 REA signaling dynamics of dopamine D2 - neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS 1R ) receptor-receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor-receptor interactions in Parkinson ' s disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET ( 2 ) ) evidence has for the first time been obtained in the current study for the existence of both D2LR / NTS 1R and D2SR / NTS 1R heteromers in living HEK 293T cells . Through confocal laser microscopy the NTS 1R ( GFP 2 ) and D2R ( YFP ) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and / or LRA ) in the two participating receptors which may contribute to the formation of the D2R / NTS 1R heteromers by participating in guide-clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 REA / 2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor-receptor interactions in the D2LR - NTS 1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) .

Comparison of rating scales used to evaluate DB01235 SUB - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 SUB - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re-validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague-Dawley rats were treated with chronic DB01235 SUB 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 SUB injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 SUB ( the D ( 1 ) and P14416 REA antagonists , P35240 REA - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 SUB , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti-dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .

Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .

Identification and characterization of mouse Erbb 2 gene in silico . The Q9UD71 - Q14849 REA - O15273 - PNMT-MGC 9753 - P04626 REA - MGC 14832 - Q14451 REA locus on human chromosome 17q12 is frequently amplified in human gastric and breast cancer . We have recently identified and characterized human MGC 9753 ( also known as wild-type CAB 2 ) and mouse Mgc 9753 . Here , we identified and characterized mouse Erbb 2 gene by using bioinformatics . BLAST programs revealed that mouse AK031099 cDNA was derived from mouse Erbb 2 gene . Because AK031099 cDNA showed 806 C --> A nucleotide substitution compared with mouse genome draft sequences and mouse Erbb 2 ESTs , the nucleotide sequence of mouse Erbb 2 cDNA was determined in silico by correcting 806 A of AK031099 cDNA to C . Nucleotide position 48-3818 of mouse Erbb 2 cDNA was the coding region . Mouse Erbb 2 gene , consisting of 27 exons , was located within the Ppp 1r1b - Grb 7 locus on the mouse chromosome 11 . Mouse Erbb 2 protein ( 1256 aa ) showed 87.5 % total-amino-acid identity with human P04626 REA protein , and 95.2 % total-amino-acid identity with rat Erbb 2 protein . Mouse Ppp 1r1b - Grb 7 locus and human Ppp 1r1b - Grb 7 locus were evolutionarily conserved in the order and the orientation of genes therein . Nucleotide and amino-acid substitution rates of Neurod 2 located centromeric to the Ppp 1r1b - Grb 7 locus were significantly lower than others within the Ppp 1r1b - Grb 7 locus . This is the first report on the complete coding sequence of mouse Erbb 2 gene as well as on the comprehensive comparison of Ppp 1r1b - Grb 7 locus within the human and mouse genomes .

Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population-based twin studies demonstrate that approximately 40-50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 REA Val 158Met , P21397 REA 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 REA , Q01959 REA 3 ' VNTR and P14416 REA exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38.51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five-Factor Inventory , Spielberger ' s State-Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 REA ) were lowest in the entire group . The effects of gender , age and the Q13049 REA gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 REA gene on the 9/9 Q01959 REA genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 REA gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 REA ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .

Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 REA signalling in DB01235 SUB - treated rats . Dopamine replacement with l-DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well-characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti-dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over-activation of the P21728 REA signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 REA . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose-dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 REA phosphorylation ratios , while the increases in P35462 REA , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 REA antagonists confirmed that normalization of both pDARPP 32 and pERK 2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP 32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 REA striatal over-expression could be instrumental in the activation of P21728 REA - downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with P21728 REA pathway normalization .

Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder . A time-to-onset analysis for family-based samples was performed on the genomewide association ( GWAS ) data for attention deficit hyperactivity disorder ( ADHD ) to determine if associations exist with the age at onset of ADHD . The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array . After data cleaning procedures , 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest . No SNP achieved genome-wide significance , and the lowest P-values had a magnitude of 10 ( - 7 ) . Several SNPs among a pre-specified list of candidate genes had nominal associations including Q8IVB4 , P21728 REA , P07550 REA , Q01959 REA , Q16649 REA , P08588 REA , P21579 REA , P28223 REA , P32121 REA , and P43681 REA . Of these findings Q8IVB4 stood out as a promising candidate , with nominally significant SNPs in six distinct regions of the gene .

Dopamine D1 , D2 and D3 receptor genes in alcohol dependence . Hereditary factors play a substantial role in the etiology of alcohol dependence . DB00898 mediates its reinforcing effects by an activation of the mesolimbic dopamine system . These findings suggest that the genes encoding the dopamine receptor ( DR ) subtypes represent high-ranking candidates for susceptibility genes to addictive disorders . Our present population-based association study investigated whether sequence variants of the dopamine D1 , D2 and D3 receptor genes confer susceptibility to alcohol dependence in 278 alcoholics , and clinically more homogeneous subgroups ascertained through positive family history , early age at onset , delirium , withdrawal seizures and antisocial tendencies . No evidence for an allelic association was found for the PCR-based TaqA RFLP fo the P14416 REA gene and a Bsp 1286I RFLP of the P21728 REA gene . Without correction for multiple testing , we found a significantly increased allele frequency of a common P35462 REA gene variant expressing a serine at position 9 in the extracellular N-terminal part of the receptor protein in 55 alcohol-dependent individuals with delirium ( chi 2 = 4.1 , df = 1 , p = 0.042 ) . Further studies have to examine whether this amino acid substitution or a nearby mutation confers genetic susceptibility to at least a subgroup of alcohol-dependent individuals with delirium .

Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? DB00072 MEN - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 REA ) - positive breast cancer . In pre-clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 REA receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 REA ) , loss of phosphatase and tensin homolog ( P60484 REA ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non-HER ) tyrosine kinase receptors , and resistance to antibody-dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 REA - positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3 - kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 REA status according to standard methods .

Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa-induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl -1,2 , 3,6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 SUB treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 SUB and did not develop LID . Our results show that DB01235 SUB treatment induces an increase in P14416 REA and P35462 REA expression in the postcommissural putamen , but only P35462 REA is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 REA - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 REA - signaling pathway , visible in the levels of Akt phosphorylated on Thr 308 and GSK 3β on Ser 9 , is associated with DB01235 SUB treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 REA receptor and the P21728 REA pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long-term DB01235 SUB administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .

Q9UD71 and inhibitor - 1 are expressed in pancreatic beta-cells . P01308 REA secretion from pancreatic beta-cells has to be tightly regulated to ensure accurate glucose homeostasis . The capacity of beta-cells to respond to extracellular stimulation is determined by several signaling pathways . One important feature of these pathways is phosphorylation and subsequent dephosphorylation of a wide range of cellular substrates . Protein phosphatase 1 ( P50391 REA ) is a major eukaryotic serine / threonine protein phosphatase that controls a multitude of physiological processes . We have investigated the expression and cellular distribution of two endogenous inhibitors of P50391 REA activity in beta-cells . RT-PCR , Western blotting , and immunohistochemistry showed that Q9UD71 and inhibitor - 1 are present in insulin-secreting endocrine beta-cells . Subcellular fractionation of mouse islets revealed that both P50391 REA inhibitors predominantly localized to cytosol-enriched fractions . Inhibitor - 1 was also present in fractions containing plasma membrane-associated proteins . These data indicate a potential role for Q9UD71 and inhibitor - 1 in the regulation of P50391 REA activity in pancreatic beta-cell stimulus-secretion coupling .

Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells . Sorting nexin 5 ( Q9Y5X3 REA ) belongs to the P20073 family , which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins , receptors , and transporters . Q9Y5X3 REA is important in the resensitization of the dopamine D1 - like receptor ( D1R ) . D1R is uncoupled from its effector proteins in hypertension and diabetes , and treatment of diabetes restores D1R function and insulin receptor ( IR ) expression . We tested the hypothesis that the D1R and Q9Y5X3 REA regulate IR by studying the expression , distribution , dynamics , and functional consequences of their interaction in human renal proximal tubule cells ( hRPTCs ) . D1R , Q9Y5X3 REA , and IR were expressed and colocalized in the brush border of RPTs . P01308 REA promoted the colocalization of Q9Y5X3 REA and IR at the perinuclear area of hRPTCs . Unlike Q9Y5X3 REA , the D1R colocalized and coimmunoprecipitated with IR , and this interaction was enhanced by insulin . To evaluate the role of Q9Y5X3 REA and D1R on IR signaling , we silenced via RNA interference the endogenous expression of Q9Y5X3 REA or the D1R gene P21728 REA in hRPTCs . We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B , which are crucial components of the IR signal transduction pathway . Our data indicate that Q9Y5X3 REA and D1R are necessary for normal IR expression and activity . It is conceivable that D1R and Q9Y5X3 REA may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling .

In vivo effects of a combined P28222 REA receptor / P31645 REA antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co-operation between the serotonin ( 5 - hydroxytryptamine , 5 - HT ) transporter and P28222 REA receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 REA receptor / serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over-expressing serotonin transporter ( P31645 REA + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 REA + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin-induced vasoconstriction and P28222 REA receptor / serotonin transporter interactions in mouse isolated pulmonary artery . DB00215 MENMAX DB00215 MEN had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs . There is synergy between P28222 REA receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 REA receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin-induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 REA receptor may be a novel therapeutic approach to PAH .

A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 REA . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 REA * 3 allele , was genotyped for additional functionally defective alleles in the P11712 REA and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 REA * 3 allele , a P11712 REA * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 MEN sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 REA and Q9BQB6 genes . The study provides additional data in support of diminished P11712 REA activity due to the presence of the rare * 11 allele .