MH_dev_89

P11362 REA - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co-immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 REA ) - 5 - hydroxytryptamine 1A ( P08908 REA ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 REA ) and a P08908 REA agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 REA agonist induced phosphorylation of P11362 REA and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing P09038 REA levels . Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 REA and 8 - OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 REA receptor protomer in the hippocampal P11362 REA - P08908 REA receptor complex enhancing the P11362 REA signaling .

The P35372 REA promotes opioid and growth factor-induced proliferation , migration and Epithelial Mesenchymal Transition ( EMT ) in human lung cancer . Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor ( MOR ) can influence cancer progression . Based on our previous observations that overexpression of MOR in human non-small cell lung cancer ( NSCLC ) cells increased tumor growth and metastasis , this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition ( EMT ) in human NSCLC cells . We utilized specific siRNA , shRNA , chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO , morphine , fentanyl , P01133 REA or IGF . Cell function assays , immunoblot and immunoprecipitation assays were then performed . Our results indicate MOR regulates opioid and growth factor-induced P01133 REA receptor signaling ( Src , Gab - 1 , PI3K , Akt and P40763 REA activation ) which is crucial for consequent human NSCLC cell proliferation and migration . In addition , human NSCLC cells treated with opioids , growth factors or MOR overexpression exhibited an increase in snail , slug and vimentin and decrease ZO - 1 and claudin - 1 protein levels , results consistent with an EMT phenotype . Further , these effects were reversed with silencing ( shRNA ) or chemical inhibition of MOR , Src , Gab - 1 , PI3K , Akt and P40763 REA ( p < 0.05 ) . Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation , migration and EMT transition during lung cancer progression . Such an effect provides a plausible explanation for the epidemiologic findings .

Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 REA ( P05231 REA ) , C-Reactive Protein ( CRP ) , P00734 REA Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 REA Activator Inhibitor 1 ( P05121 REA ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 REA and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 REA level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .

Role of the P08908 REA receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 REA receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy-DPAT ( 8 - OH-DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3-10 , 10-17 or 17-24 ) were injected daily with 1 mg / kg 8 - OH-DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye-opening , a possible consequence of P08908 REA receptor interactions with epidermal growth factor ( P01133 REA ) . Behaviorally , the animals were more anxious . Animals treated from P01160 REA 10-17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 REA 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .

Anti-stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti-inflammatory , anti-oxidative , anti-fibrotic , anti-infarction and immunoregulatory effects . To clarify anti-stress effect of AM , anxiolytic and anti-inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti-inflammatory activity assay , serum levels of corticosterone , P05231 REA and P01375 REA - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose-dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0.5 mg / kg , i . p . ) , a P08908 REA receptor antagonist ( p < 0.01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0.5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 REA and P01375 REA - α dose-dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress-induced anxiety and inflammation .

Transmitter neurochemistry of the efferent neuron system innervating the labyrinth . It is likely that several mechanisms contribute to the efferent control of cochlear and vestibular function . Different effects are probably mediated by different neuronal transmitters . In spite of a number of transmitter candidates , it is still widely assumed that the entire efferent system can be globally characterized as cholinergic . We attempted to label retrogradely identified efferent neurons in the brainstem with a monoclonal antibody against choline acetyltransferase ( P28329 REA ) , the acetylcholine ( ACh ) synthesizing enzyme . Only a portion of the vestibular efferents could thus be shown to be cholinergic in the rat . Medial cochlear efferents , terminating under outer hair cells , may also be cholinergic since they stain intensely for acetylcholine esterase ( P22303 REA ) after pre-treatment with the P22303 REA inhibitor diisopropylfluorophosphate ( DB00677 MEN ) . The lateral cochlear efferents terminating under inner hair cells , as well as more than half of the vestibular efferent neuron population , reacted negatively with either method designed to identify cholinergic neurons . Half of the lateral olivo-cochlear neuron population filled retrogradely with tritiated gamma-amino butyric acid [ ( 3H ] - GABA ) . These cells were similar in size and distribution to neurons staining for the GABA synthesizing enzyme glutamic acid decarboxylase ( Q99259 REA ) . Retrograde transport of [ 3H ] - aspartate from the inner ear to the brainstem was seen in half of the lateral olivocochlear population , as well as in part of the efferent vestibular population in group E and in the caudal pontine reticular nucleus ( P16435 REA ) . Since various peptides have also been located in efferent neurons , this system is chemically diversified . Several distinct mechanisms of efferent control with presumably differing functions must , therefore , exist .

Exposure to an organophosphate ( DB00677 MEN ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate DB00677 MEN ( DB00677 MEN ) is a well-known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of DB00677 MEN induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1.5 mg / kg DB00677 MEN b.wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 REA . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to DB00677 MEN on postnatal day ( P01160 REA ) 3 or 10 showed significant ( P < or = 0.01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0.01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 REA 19 . The proportions and affinity-constants of high - and low-affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 REA 19 was not due to differences in P22303 REA activity .

Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence . Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations . Using a case-control design this study ' s purpose was to explore , among a population of methamphetamine-dependent Caucasians , six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations . A total of 193 non-psychotic males ( 117 methamphetamine-dependent and 76 controls ) were genotyped for variants located in six genes ( P31749 REA , P32121 REA , P23560 REA , P21964 REA , P09211 REA , P35372 REA ) . Genotypic and allelic frequencies , odds ratios , and 95 % confidence intervals were calculated . None of the putative gene associations was significantly replicated in our sample of Caucasian men . Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 ( P32121 REA ) and glutathione S-transferase P1 ( P09211 REA ) and allelic convergence for brain-derived neurotrophic factor ( P23560 REA ) . Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms ( SNPs ) for methamphetamine ( METH ) dependence reported among Asian populations across other ethnic / ancestral groups .

Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy-induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll-like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil-based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 REA , P05231 REA , IL - 6R , P22301 REA , P01375 REA , TGF-b , O60603 REA , O00206 REA , Q9Y6Y9 REA , Q99836 REA , P23560 REA , CRP , ICE , and P35372 REA . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 REA and P01375 REA genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87.3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .

Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 REA , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 REA ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 REA ) 293 cells co-expressing P35372 REA and O14939 REA , treatment with ( D-Ala 2 , Me Phe 4 , Glyol 5 ) enkephalin ( DAMGO ) led to an increase in O14939 REA activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 REA . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR 1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR 1D also mediates an agonist-independent ( constitutive ) O14939 REA - activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 REA activity by over-expression of a dominant negative O14939 REA ( nPLD 2 ) blocked the constitutive O14939 REA activation and impaired the endocytosis of MOR 1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 REA ) is also mediated by a O14939 REA - dependent pathway . These data indicate the generally important role for O14939 REA in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis .

Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 REA ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ) . tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 MEN ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 REA ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 REA than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .

Ex vivo binding of flibanserin to serotonin P08908 REA and 5 - Q13049 REA receptors . DB04908 MEN has been reported to be an agonist at P08908 REA - receptors and an antagonist at 5 - Q13049 REA receptors , with higher affinity for P08908 REA receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 REA antagonism at doses ( 4-5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 REA receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 REA and 5 - Q13049 REA receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ]8 - OH-DPAT and [ 3H ] ketanserin to label P08908 REA and 5 - Q13049 REA receptors , respectively . DB04908 MEN was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects .

P35367 REA antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 MEN 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 MEN affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .

Evidence of an Epigenetic Modification in Cell-cycle Arrest Caused by the Use of Ultra-highly-diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra-highly-diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically-diluted anti-cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 ( - 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis-a-vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 REA ( WAF ) , p53 , Akt , P40763 REA ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell-cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de-acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 REA activity quite strikingly , it apparently did not alter the Q13547 REA enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 REA ( WAF ) , p53 , Akt , and P40763 REA activities and a cell-cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell-cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .

Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 MEN is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT 2 or P13866 REA ; ( 3 ) H - 2 - deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT 3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . DB08907 MEN dose-dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA 1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 MEN lowered RT ( G ) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .

Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 REA ( P04275 REA ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 REA , plasminogen activator inhibitor type 1 ( P05121 REA ) , antithrombin III ( P01008 REA ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 REA ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 REA secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 REA are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 REA and P01008 REA difference between FAECs and FVECs . P09038 REA ( 10 ng / ml ) significantly increased P04275 REA secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .

Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders . There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders . Using a sensitive radioligand assay , we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 ( P11229 REA , 34.4 % ) , mu-opioid receptor ( P35372 REA , 13.1 % ) , P08908 REA ( P08908 REA , 7.4 % ) , and dopamine receptor D2 ( P14416 REA , 4.9 % ) in 122 psychiatric patients . Positive antibodies to P11229 REA were found in 34.1 % , 34.9 % , 33.3 % , and 9.1 % of patients with schizophrenic disorders ( n = 44 ) , mood disorders ( n = 63 ) , other psychiatric disorders ( n = 15 ) and autoimmune diseases ( n = 33 ) , respectively . All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to P11229 REA , P35372 REA , and / or P08908 REA . Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome .

2 ( 3H ) - benzoxazolone and bioisosters as " privileged scaffold " in the design of pharmacological probes . The 2 ( 3H ) - benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2 ( 3H ) - benzothiazolinone , benzoxazinone , etc . ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa ' s , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti-inflammatory compounds ( including P37231 REA antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 REA and P28223 REA ) , sigma - 1 and sigma - 2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2 ( 3H ) - benzoxazolone template certainly deserves the title of " privileged scaffold " in medicinal chemistry .

Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 MENMAX DB00734 MEN ( 1.0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 REA antagonist , WAY 100635 ( 0.2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 REA receptor stimulation and 5 - Q13049 REA and alpha 2 adrenergic receptor antagonism to this augmentation are discussed .

Association analysis between the A118G polymorphism in the P35372 REA gene and treatment response to venlafaxine XR in generalized anxiety disorder . Patients diagnosed with generalized anxiety disorder ( Q99259 REA ) exhibit differential responses to standard antidepressant pharmacotherapy . Mounting evidence demonstrates that genetic differences may be implicated in treatment response in disorders like Q99259 REA . In this study , we examined whether the P35372 REA gene , which has been implicated in antidepressant treatment response in major depressive disorder , also has an effect in Q99259 REA . In our study , 156 patients diagnosed with Q99259 REA received venlafaxine XR treatment as part of an 18 - month relapse prevention study . Genotypes were obtained for the P35372 REA functional variant A118G for the entire sample ( n = 151 ) ; however , only the European American population was considered ( n = 108 ) for pharmacogenetic analysis . We found no significant association between A118G and antidepressant treatment response in our Q99259 REA population . Future studies that include different single nucleotide polymorphisms of the P35372 REA gene as well as larger populations will need to be conducted to further elucidate the pharmacogenetic role of the endogenous opioid system in anxiety disorders .

P04150 REA antagonism disrupts the reconsolidation of social reward-related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 REA cannabinoid receptors , in the reconsolidation of social play-induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play-induced CPP . DB00834 MEN did not affect social play-induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play-induced CPP . However , the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and P21554 REA cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories .

DB00741 MEN is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . DB00741 MEN ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 REA ) and caspase 3 ( P42574 REA ) and reduced the enzymatic activity of P42574 REA and cell death induced by tumor necrosis factor ( P01375 REA ) and interferon gamma ( P01579 REA ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 REA ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 REA ) , and P8 0365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 REA were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 REA - P01579 REA - induced apoptosis in vitro by reducing apoptosis signals via Q14790 REA and P42574 REA in bovine CL and that the local increase in cortisol production resulting from increased P28845 REA at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .

DB00193 SUB and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects , but decreased analgesic effects , in genetically deficient serotonin transporter ( P31645 REA ) mice . The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs , including antidepressants such as selective serotonin reuptake inhibitors ( SSRIs ) and monoamine oxidase inhibitors ( MAOIs ) . We recently reported a genetic mouse model for the serotonin syndrome , as serotonin transporter ( P31645 REA ) - deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5 - hydroxy-l-tryptophan ( 5 - HTP ) . As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome , we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in P31645 REA wild-type ( + / + ) , heterozygous ( + / - ) and knockout ( - / - ) mice . Comparisons were made with P31645 REA mice treated with either vehicle or morphine , an opioid not implicated in the serotonin syndrome in humans . Here we show that tramadol and meperidine , but not morphine , induce serotonin syndrome-like behaviours in mice , and we show that this response is exaggerated in mice lacking one or two copies of P31645 REA . The exaggerated response to tramadol in P31645 REA - / - mice was blocked by pretreatment with the P08908 REA antagonist WAY 100635 . Further , we show that morphine - , meperidine - and tramadol-induced analgesia is markedly decreased in P31645 REA - / - mice . These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents . These findings suggest that it is conceivable that there might be increased vulnerability in individuals with P31645 REA polymorphisms that may reduce P31645 REA by more than 50 % , the level in P31645 REA + / - mice .

Tandospirone activates neuroendocrine and P29323 REA ( Q96HU1 kinase ) signaling pathways specifically through P08908 REA receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen-activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose-dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1.0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3.0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1.3 mg / kg for oxytocin , 1.2 mg / kg for DB01285 , 3.0 mg / kg for corticosterone , and 0.24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100,635 ( 0.3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose-response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal-regulated kinase ( P29323 REA ) . Western blot analysis revealed a significant increase in phosphorylated P29323 REA ( p - P29323 REA ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100,635 ( 0.3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 REA levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .

Targeting Q01196 REA / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in Q01196 REA / Q06455 - positive acute myeloid leukemia cells . In t (8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 REA / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 REA target genes . Valproic acid ( DB00313 MEN ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . DB00313 MEN causes selective proteasomal degradation of Q92769 REA but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 REA / Q06455 fusion protein that also recruits Q13547 REA , a key regulator of normal and aberrant histone acetylation . We report here that DB00313 MEN treatment disrupts the Q01196 REA / Q06455 - Q13547 REA physical interaction , stimulates the global dissociation of Q01196 REA / Q06455 - Q13547 REA complex from the promoter of Q01196 REA / Q06455 target genes , and induces relocation of both Q01196 REA / Q06455 and Q13547 REA protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 REA ) otherwise silenced by Q01196 REA / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase-dependent apoptosis . Taken together , these data support the notion that DB00313 MEN might effectively target Q01196 REA / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 REA function and that DB00313 MEN should be integrated in novel therapeutic approaches for Q01196 REA / Q06455 - positive AML .

Purification and characterization of a high molecular weight histone deacetylase complex ( Q92769 REA ) of maize embryos . The dynamic state of core histone acetylation is maintained by histone acetyltransferases and deacetylases . In germinating maize embryos , four nuclear histone deacetylases can be distinguished . From a chromatin fraction prepared at 72 h after start of embryo germination , we have purified the nuclear histone deacetylase Q92769 REA to homogeneity . Using a sequence of chromatographic steps , we achieved the purification of an enzymatically active high molecular weight protein complex with an apparent molecular mass of 400 kDa , as determined by gel filtration chromatography . The purified enzyme was characterized in terms of enzymatic and kinetic properties , and sensitivity to several histone deacetylase inhibitors . In SDS-polyacrylamide gels , Q92769 REA split into three polypeptides of 45 , 42 , and 39 kDa , suggesting that the native enzyme is a multimer-protein complex . Electrophoresis under nondenaturing conditions in combination with second dimension SDS-gel electrophoresis indicated that all three protein components of the Q92769 REA complex were enzymatically active . Polyclonal antibodies against each of the three polypeptides were raised in rabbits . Each antiserum reacted with all three polypeptides on Western blots , suggesting that P29466 REA , Q8NFH3 , and p39 are highly homologous . This homology was confirmed by amino acid sequencing of peptides generated from each of the three Q92769 REA components .

Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol-mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol ' s ( 400mg / kg , oral ) antinociceptive activity was assessed through formalin-induced nociception . Serotonin content and gene expression of P08908 REA , 5 - Q13049 REA and P21554 REA receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol-mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol-mediated increase in serotonin level . DB00316 did not alter P08908 REA expression , but caused down-regulation of 5 - Q13049 REA and up-regulation of P21554 REA receptors . Arsenic down-regulated these receptors . However , paracetamol-mediated down-regulation of 5 - Q13049 REA was more pronounced . Arsenic did not modify paracetamol ' s effect on P08908 REA expression , but reduced paracetamol-mediated down-regulation of 5 - Q13049 REA and reversed up-regulation of P21554 REA receptors . Results suggest arsenic reduced paracetamol-induced analgesia possibly by interfering with pronociceptive 5 - Q13049 REA and antinociceptive P21554 REA receptors .

Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha-glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy-D-glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy-D-glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 REA content , activating P14672 REA promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 REA / Akt . The effect of mangiferin on 2 - deoxy-D-glucose uptake was blocked by GW9662 , an irreversible P37231 REA antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 REA expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 REA .

Further characterization of a somatic cell hybrid panel : ten new assignments to the bovine genome . Thirty-six partially characterized hamster-bovine hybrid cell lines were used for the determination of synteny groups . Sixteen additional reference loci , selected for their coverage of the bovine genome , were analysed on these hybrid cells . This increases to 25 the number of synteny groups detected . This panel was then used to make synteny assignments for 10 additional loci , eight by Southern blotting ( P02452 REA , P08123 REA , FAS , P07858 REA , P07711 REA , P07510 REA , P07686 REA and P08908 REA ) and two by polymerase chain reaction ( PCR ) amplification ( P35367 REA and ETH 1112 ) . These loci were assigned to international synteny groups U12 ( P35367 REA ) , U13 ( P08123 REA ) , U17 ( P07510 REA ) , U21 ( P02452 REA , FAS ) , U29 ( ETH 1112 ) , to chromosome 20 ( U14 or U25 ) for P07686 REA and P08908 REA , and to the same local synteny group ( A ) , which is probably U18 , for P07858 REA and P07711 REA . For three loci already mapped in humans ( P02452 REA , P08123 REA and P07510 REA ) , the present results are in accordance with the predictions based on comparative mapping between the human and bovine species .

P35372 REA - dependent and independent components in effects of tramadol . DB00193 SUB is thought to induce analgesia via both opioid and non-opioid pathways , although the precise mechanisms remain to be elucidated . In this study , we investigated the roles of the mu-opioid receptor ( MOP ) in analgesic and rewarding effects of tramadol by using MOP knockout ( KO ) mice . DB00193 SUB - induced antinociception , assessed by hot-plate and tail-flick tests , was significantly reduced in heterozygous and homozygous MOP-KO mice when compared with that in wild-type mice . Interestingly , however , tramadol retained its ability to induce significant antinociception in homozygous MOP-KO mice . The tramadol-induced antinociception remaining in homozygous MOP-KO mice was not significantly affected by methysergide , a serotonin receptor antagonist , but was partially blocked by yohimbine , an adrenaline alpha 2 receptor antagonist , and both naloxone , a non-selective opioid receptor antagonist , and yohimbine . In addition , antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP-KO mice . On the other hand , neither wild-type nor homozygous MOP-KO mice showed significant place preference for tramadol in a conditioned place preference test , although there were slight tendencies toward preference in wild-type mice and avoidance in homozygous MOP-KO mice . These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha 2 receptor mediate most of the analgesic properties of tramadol .

Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 REA , P35372 REA , P41145 REA , P32121 REA , P42226 REA , P21964 REA , P20309 REA , P08912 REA , P35367 REA , P14416 REA , P35462 REA , P25103 REA , P46098 REA , O95264 REA , Q8WXA8 , P21554 REA ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 REA ; rs165722 , rs4680 and rs4633 in P21964 REA ; rs10802789 and rs685550 in P20309 REA . Only the SNP rs1672717 in O95264 REA passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 REA , P21964 REA and P20309 REA genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .