MH_dev_103

Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1 A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co-medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 REA ) induced cytotoxicity and P60568 REA - induced-ADCC . We found that dexamethasone markedly inhibited the P60568 REA induced cytotoxicity and the P60568 REA - induced-ADCC . DB00904 MEN , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 REA - induced-ADCC . The P01375 REA antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .

Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 REA ) . DB08815 MEN , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 REA , 5 - Q13049 REA and P08908 REA receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose-dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .

P43220 REA agonists for type 2 diabetes mellitus : recent developments and emerging agents . More than 26 million people in the United States have type 2 diabetes mellitus ( T2D ) . Many treatment options exist , but achieving long-term glycemic control in patients with T2D remains challenging . The glucagon-like peptide - 1 receptor agonists ( P0C6A0 RAs ) offer a treatment option that improves glycemic control and reduces weight , with a low risk of hypoglycemia . They have emerged as attractive options for the treatment of T2D , and significant advances and developments continue to be published regarding these agents . To identify relevant literature on emerging issues related to P0C6A0 RAs , a search of the MEDLINE database was performed . Studies published in English evaluating the safety and efficacy of P0C6A0 RAs were analyzed . Because of their advantages and unique mechanism of action , P0C6A0 RAs are currently being studied in new clinical areas , including in combination with basal insulin , as adjunctive therapy in type 1 diabetes , and for weight loss . In addition , there are several emerging agents in development . DB09265 is a once-daily P0C6A0 RA that targets postprandial glucose and may be most useful when added to basal insulin as an alternative to rapid-acting insulin . DB09043 SUB and dulaglutide are once-weekly P0C6A0 RAs that may offer more convenient dosing . The most common adverse effects of all P0C6A0 RA agents are gastrointestinal ( e . g . , nausea , diarrhea , and vomiting ) , but the rates of occurrence vary among agents . Due to the differences in pharmacokinetics , efficacy , rates of adverse effects , and administration requirements within the P0C6A0 RA class , each agent should be evaluated independently . The future of P0C6A0 RAs offers broader treatment options for T2D as well as potential in other treatment areas .

[ DB09043 SUB ( Eperzan ) : a new once-weekly agonist of glucagon-like peptide - 1 receptors ] . DB09043 SUB ( Eperzan ) is a new once-weekly agonist of Glucagon-Like Peptide - 1 ( P0C6A0 ) receptors that is indicated in the treatment of type 2 diabetes . Two doses are available , 30 mg and 50 mg , to be injected subcutaneously once a week . It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes , in comparison with placebo or an active comparator . The endocrine and metabolic effects of albiglutide are similar to those of other P43220 REA agonists : stimulation of insulin secretion ( incretin effect ) and inhibition of glucagon secretion , both in a glucose-dependent manner , retardation of gastric emptying and increase of satiety . These effects lead to a reduction in glycated haemoglobin ( HbA ( 1c ) ) levels , combined with a weight reduction . The overall tolerance profile is good . DB09043 SUB is currently reimbursed in Belgium after failure ( HbA ( 1c ) > 7.5 % ) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin ( with or without oral antidiabetic drugs ) . To avoid hypoglycaemia , a reduction in the dose of sulfonylurea or insulin may be recommended . A once-weekly administration should increase patient ' s acceptance of injectable therapy and improve compliance .

Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 REA antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 MENMAX DB09048 MEN was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .

Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole-cell patch-clamp recordings were made from P00915 REA pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 MEN ( 10 ( - 9 ) - 10 ( - 7 ) M ) , a specific DB00644 analog , concentration-dependently elicited a long-lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 REA - induced synaptic potentiation was blocked by 1 microM [ Acetyl -3,4- dehydro-Pro 1 , D-p-F-Phe 2 , D-Trp 3,6 ] - P01148 REA , a specific P30968 REA antagonist . Furthermore , P30968 REA - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long-term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .

Clinical pharmacology of albiglutide , a P43220 REA agonist . DB09043 SUB is a glucagon-like peptide - 1 analogue composed of tandem copies of modified human glucagon-like peptide - 1 ( 7-36 ) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus . After subcutaneous administration , albiglutide is likely primarily absorbed via the lymphatic circulation , with maximum concentrations being reached in 3 to 5 days ; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration . The elimination half-life of albiglutide is approximately 5 days . Clearance of albiglutide is 67 mL / h with between-subject variability of 34.9 % ; no covariates have been identified that would require dose adjustment of albiglutide . DB09043 SUB lowers the fasting plasma glucose and reduces postprandial glucose excursions . In addition , β-cell secretion is enhanced by albiglutide during hyperglycemia , whereas secretion is suppressed during hypoglycemia ; α-cell response to hypoglycemia is not impaired by albiglutide . DB09043 SUB does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus . Dose adjustment is not suggested in patients with renal impairment , but experience in patients with severe renal impairment is very limited , and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea , nausea , and vomiting . No clinically relevant drug interactions have been observed in clinical trials . TRIAL REGISTRATION : NCT 00938158 , NCT 01406262 , NCT 00537719 , NCT 01077505 , NCT 01147731 , NCT 01147718 , NCT 01147692 , NCT 00354536 , NCT 00394030 , NCT 00530309 , NCT 01357889 , NCT 00518115 , NCT 01098461 , NCT 01475734 , NCT 00849017 , NCT 00838916 , NCT 00839527 , NCT 01098539 .

Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury : involvement of P19957 REA kinase signal pathway . AIM : Oxidative stress plays a critical role in the pathogenic cascade leading to neuronal degeneration in AD . Consequently , the induction of endogenous antioxidative proteins by antioxidants seems to be a very reasonable strategy for delaying the disease ' s progression . In previous work , we identified the neurotrophic and neuroprotective effects of geniposide , which result from the activation of glucagon-like peptide 1 receptor ( P43220 REA ) . In this study , we explore the role of P19957 REA kinase signaling pathway in the neuroprotection of geniposide in PC12 cells . METHODS : Cell viability was determined by MTT assay . Apoptosis was detected by Hoechst and PI double staining . The protein expression of Bcl - 2 and phosphorylation of Akt 308 , Akt 473 , GSK - 3beta , and PDK 1 was measured by Western blot . RESULTS : Geniposide induced the expression of the antiapoptotic protein Bcl - 2 , which inhibited apoptosis in PC12 cells induced by H ( 2 ) O ( 2 ) , and this effect could be inhibited by preincubation with LY294002 , a selective inhibitor of PI3K . Furthermore , geniposide enhanced the phosphorylation of Akt 308 , Akt 473 , GSK - 3beta and PDK 1 under conditions of oxidative stress . CONCLUSION : These results demonstrate that the PI3K signaling pathway is involved in the neuroprotection of geniposide in PC12 cells against the oxidative damage induced by H ( 2 ) O ( 2 ) in PC12 cells .

Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment . Accumulation of toxic lipids evokes the unfolded protein response ( UPR ) and apoptotic death of macrophages and vascular cells in atherosclerotic plaques . Primary macrophages from insulin-resistant ob / ob and insulin receptor ( Insr ) ( - / - ) mice display increased apoptosis in response to loading with free cholesterol or oxysterol , but underlying mechanisms have not been elucidated . We show increased activation of all three major branches of the UPR in response to free cholesterol or oxysterol loading in insulin-resistant macrophages . Inhibition and rescue experiments revealed that defective MEK / extracellular signal \ x { 2013 } related kinase ( P29323 REA ) / DB02527 - responsive element-binding protein ( CREBP ) signaling in insulin-resistant macrophages leads to decreased expression of sarcoplasmic endoplasmic reticulum ( ER ) Ca ( 2 + ) - ATPase , depletion of ER calcium stores , P19525 REA - like ER kinase activation , and ER stress-associated apoptosis . Activation of macrophage glucagon-like peptide 1 ( P0C6A0 ) receptor via the antidiabetic drug exenatide led to improvements in both P29323 REA and AKT signaling and reversed the increase in UPR and apoptosis of insulin-resistant macrophages in atherosclerotic lesions of ob / ob.Ldlr ( - / - ) and Insr ( - / - ) . Ldlr ( - / - ) mice . Increased signaling via P43220 REA or the CREBP activator protein kinase A thus offers a way to rescue insulin-resistant macrophages from excessive ER stress responses and apoptosis in insulin resistance and type 2 diabetes .

Mass spectrometry and hydrogen / deuterium exchange measurements of alcohol-induced structural changes in cellular retinol-binding protein type I . To bind and release its ligand , cellular retinol-binding protein type I ( P09455 REA ) needs to undergo conformational and dynamic changes to connect the inner , solvent-shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water / alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo - and holo - P09455 REA , in either water / methanol or water / trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time-of-flight mass spectrometry ( P19957 REA - Q-TOFMS ) to identify the alcohol-induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen / deuterium ( H / D ) exchange monitored by continuous-labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo - P09455 REA exhibits a progressively more compact conformation , resulting in reduced H / D exchange with respect to the native protein in water . DB00162 dissociation from the holo-protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo-protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo - P09455 REA to a new alpha-helix conformation capable of exchanging all available hydrogen atoms .

Glucagon-like peptide - 1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes . AIMS / HYPOTHESIS : Obesity and insulin resistance are associated with low-grade chronic inflammation . Glucagon-like peptide - 1 ( P0C6A0 ) is known to reduce insulin resistance . We investigated whether P0C6A0 has anti-inflammatory effects on adipose tissue , including adipocytes and adipose tissue macrophages ( Q13315 REA ) . METHODS : We administered a recombinant adenovirus ( rAd ) producing P0C6A0 ( rAd - P0C6A0 ) to an ob / ob mouse model of diabetes . We examined insulin sensitivity , body fat mass , the infiltration of Q13315 REA and metabolic profiles . We analysed the mRNA expression of inflammatory cytokines , lipogenic genes , and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR . We also examined the activation of nuclear factor κB ( NF-κB ) , extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase ( JNK ) in vivo and in vitro . RESULTS : Fat mass , adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Macrophage populations ( F4 /8 0 ( + ) and F4 /8 0 ( + ) CD11b ( + ) CD11c ( + ) cells ) , as well as the expression and production of P05231 REA , P01375 REA - α and monocyte chemoattractant protein - 1 , were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Expression of M1 - specific mRNAs was significantly reduced , but that of M2 - specific mRNAs was unchanged in rAd - P0C6A0 - treated ob / ob mice . NF-κB and JNK activation was significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Lipopolysaccharide-induced inflammation was reduced by the P43220 REA agonist , exendin - 4 , in 3T3 - Q9NUQ9 adipocytes and Q13315 REA . CONCLUSIONS / INTERPRETATION : We suggest that P0C6A0 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and Q13315 REA , possibly contributing to the improvement of insulin sensitivity .

Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 REA ( IKK ) activity was investigated using purified recombinant O15111 REA and - beta proteins . RESULTS : NF-kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O-tetradecanoylphorbol - 13 - acetate , or overexpression of NF-kappaB-inducing kinase , O15111 REA , O14920 REA , or constitutively active O15111 REA and O14920 REA mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 REA and O14920 REA in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 MEN had no effect . Activation of extracellular signal-related kinase ( P29323 REA ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 REA and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 REA and - beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine .

P27487 REA deficiency preserves cardiac function via P0C6A0 signaling in rats subjected to myocardial ischemia / reperfusion . Dipeptidyl peptidase - 4 ( P27487 REA ) enzyme inhibition has been reported to increase plasma glucagon-like peptide - 1 ( P0C6A0 ) level for controlling postprandial glucose concentration . Both P27487 REA inhibitors and P0C6A0 analog have been approved for antihyperglycemic agents . In addition to the insulinotropic effect , P0C6A0 signaling was reported to modulate cardiac function . P27487 REA inhibition was shown to improve survival rate after myocardial infarction in mice , but the precise mechanism remains unknown . We aimed to compare the cardiovascular responses of ischemia / reperfusion ( I / R ) between wild-type and P27487 REA - deficient rats and investigate the underlying mechanism . Rats were subjected to 45 min of coronary artery occlusion , followed by reperfusion for 2 h . Cardiac function was characterized by analyzing pressure-volume loops . As compared to wild-type rats , after I / R , P27487 REA - deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers ( LDH , P01160 REA , and DB04899 ) , which could be attenuated by exendin - ( 9-39 ) , a P43220 REA antagonist . Exendin - ( 9-39 ) could diminish the increased phosphorylation levels of myocardial AKT and GSK - 3β as well as the higher expression of P14672 REA in post-infarcted P27487 REA - deficient rats . However , exendin - ( 9-39 ) could not completely abrogate the less infarct size in P27487 REA - deficient rats as compared with that in wild-type rats , implicating the involvement of P43220 REA - independent pathway . In summary , this study demonstrated that the benefit of cardiac protective action against I / R injury was demonstrated in P27487 REA - deficient rats , which is mediated through both P43220 REA - dependent and receptor-independent mechanisms .

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents . The risk of developing pancreatitis is elevated in type 2 diabetes and obesity . Cases of pancreatitis have been reported in type 2 diabetes patients treated with P0C6A0 ( P43220 REA ) receptor agonists . To examine whether the P43220 REA agonist exenatide potentially induces or modulates pancreatitis , the effect of exenatide was evaluated in normal or diabetic rodents . Normal and diabetic rats received a single exenatide dose ( 0.072 , 0.24 , and 0.72 nmol / kg ) or vehicle . Diabetic ob / ob or HF - Q11206 REA mice were infused with exenatide ( 1.2 and 7.2 nmol · kg ( - 1 ) · day ( - 1 ) ) or vehicle for 4 wk . Post-exenatide treatment , pancreatitis was induced with caerulein ( CRN ) or sodium taurocholate ( ST ) , and changes in plasma amylase and lipase were measured . In ob / ob mice , plasma cytokines ( IL - 1β , P60568 REA , P05231 REA , P13500 REA , IFNγ , and TNFα ) and pancreatitis-associated genes were assessed . Pancreata were weighed and examined histologically . Exenatide treatment alone did not modify plasma amylase or lipase in any models tested . Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob / ob mice but did not modify the response to ST infusion . Plasma cytokines and pancreatic weight were unaffected by exenatide . Exenatide upregulated Reg 3b but not Il6 , Ccl 2 , Nfkb 1 , or Vamp 8 expression . Histological analysis revealed that the highest doses of exenatide decreased CRN - or ST-induced acute inflammation , vacuolation , and acinar single cell necrosis in mice and rats , respectively . Ductal cell proliferation rates were low and similar across all groups of ob / ob mice . In conclusion , exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents .

DB04946 MEN binding to human and rat dopamine and 5 - HT receptors . DB04946 MEN ( DB04946 MEN ; 1 - [ 4 - [ 3 - [ 4 - ( 6 - fluoro -1,2- benzisoxazol - 3 - yl ) - 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 MEN displays affinity for dopamine D2 receptors and for 5 - Q13049 REA receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 REA and P28335 REA receptors and rat P50406 REA and P34969 REA receptors . DB04946 MEN displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 MEN displayed high affinity for the P50406 REA and P34969 REA receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 REA ( Ki = 5.6 nM ) than for the P28335 REA receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .

Constructing glucagon like peptide - 1 receptor fused with derivatives of GFP for visualizing protein-protein interaction in living cells . The glucagon-like peptide - 1 receptor ( P43220 REA ) mediates important antidiabetogenic effects on peripheral tissues . It appears to be one of the most promising therapeutic targets for treatment of diabetes mellitus type 2 . Surprisingly , very little is known about the cellular mechanisms that regulate receptor function in living cells . One of the approaches how to study receptor dynamics is by using tagged fluorescent proteins . In this study , YFP-tagged P0C6A0 ( YFP - P0C6A0 ) receptor and P27918 REA - tagged P0C6A0 ( P27918 REA - P0C6A0 ) receptor for visualizing protein-protein interaction in living cells were constructed and localized in CHO cells . Cells expressing YFP - P0C6A0 and P27918 REA - P43220 REA showed characteristic P0C6A0 mediated increase in DB02527 , similar to cells expressing a wild type P43220 REA . This means that both types of receptors are functional and localized in plasma membrane .

[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 REA ) in the lung tissue , and the relationship between expression of P25103 REA and lung injury in rats with acute necrotizing pancreatitis ( P01160 REA ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 REA and control groups . Animals in group P01160 REA were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 REA ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 REA , western blot analysis was used to determine P25103 REA protein expression levels , and immunohistochemistry was used to localize expression site of P25103 REA . RESULTS : P25103 REA mRNA level was enhanced in the lung of P01160 REA compared with normal control group . Western blot analysis showed overexpression of P25103 REA protein level exited in P01160 REA group . Statistical analysis revealed correlation between P25103 REA mRNA and P05164 REA ( r = 0.83 , P < 0.01 ) and LCP ( r = 0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 REA immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 REA . CONCLUSION : In P01160 REA , overexpression of P25103 REA contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .

Therapy with a synthetic retinoid - - ( Ro 10-1670 ) etretin - - increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 REA ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 MEN ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 REA levels were not altered during therapy . The results show that P09455 REA and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .

Glucagon-like peptide - 1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line . To examine the influence of the putative satiety factor ( P0C6A0 ) on the hypothalamo-pituitary-gonadal axis , we used GT1 - 7 cells as a model of neuronal luteinizing hormone - releasing hormone ( P01148 REA ) release . P0C6A0 caused a concentration-dependent increase in P01148 REA release from GT1 - 7 cells . Specific , saturable P0C6A0 binding sites were demonstrated on these cells . The binding of [ 125I ] P0C6A0 was time-dependent and consistent with a single binding site ( Kd = 0.07+ / -0.016 nM ; binding capacity = 160 + / - 11 fmol / mg protein ) . The specific P43220 REA agonists , exendin - 3 and exendin - 4 , also showed high affinity ( Ki = 0.3+ / -0.05 and 0.32+ / -0.06 nM , respectively ) as did the antagonist exendin - ( 9-39 ) ( Ki = 0.98+ / -0.24 nM ) . At concentrations that increased P01148 REA release , P0C6A0 ( 0.5- 10 nM ) also caused an increase in intracellular DB02527 in GT1 - 7 cells ( 10 nM P0C6A0 : 7.66+ / -0.4 vs . control : 0.23+ / -0.02 nmol / mg protein ; P < 0.001 ) . Intracerebroventricular injection of P0C6A0 at a single concentration ( 10 microg ) produced a prompt increase in the plasma luteinizing hormone concentration in male rats ( P0C6A0 : 1.09+ / -0.11 vs . saline : 0.69+ / -0.06 ng / ml ; P < 0.005 ) . P0C6A0 levels in the hypothalami of 48 - h-fasted male rats showed a decrease , indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance .

Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long-term single daily oral dose of a longer half-life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half-life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno-occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 REA ) or bilateral P21554 REA , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : DB00820 MEN treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 REA compared with sham-operated rats . DB00820 MEN also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 REA , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta 1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long-term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP-related mechanism that appears to be independent of inducible nitric oxide synthase induction .

The contribution of serotonin P28335 REA and melanocortin - 4 receptors to the satiety signaling of glucagon-like peptide 1 and liraglutide , a glucagon-like peptide 1 receptor agonist , in mice . Glucagon-like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells , and liraglutide , a P43220 REA ( P43220 REA ) agonist , induce satiety . The serotonin P28335 REA receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 REA ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 REA mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 REA and wild-type mice matched for age . Moreover , once-daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 REA as well as wild-type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .

Concurrent pharmacological modification of cannabinoid - 1 and glucagon-like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free-choice , high-carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon-like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free-choice , high-carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high-sucrose chow . After 4 days of the high-calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 REA receptor antagonist ) or 1 mg / kg Q08050 REA 55,212- 2 ( a P21554 REA receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 REA agonist ) or 160 µg / kg exendin ( 9-39 ) [ Ex ( 9-39 ) , a P43220 REA antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 REA 55,212- 2 compared with either of the drugs injected alone and the saline-injected controls . Both drug combinations selectively inhibited ingestion of the high-sucrose chow . Although Ex ( 9-39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 REA antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 REA 55,212- 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high-sugar food .

Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 REA and P01375 REA released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 REA and P05231 REA are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 REA were measured in monocyte supernatants . The spontaneous release of P05231 REA or P01375 REA was increased in young athletes when compared to older subjects . The spontaneous release of P01375 REA was increased , but not significantly , by exercise and there was no correlation between the release of P05231 REA and P01375 REA and lung function measured during hypoxemia . DB00668 MEN inhibited the release of P05231 REA or P01375 REA . Correlations were observed between the in vitro release of P05231 REA or P01375 REA and age , VO2max , maximal ventilation and maximal power output of the subjects .