interacts_with DB09043?
Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1A 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 ) induced cytotoxicity and P60568 -induced-ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 -induced-ADCC . DB00904 , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type-2 receptor antagonist augmented the P60568 -induced-ADCC . The P01375 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 ) . DB08815 , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5- Q13049 and P08908 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 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 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 ( Eperzan ) : a new once-weekly agonist of glucagon-like peptide-1 receptors ] . DB09043 ( 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 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 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 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 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 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 ( 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 -induced synaptic potentiation was blocked by 1 microM [ Acetyl-3,4-dehydro-Pro1,D-p-F-Phe2,D-Trp3,6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 -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 agonist . DB09043 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 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 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 : NCT00938158 , NCT01406262 , NCT00537719 , NCT01077505 , NCT01147731 , NCT01147718 , NCT01147692 , NCT00354536 , NCT00394030 , NCT00530309 , NCT01357889 , NCT00518115 , NCT01098461 , NCT01475734 , NCT00849017 , NCT00838916 , NCT00839527 , NCT01098539 . Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury : involvement of P19957 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 ) . In this study , we explore the role of P19957 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 Akt308 , Akt473 , GSK-3beta , and PDK1 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 Akt308 , Akt473 , GSK-3beta and PDK1 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 ) / 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 -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 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 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 ) 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 , 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 -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 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 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 ) . 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 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 ( F4/80(+) and F4/80(+)CD11b(+)CD11c(+) cells ) , as well as the expression and production of P05231 , P01375 -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 agonist , exendin-4 , in 3T3- Q9NUQ9 adipocytes and Q13315 . CONCLUSIONS/INTERPRETATION : We suggest that P0C6A0 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and Q13315 , 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 ( IKK ) activity was investigated using purified recombinant O15111 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 , O14920 , or constitutively active O15111 and O14920 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 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 had no effect . Activation of extracellular signal-related kinase ( P29323 ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 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 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 deficiency preserves cardiac function via P0C6A0 signaling in rats subjected to myocardial ischemia/reperfusion . Dipeptidyl peptidase-4 ( P27487 ) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 ( P0C6A0 ) level for controlling postprandial glucose concentration . Both P27487 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 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 -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 -deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers ( LDH , P01160 , and DB04899 ) , which could be attenuated by exendin-(9-39) , a P43220 antagonist . Exendin-(9-39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3β as well as the higher expression of P14672 in post-infarcted P27487 -deficient rats . However , exendin-(9-39) could not completely abrogate the less infarct size in P27487 -deficient rats as compared with that in wild-type rats , implicating the involvement of P43220 -independent pathway . In summary , this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in P27487 -deficient rats , which is mediated through both P43220 -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 ) receptor agonists . To examine whether the P43220 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 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 , P05231 , P13500 , 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 Reg3b but not Il6 , Ccl2 , Nfkb1 , or Vamp8 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 binding to human and rat dopamine and 5-HT receptors . DB04946 ( DB04946 ; 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 displays affinity for dopamine D2 receptors and for 5- Q13049 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 and P28335 receptors and rat P50406 and P34969 receptors . DB04946 displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 displayed high affinity for the P50406 and P34969 receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5- Q13049 ( Ki = 5.6 nM ) than for the P28335 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 ) 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 -tagged P0C6A0 ( P27918 - P0C6A0 ) receptor for visualizing protein-protein interaction in living cells were constructed and localized in CHO cells . Cells expressing YFP- P0C6A0 and P27918 - P43220 showed characteristic P0C6A0 mediated increase in DB02527 , similar to cells expressing a wild type P43220 . 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 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 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 ) 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 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r=0.83 , P < 0.01 ) and LCP ( r=0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 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 ) -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 ( 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 levels were not altered during therapy . The results show that P09455 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 ) release . P0C6A0 caused a concentration-dependent increase in P01148 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 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 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 ) or bilateral P21554 , 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 treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham-operated rats . DB00820 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 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , 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 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 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5-HT2CR ) and melanoroctin-4 receptor ( P32245 ) 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 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 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 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 receptor antagonist ) or 1 mg/kg Q08050 55,212-2 ( a P21554 receptor agonist ) together with 3 µg/kg exendin-4 ( Ex-4 , a P43220 agonist ) or 160 µg/kg exendin ( 9-39 ) [ Ex ( 9-39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex-4 and AM 251 or Q08050 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 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 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 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 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 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . DB00668 inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .