interacts_with DB00966?
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 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , 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 . Molecular weight and biochemical profile of a chemically modified heparin derivative , Suleparoide . Recently , a new chemically modified derivative of heparin ( Suleparoide , Syntex Laboratories Buenos Aires , Argentina ) was introduced for the prophylaxis of thrombosis and treatment of vascular disorders . This agent is claimed to contain a depolymerized , chemically modified , heparin derivative with similar biologic actions as heparan sulfate . To study the pharmacologic profile of this agent , we have defined its molecular weight distribution profile , utilizing a computerized gel permeation chromatographic system equipped with ultraviolet and refractive index detectors . Suleparoide exhibited a normal molecular distribution profile with no contaminants . It exhibited a weight average of 9.3 K DA and an apparent peak MW of 8.0 K DA . Approximately 50 % of the molecular components were < 5.0 K DA and 40 % > 5.0 K DA . The results from these studies on the mechanisms show that Suleparoide has anticoagulant activity primarily mediated through DB01109 Cofactor-II ( P05546 ) and because of its novel mechanism of action , further investigations on the biochemical profile of Suleparoide are carried out . Global clotting tests such as Activated Partial P13726 Time ( APTT ) , Heptest and Thrombin Time ( TT ) revealed a concentration dependent effect in all assays . Plasma samples supplemented with Suleparoide exhibited no significant anti-Xa and anti-IIa activities . However , in the P05546 mediated inhibitory assay for IIa , Suleparoide exhibited significant activity . In contrast , the P01008 ( DB11598 ) mediated inhibition of IIa was much weaker . Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n=5 ) . Selected genes up-regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin-2 receptor beta ) ; Q92843 ( P10415 -like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF-hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator-activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras-like 2 ) ; P05112 ( interleukin-4 ) ; IL-4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 -related protein A1 ) ; P24522 ( growth arrest and DNA-damage-inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide-3-kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member-associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) . Differential effects of amfonelic acid on the haloperidol- and clozapine-induced increase in extracellular DOPAC in the nucleus accumbens and the striatum . This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid ( DOPAC ) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats . DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes . Amfonelic acid ( 2.5 mg/kg s.c. ) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens . DB00502 ( 1 mg/kg s.c. ) increased extracellular DOPAC in both regions . When amfonelic acid was injected 5 min before haloperidol , the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum . Clozapine ( 30 mg/kg i.p. ) increased extracellular DOPAC in both regions , an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum . When ritanserin ( 5 mg/kg i.p. ) , a serotonergic antagonist ( P28223 ) , was co-administered with haloperidol , the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum . The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo . The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens . These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms , supporting the view that the regulation of dopamine metabolism differs in the two regions. ( ABSTRACT TRUNCATED AT 250 WORDS ) Q13547 contributes to cell cycle and apoptosis . Histone deacetylases ( HDACs ) are generally thought to play important roles in human disease . However , little information is available concerning the specific functions of individual HDACs . We previously reported on transgenic mice that expressed human Q13547 and experienced steatosis and nuclear pleomorphism in their hepatic tissues . To find out if the over-expression of Q13547 contributes to the expression of genes related to the cell cycle , apoptosis , and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice , the expression profiles of the related genes in liver tissues were determined by reverse transcription-polymerase chain reaction ( RT-PCR ) and Western blot analysis . The activated human Q13547 significantly induced the expression levels of mRNA for p53 , P37231 and Bak and reduced the P38936 expression level compared with the levels in control littermates . However , the protein levels of p53 and P37231 were significantly decreased . In conclusion , our results indicate that Q13547 can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over-express Q13547 . 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 , 34.4 % ) , mu-opioid receptor ( P35372 , 13.1 % ) , P08908 ( P08908 , 7.4 % ) , and dopamine receptor D2 ( P14416 , 4.9 % ) in 122 psychiatric patients . Positive antibodies to P11229 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 , P35372 , and/or P08908 . 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 . P37231 regulates P12830 expression and inhibits growth and invasion of prostate cancer . P37231 ( PPARgamma ) might not be permissive to ligand activation in prostate cancer cells . Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma ligands in a recent randomized clinical trial . Using cells and prostate cancer xenograft mouse models , we demonstrate in this study that a combination treatment using the PPARgamma agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy . We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice . In addition , we demonstrate that expression of P12830 , a protein involved in the control of cell migration and invasion , is highly up-regulated in the presence of valproic acid and pioglitazone . We show that P12830 expression responds only to the combination treatment and not to single PPARgamma agonists , defining a new class of PPARgamma target genes . These results open up new therapeutic perspectives in the treatment of prostate cancer . Potential utility of telmisartan , an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma ( P37231 ) -modulating activity for the treatment of cardiometabolic disorders . The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus . There is widespread agreement that the renin-angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end-organ protection . Thus the blockade of the DB01367 may be a promising strategy for the treatment of the patients with the metabolic syndrome . Although several types of angiotensin II type 1 ( AT(1) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT(1) receptor . Further , telmisartan is reported to act as a partial agonist of peroxisome proliferator-activated receptor-gamma ( P37231 ) . These observations suggest that , due to its unique P37231 -modulating activity , telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders . In this paper , we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes . [ DB00391 in the management of functional dyspepsia and delayed gastric emptying ] . DB00391 is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT(4) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying . Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives . Many women using progestogen ( P ) -only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to DB00294 users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) -exposed pseudo-pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12- , 18- , 24- and 48-h post-treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 -positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using DB00294 who were treated with a single dose of mifepristone . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . Novel cinnamyl hydroxyamides and 2-aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl-containing histone deacetylase ( HDAC ) inhibitors 1-4 are described , containing hydroxamate ( 1 and 3 ) or 2-aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1-B and human Q13547 ) and class II ( maize HD1-A and human P56524 ) HDACs , most hydroxamates and 2-aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl-H3 and low acetyl-α-tubulin levels . Exceptions are compounds 3 f-i , 3 m-o , and 4 k , which showed higher tubulin acetylation than DB02546 . In U937 cells , cell-cycle blockade in either the G₂/M or G₁/S phase was observed with 1-4 . Five hydroxamates ( compounds 1 h-l ) effected a two- to greater than threefold greater percent apoptosis than DB02546 , and in the CD11c cytodifferentiation test some 2-aminoanilides belonging to both series 2 and 4 were more active than MS-275 . The highest-scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts . The role of serotonin receptor subtypes in the behavioural effects of neuroleptic drugs . A paw test study in rats . The present study was designed to evaluate the roles of serotonin P08908 and 5-HT2 receptors in the effects of neuroleptic drugs in the paw test . This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side-effect liability of neuroleptic drugs . Whereas the P08908 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin ( 8-OHDPAT ) reduced the effects of the classical neuroleptic haloperidol , it increased the effects of the atypical neuroleptic clozapine . The 5-HT2 receptor antagonist ketanserin as well as the P28335 /5-HT2 receptor antagonist ritanserin , on the other hand reduced the effects of haloperidol , whereas the P28335 /5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ( DOI ) reduced the effects of clozapine . The most important finding , however , was that the behavioural effects of different ( putative ) neuroleptics ( fluphenazine , P35240 -39166 , remoxipride , prothipendyl , thioridazine and risperidone ) were differentially influenced by both 8-OHDPAT and DOI , suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs , even within the subclasses of classical and atypical neuroleptics . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 -length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E(2) ) binding was similar , E(2) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4-hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E(2) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females , but none from males . E(2) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF-7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males . Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib-pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation . Telmisartan , its potential therapeutic implications in cardiometabolic disorders . There is a growing body of evidence that the renin-angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of cardiovascular diseases . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular-organ protection . Although several types of angiotensin II type 1 ( AT(1) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT(1) receptor . Telmisartan will be a promising cardiometabolic sartan due to its unique peroxisome proliferator-activated receptor-gamma ( P37231 ) -inducing properties as well . In this review , we focused on telmisartan , and discussed its potential therapeutic implications in cardiometabolic disorders . The P28335 receptor agonist lorcaserin reduces nicotine self-administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . DB04871 ( ( 1R ) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl ) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0.3-3 mg/kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22-h food deprivation or palatability . Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation . DB04871 ( 0.6-1 mg/kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self-administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . DB04871 also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . DB04871 did not reinstate nicotine-seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0.3-1 mg/kg ) reduced nicotine-induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five-choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5-HT(2C) receptor agonists , similarly affect both food- and nicotine-motivated behaviors , and nicotine-induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence . Exposure to an organophosphate ( DB00677 ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate DB00677 ( DB00677 ) is a well-known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of DB00677 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 b.wt. on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . 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 on postnatal day ( P01160 ) 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 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 19 was not due to differences in P22303 activity . New aspects in the pathogenesis of diabetic atherothrombosis . Diabetes mellitus is increasing worldwide , resulting from the interaction of obesity , inflammation , and hyperglycemia . Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome , establishing the link between diabetes and atherosclerosis . Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress , a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis . Recent studies have documented increased inflammation , neovascularization , and intraplaque hemorrhage in human diabetic atherosclerosis . This inflammatory microangiopathic process is independently associated with plaque rupture , leading to coronary thrombosis . P13726 , the most potent trigger of the coagulation cascade , is increased in diabetic patients with poor glycemic control . Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages , closing the link among inflammation , plaque rupture , and blood thrombogenicity . High-density lipoproteins , responsible for free cholesterol removal , are reduced in patients with insulin resistance and diabetes . High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells . These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant P02647 Milano/phospholipid complex . Finally , peroxisomal proliferator-activated receptors ( PPARs ) are now considered the nuclear transcriptional regulators of atherosclerosis . Three subfamilies , including Q07869 , -delta , and -gamma , have been identified with crucial roles in lipid metabolism , plaque inflammation , expression of adhesion molecules and cytokines , and regulation of matrix metalloproteinases . Multiple experimental studies have documented plaque stabilization with P37231 agonists , a group of medications holding great promise in the treatment of diabetes atherosclerosis . Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese mice . Obesity increases severity of acute pancreatitis ( AP ) by unclear mechanisms . We investigated the effect of the P37231 agonist rosiglitazone ( RGZ , 0.01 % in the diet ) on severity of AP induced by administration of IL-12+ Q14116 in male C57BL6 mice fed a low fat ( LFD ) or high fat diet ( HFD ) , under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals . In both LFD and HFD mice without AP , RGZ significantly increased body weight and % fat mass , with significant upregulation of adiponectin and suppression of erythropoiesis . In HFD mice with AP , RGZ significantly increased survival and hastened recovery from pancreatic inflammation , as evaluated by significantly improved pancreatic histology , reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP . This was associated with significantly lower circulating and pancreas-associated levels of P05231 , P17931 , osteopontin and P01033 in HFD + RGZ mice , particularly at Day 7 post-AP . In LFD mice with AP , RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification , without affecting other parameters of disease severity or inflammation . Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice . In conclusion , RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity , indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu . However , RGZ worsens selective parameters of AP severity in LFD mice . DB05039 inhibits tumor cell invasiveness and P14780 expression by suppressing IKK/NF-κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra-long-acting inhaled β2-agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β-arrestin-2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α ( P01375 -α ) -induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα , thereby decreasing NF-κB nuclear translocation and the expression of P14780 , an NF-κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 -α/NF-κB-induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner , preventing further lung damage and improving lung function in P48444 patients .