interacts_with DB01032?
P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist-induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D-Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l-alpha-acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta-endorphin(1-31) , enkephalins , and dynorphin A(1-17) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist-induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies . Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase , calcineurin , protein phosphatase 2A , and P60484 phosphatases . Akt is an important oncoprotein , and data suggest a critical role for nuclear Akt in cancer development . We have previously described a rapid ( 3-5 min ) and Q99572 -dependent depletion of nuclear phosphorylated Akt ( pAkt ) and effects on downstream targets , and here we studied mechanisms behind the pAkt depletion . We show that cholesterol-lowering drugs , statins , or extracellular DB00171 , induced a complex and coordinated response in insulin-stimulated A549 cells leading to depletion of nuclear pAkt . It involved protein/lipid phosphatases P60484 , pleckstrin homology domain leucine-rich repeat phosphatase ( O60346 and -2 ) , protein phosphatase 2A ( PP2A ) , and calcineurin . We employed immunocytology , immunoprecipitation , and proximity ligation assay techniques and show that O60346 and calcineurin translocated to the nucleus and formed complexes with Akt within 3 min . Also P60484 translocated to the nucleus and then co-localized with pAkt close to the nuclear membrane . An inhibitor of the scaffolding immunophilin FK506-binding protein 51 ( FKBP51 ) and calcineurin , FK506 , prevented depletion of nuclear pAkt . Furthermore , okadaic acid , an inhibitor of PP2A , prevented the nuclear pAkt depletion . Chemical inhibition and siRNA indicated that O60346 , PP2A , and P60484 were required for a robust depletion of nuclear pAkt , and in prostate cancer cells lacking P60484 , transfection of P60484 restored the statin-induced pAkt depletion . The activation of protein and lipid phosphatases was paralleled by a rapid proliferating cell nuclear antigen ( P12004 ) translocation to the nucleus , a P12004 - P38936 (cip1) complex formation , and cyclin D1 degradation . We conclude that these effects reflect a signaling pathway for rapid depletion of pAkt that may stop the cell cycle . Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation . Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis . Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice . Here , we report that disabling one of these Myc targets , P11926 ( Odc ) , abolishes Myc-induced suppression of the Cdk inhibitors P38936 (Cip1) and p27(Kip1) , thereby impairing Myc 's proliferative , but not apoptotic , response . Moreover , lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine ( DB06243 ) . Strikingly , tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf , suggesting that targeting Odc forces other routes of transformation . Therefore , Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention . Involvement of the Q99572 purinergic receptor and c-Jun N-terminal and extracellular signal-regulated kinases in cyclooxygenase-2 and prostaglandin E2 induction by LL-37 . Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 ( P35354 ) expression and prostaglandin E(2) ( PGE(2) ) production . We previously demonstrated that human β-defensin-3 induces P35354 and PGE(2) in human gingival fibroblasts ( HGFs ) . We , therefore , aimed to examine the inducible effects of LL-37 , the only cathelicidin expressed in humans , on P35354 expression and PGE(2) synthesis in HGFs and to elucidate the relevant signaling pathways . The P35354 expression was upregulated by LL-37 in dose- and time-dependent manners . Accordingly , the synthesis of PGE(2) in cell-free culture supernatants was raised by LL-37 ( p < 0.01 ) and blocked by NS-398 , a specific P35354 inhibitor ( p < 0.01 ) . P2X inhibitors and a neutralizing antibody against P2X(7) purinergic receptor significantly abrogated P35354 induction and PGE(2) production by LL-37 ( p < 0.01 ) . LL-37 upregulated P35354 expression and PGE(2) synthesis via activation of extracellular signal-regulated kinase ( P29323 ) and Q9BY77 c-Jun N-terminal kinase ( JNK ) , while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases . In summary , LL-37 can control arachidonic acid metabolism by induction of P35354 expression and PGE(2) synthesis via the P2X(7) receptor , P29323 , and Q9BY77 JNK . The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease . DB00644 analogues reduce the proliferation of endometrial stromal cells but not endometriotic cells . AIMS : We investigated the potential of gonadotropin-releasing hormone ( DB00644 ) agonists and DB00644 antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells . METHODS : Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited . Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas , respectively . RESULTS : DB00644 agonist or antagonist treatment attenuated tumor necrosis factor ( P01375 ) -α-induced cell proliferation in the endometrial stromal cells , whereas endometriotic stromal cells did not respond to treatment . The endometriotic stromal cells exhibited a decreased expression of the type I P30968 compared with the endometrial stromal cells . DB00644 agonists or antagonists did not repress P01375 -α-induced P10145 production in endometriotic stromal cells . CONCLUSION : DB00644 agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells . Endometriotic stromal cells resist the antiproliferative effect of DB00644 agonists and antagonists . Q08431 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury . Milk fat globule- P01133 8 ( Q08431 ) plays important , nonredundant roles in several biological processes , including apoptotic cell clearance , angiogenesis , and adaptive immunity . Several recent studies have reported a potential role for Q08431 in regulation of the innate immune response ; however , the precise mechanisms underlying this role are poorly understood . Here , we show that Q08431 is an endogenous inhibitor of inflammasome-induced IL-1β production . Q08431 inhibited necrotic cell-induced and DB00171 -dependent IL-1β production by macrophages through mediation of integrin β(3) and Q99572 receptor interactions in primed cells . Itgb3 deficiency in macrophages abrogated the inhibitory effect of Q08431 on DB00171 -induced IL-1β production . In a setting of postischemic cerebral injury in mice , Q08431 deficiency was associated with enhanced IL-1β production and larger infarct size ; the latter was abolished after treatment with IL-1 receptor antagonist . Q08431 supplementation significantly dampened caspase-1 activation and IL-1β production and reduced infarct size in wild-type mice , but did not limit cerebral necrosis in Il1b- , Itgb3- , or P2rx7-deficient animals . In conclusion , we demonstrated that Q08431 regulates innate immunity through inhibition of inflammasome-induced IL-1β production . Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy-induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll-like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5-fluoruracil-based chemotherapy regimens was analyzed for variants of IL-1B , P60568 , P05231 , IL-6R , P22301 , P01375 , TGF-b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87.3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population . Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa . DB00945 causes gastroduodenal ulcers and complications . Food bioactive compounds could exert beneficial effects in the gastrointestinal tract . We evaluated whether apple polyphenol extract ( APE ) reduced aspirin-induced injury to the rat gastric mucosa . Rats were treated with APE ( 10(-4) m catechin equivalent ) before oral aspirin ( 200 mg/kg ) . Cyclo-oxygenase-2 ( P35354 ) , transforming growth factor-alpha ( TGF alpha ) and heparin-binding epidermal-growth-factor-like growth factor ( HB- P01133 ) mRNA and protein expression were assessed by RT-PCR and Western blot analysis , respectively ; malondialdehyde ( MDA ) was determined by HPLC ; gastric secretion was evaluated in pylorus-ligated rats . APE decreased acute and chronic aspirin injury both macroscopically and microscopically ( approximately 50 % decrease in lesion score ; P < 0.05 ) . DB00945 up-regulated mRNA and protein expression of P35354 and HB- P01133 , but not of TGF alpha ; APE reduced aspirin-induced mRNA and protein over-expression of P35354 and HB- P01133 ; aspirin significantly increased gastric MDA and this effect was counteracted by APE pre-treatment . APE did not significantly affect gastric acid secretion . In conclusion , APE reduces aspirin-induced gastric injury independently of acid inhibition . We speculate that APE might be of therapeutic use in the prophylaxis of aspirin-related gastropathy . P11511 inhibitors and cyclooxygenase-2 ( P35354 ) inhibitors in endometriosis : new questions -- old answers ? The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is providing important results for the development of new , specific treatment modalities . P11511 overexpression has recently been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for converting C19 androgens into estrogen in several types of human tissue . P11511 activity causes local estrogen biosynthesis , which , in turn , stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 ( P35354 ) . Thus , a positive feedback cycle develops between the two systems . Another abnormality in endometriosis , the deficient 17beta-hydroxysteroiddehydrogenase type II ( 17beta-HSD-Type-II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance and even invasiveness . Consequently , aromatase and P35354 are thought to be promising new therapeutic targets . Thus , specific aromatase inhibitors ( e.g. DB01006 / DB01006 , DB01217 /Arimidex or Exemestan/Aromasin ) or selective P35354 inhibitors ( e.g. Celecoxib/ DB00482 , DB00533 /Vioxx , DB00580 /Bextra ) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options . Ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1 % in human aqueous humor . PURPOSE : The aim of this study was to evaluate the ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1 % in subjects undergoing routine cataract surgery with intraocular lens implantation . METHODS : An open-label , phase II confirmatory study of 54 subjects undergoing cataract surgery with intraocular lens implantation . A single drop of bromfenac sodium ophthalmic solution 0.1 % was administered at 30 , 60 , 90 , 120 , 180 , or 240 min prior to the initiation of cataract surgery . Samples of aqueous humor were aspirated through a paracentesis and analyzed by using high-performance liquid chromatography . Based upon these data , predicted concentrations of bromfenac in the aqueous humor over 24 h were generated by using computer simulation and compared with the IC(50) for bromfenac as a measure of anti-inflammatory efficacy . RESULTS : Peak aqueous-humor concentrations of bromfenac occurred between 150 and 180 min following ophthalmic dosing , with a mean concentration of 78.7 ng/mL . The level of bromfenac decreased in a log-linear fashion with an elimination-rate constant of 1.4 . DB00963 remained above the IC(50) value of cyclo-oxygenase-2 ( P35354 ) during the evaluated time points and over the 12-h dosing interval , using a computer model of extrapolated time points and assuming first-order elimination . CONCLUSIONS : Pharmacokinetic modeling , based upon samples collected over 240 min after a single dose of bromfenac sodium ophthalmic solution 0.1 % suggests that aqueous-humor concentrations remain at clinically effective levels ( above its IC(50) value for P35354 ) for over 12 h . Based upon this rationale , these results supported clinical trials that demonstrated the efficacy of twice-daily dosing of bromfenac sodium ophthalmic solution 0.1 % to manage patients with postoperative ocular pain and inflammation . The tolerability and pharmacokinetics of the novel antimigraine compound DB00315 in healthy male volunteers . 1. DB00315 is a novel and selective agonist at P28221 receptors , with central and peripheral actions , currently in development for the acute oral treatment of migraine . 2 . The pharmacokinetic and tolerability profiles of single oral doses from 1-50 mg DB00315 were investigated in 12 healthy male volunteers in a double-blind , placebo-controlled , dose-escalating study . 3 . DB00315 was well tolerated with most adverse experiences of mild and transient nature . 4 . Absorption was rapid with dose-independent kinetics . Median tmax was 2-4 h although 50-85 % of eventual Cmax was attained within 1 h . The t1/2 was 2.5-3 h with a high apparent plasma clearance ( CL/F > 2000 ml min-1 ) and apparent volume of distribution ( Vz/F ) of 400-500 l . 5 . Three metabolites were detected in plasma and urine , one of which , the N-desmethyl metabolite , has P28221 agonist activity . 6 . DB00315 showed no clinically significant effects on blood pressure , heart rate , ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment . DB00107 improves mentalizing - pronounced effects for individuals with attenuated ability to empathize . The ability to predict the behavior of others based on their mental states is crucial for social functioning . Previous studies have provided evidence for the role of DB00107 ( P01178 ) in enhancing the ability to mentalize . It has also been demonstrated that the effect of P01178 seems to strongly depend on socio-cognitive skills with more pronounced effects in individuals with lower socio-cognitive skills . Although recent studies indicate that mentalizing is related to empathy , no study has yet examined whether the effects of P01178 on mentalizing depend on the ability to empathize . 71 male participants participated in a double-blind , between-subjects , placebo-controlled experiment . The Reading the Mind in the Eye Test ( RMET ) was used to investigate mentalizing abilities . We analyzed the effect of P01178 on easy and difficult items of the RMET depending on differential empathy scores of the participants as assessed with the Empathy Quotient ( EQ ) . Our results showed that P01178 improves mentalizing for difficult but not for easy items . We generally observed increased mentalizing accuracy in participants with higher empathy scores . Importantly , however , whereas the performance in participants with higher empathy scores was comparable in both P01178 and placebo condition , P01178 specifically enhanced mentalizing accuracy in participants with lower empathy scores . Our findings suggest that P01178 enhances mentalizing abilities . However , we also demonstrate that not all participants benefited from P01178 application . It seems that the effects of P01178 strongly depend on baseline social-cognitive skills such as empathy . Structure-function studies of linear and cyclized peptide antagonists of the P30968 . Structurally new analogs of the peptidic P30968 antagonist DB00050 as well as conformationally constrained cyclized deca- or pentapeptides were synthesized and selected peptides evaluated comprehensively . To understand how structural variations of the antagonistic peptide effect pharmacodynamic properties , binding affinities and antagonistic potencies toward the human and rat P30968 were determined . Whereas large substituents in position 6 of linear peptides are compatible with high binding affinity ( K(D) < 0.5 nM ) , all cyclized peptides except the cyclo[3-10] analog D-52391 depicted low binding affinity ( K(D) > 10 nM ) . Binding affinity and antagonistic potency in vitro correlated for all peptides and surprisingly no discrimination between human and rat receptor proteins was observed . Since receptor residues W(101) and N(102) are involved in agonist and antagonist binding , equally potent but structurally different antagonists were tested for binding to the respective W(101)A and N(102)A mutants . In contrast to linear decapeptides , residues N(102) and W(101) are not involved in binding of D-23938 and W(101) is the critical residue for D-52391 binding . We conclude that although equally potent , peptidic P30968 antagonists do have distinct interactions within the ligand binding pocket . Finally , selected antagonists were tested for testosterone suppression in male rats . The duration of testosterone suppression below castration levels differed largely from 1 day for DB06785 to 27 days for D-23487 . Systemic availability became evident as the most important parameter for in vivo efficacy . DB01032 reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase-1 and release of IL-1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia . Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators , such as IL-1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation . [ Comparative study of main components of ginseng on immune function of rats ] . DB01404 and its effective components are famous for their influence to enhance human immunity , regulate endocrine and antioxidant action . However , the different effects of different components are not clear . In this study , Wistar rats were used to study the effects of main components of ginseng , including total ginsenoside , panaxadiol saponins , panaxtrol saponin and ginseng polysaccharide . The results showed that the effects of panaxadiol saponins and ginseng polysaccharide on improving animal immune organ weight , plasma interleukin 2 ( P60568 ) , interleukin 6 ( P05231 ) , plasma gamma-interferon ( IFN-γ ) , tumor necrosis factor alpha ( P01375 -α ) were better than that of the other groups . Total ginsenoside and panaxtrol saponin can effectively increase the concentration of spleen NK cells ( NKC ) while panaxadiol saponins and ginseng polysaccharide can significantly increase the concentrations of rat plasma adrenocorticotrophic hormone ( DB01285 ) , corticosterone ( O00230 ) and thyroid stimulating hormone ( DB00024 ) . As for the effect of increasing organization nitric oxide ( NO ) and superoxide dismutase ( SOD ) , glutathione ( DB00143 ) and malondialdehyde ( MDA ) , total ginsenoside is better than that of other groups . In brief , different components in ginseng possess different effects on enhancing immunity , regulating endocrine and resisting oxidation . Panaxadiol saponins and ginseng polysaccharide are better in enhancing immune , and total ginsenoside shows advantages in resisting oxidation and stress . Q99572 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 -gated P2X(7) receptor ( P2X(7)R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release . Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X(7)R knockout mice ( P2X(7)R(-/-) ) to investigate the role of P2X(7)R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse . During acute nematode infection , IL-1β-containing cells and P2X(7)R expression were increased in the jejunum of wild-type ( WT ) mice . Peritoneal and serum IL-1β levels were also increased , which was indicative of elevated IL-1β release . However , in the P2X(7)R(-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL-1β levels . Conversely , infection augmented peritoneal P01375 -α levels in both WT and P2X(7)R(-/-) animals . Infection was also associated with a P2X(7)R-dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X(7)R(-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X(7)R(-/-) animals . Therefore , our results demonstrated that P2X(7)Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity . DB00107 and tumor necrosis factor alpha stimulate expression of prostaglandin E2 synthase and secretion of prostaglandin E2 by luminal epithelial cells of the porcine endometrium during early pregnancy . DB00107 ( P01178 ) and tumor necrosis factor α ( P01375 ) have been implicated in the control of luteolysis by stimulating endometrial secretion of luteolytic prostaglandin F(2α) ( P49763 (2α) ) . Nevertheless , P01178 concentration in porcine uterine lumen increases markedly on days 11-12 of pregnancy , and P01375 is expressed in endometrium during pregnancy . The objective of the study was to determine the effect of P01178 and P01375 on expression of the enzymes involved in PG synthesis : PG-endoperoxide synthase 2 ( P35354 ) , PGE(2) synthase ( mPGES-1 ) and P49763 synthase , and PGE(2) receptor ( PTGER2 ) , as well as on PG secretion by endometrial luminal epithelial cells ( LECs ) on days 11-12 of the estrous cycle and pregnancy . LECs isolated from gilts on days 11-12 of the estrous cycle ( n=8 ) and pregnancy ( n=7 ) were treated with P01178 ( 100 nmol/l ) and P01375 ( 0.6 nmol/l ) for 24 h . P01178 increased P35354 mRNA and mPGES-1 protein contents , as well as PGE(2) secretion but only on days 11-12 of pregnancy . P01375 stimulated P35354 and mPGES-1 mRNA , as well as mPGES-1 protein expression and PGE(2) release on days 11-12 of pregnancy and the estrous cycle . In addition , expressions of PTGER2 and P35408 were determined in corpus luteum ( CL ) . Abundance of PTGER2 mRNA and P35408 protein in CL was upregulated on day 14 of pregnancy versus day 14 of the estrous cycle . This study indicates that P01375 and P01178 regulate PGE(2) synthesis in LECs during early pregnancy . PGE(2) secreted by LECs , after reaching ovaries , could have a luteoprotective effect through luteal PTGER2 and P35408 , or may directly promote uterine function and conceptus development . GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti-glaucoma drug showed in an endotoxin-induced-uveitis model ( EIU ) in rats a significant tumor necrosis factor-alpha ( P01375 ) decrease in serum , indicating an additional anti-inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha-1 , alpha-2 , P08908 , P28335 , P28221 , 5-HT2 A , beta-1 , and beta-2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU-induction animals received either one of the CP 's or GLC756 alone , or GLC756 in combination with one of the CP 's . P01375 was determined in serum 2h post EIU-induction . Treatment with CP 's alone indicated that agonistic effects on beta-2 adrenoceptors and antagonistic effects on alpha-2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS-control group . In combination with GLC756 , the counteracting CP 's domitor ( alpha-2 adrenoceptor agonist ) and ICI 118551 ( beta-2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8-OH-DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha-2 adrenoceptors and the agonistic effect on beta-2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .