interacts_with DB00341?
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 ) . The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats . Chronic amphetamine use results in anxiety-like states after drug cessation . The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptor ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats . In our study memantine ( 8 and 12 mg/kg ) , a noncompetitive N-methyl-d-aspartate ( DB01221 ) receptor antagonist did not reduce amphetamine withdrawal anxiety . DB00659 ( DB01221 and metabotropic glutamate 5 receptor ( P41594 ) antagonist ) at the dose 200 and 400mg/kg showed anxiolytic-like effect , thus increasing the percent of time spent in open arms and a number of open arm entries . P41594 selective antagonist , MTEP ( 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride ) and Q14416 /3 agonist , LY354740 ( 1S,2S,5R,6S ) -2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ) , caused effects similar to acamprosate at doses 1.25-5mg/kg and 2.5-5mg/kg , respectively . None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group . Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking , our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy . DB00074 induction in patients receiving tacrolimus-based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine-based immunosuppression . However , its clinical utility in patients receiving tacrolimus-based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC- P01589 ) , 100 received basiliximab and delayed tacrolimus(dTAC- P01589 ) , and 132 patients received tacrolimus without basiliximab(TAC-No) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC- P01589 compared to TAC-IL-2RA and TAC-No Groups ( 33 vs.14.9 vs. 14.3 % , p < 0.001 ) . Inferior creatinine clearance was observed in dTAC- P01589 Group compared to TAC- P01589 and TAC-No Groups at months 1 ( 41.6 vs. 49.9 vs. 44.8 mL/min , p = 0.004 ) , 3 ( 49.8 vs. 57.2 vs. 53.5 mL/min , p = 0.017 ) , and 6 ( 53.1 vs. 61.8 vs. 57.0 mL/min , p = 0.001 ) . Patients who received basiliximab ( TAC- P01589 and dTAC- P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs.18 vs. 39.3 % , p = 0.009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction . Isoenzyme-specific cyclooxygenase inhibitors : a whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6 . NSAIDs inhibit the conversion of arachidonic acid into DB03866 and Prostaglandin H2 which is catalyzed by the enzyme cyclooxygenase ( P36551 ) . Two genetically distinct isoforms have been discovered , P23219 and P35354 . While P23219 is thought to account for homeostatic amounts of eicosanoids , P35354 is induced during inflammation leading to pathologic amounts of eicosanoids . Since NSAIDs inhibit both P36551 isoforms , antiinflammatory drug research has refocused to discovering P35354 inhibitors that do not inhibit P23219 . For this purpose , we have developed a whole cell assay system using the human erythroleukemic cell line HEL as a source for P23219 and the human monocytic cell line Mono Mac 6 as a source for P35354 . Mono Mac 6 cells express high amounts of P35354 upon stimulation with lipopolysaccharide ( LPS ) in the absence of any detectable P23219 protein . On the other hand , we find HEL cells to naturally express P23219 protein , but not P35354 . Testing of a panel of NSAIDs as well as some P35354 specific inhibitors showed that this assay system is suitable for identifying compounds that selectively inhibit either P23219 or P35354 . This test system offers the advantage of assessing P23219 and P35354 inhibitors within the human species , within a similar test set-up , and circumvents the need for tedious purification of either platelets or peripheral blood monocytes . Altered gene expression in the spleen of adolescent rats following high ethanol concentration binge drinking . Binge drinking of alcoholic beverages among adolescents is a common practice that can have serious health consequences . DB00898 is a potent immunomodulator that alters a wide range of immune responses . However , it is unclear whether there is a differential immune response to alcoholic beverages with a high versus low concentration of ethanol . In this study , we used a PCR array containing 46 primer pairs of selected genes to compare mRNA expression in the spleen , an immune system organ , of adolescent rats following binge drinking of alcohol solutions containing either 20 % or 52 % ethanol ( v/v , 4.8 g/kg daily dosage ) , or water ( control ) for 3 d . We found that , expression of IL-1β , P05231 , P13500 , and GABA(A) receptor α2 subunit in the spleen were decreased , and P41594 and P46098 receptor expression were increased after administration of an ethanol solution containing 52 % ethanol , but not one with 20 % ethanol . Our data suggest that alcohol-mediated immunomodulatory effects are , in part , dependent on the ethanol by volume concentration . This is the first study to show that exposure to a high ethanol percentage beverage can have more profound effects on immune responses than one with a low percentage of ethanol . Families of retinoid dehydrogenases regulating vitamin A function : production of visual pigment and retinoic acid . DB00162 ( retinol ) and provitamin A ( beta-carotene ) are metabolized to specific retinoid derivatives which function in either vision or growth and development . The metabolite 11-cis-retinal functions in light absorption for vision in chordate and nonchordate animals , whereas all-trans-retinoic acid and 9-cis-retinoic acid function as ligands for nuclear retinoic acid receptors that regulate gene expression only in chordate animals . Investigation of retinoid metabolic pathways has resulted in the identification of numerous retinoid dehydrogenases that potentially contribute to metabolism of various retinoid isomers to produce active forms . These enzymes fall into three major families . Dehydrogenases catalyzing the reversible oxidation/reduction of retinol and retinal are members of either the alcohol dehydrogenase ( DB00067 ) or short-chain dehydrogenase/reductase ( SDR ) enzyme families , whereas dehydrogenases catalyzing the oxidation of retinal to retinoic acid are members of the aldehyde dehydrogenase ( ALDH ) family . Compilation of the known retinoid dehydrogenases indicates the existence of 17 nonorthologous forms : five ADHs , eight SDRs , and four ALDHs , eight of which are conserved in both mouse and human . Genetic studies indicate in vivo roles for two ADHs ( P07327 and P08319 ) , one SDR ( Q92781 ) , and two ALDHs ( P00352 and O94788 ) all of which are conserved between humans and rodents . For several SDRs ( RoDH1 , RoDH4 , CRAD1 , and CRAD2 ) androgens rather than retinoids are the predominant substrates suggesting a function in androgen metabolism as well as retinoid metabolism . LPS induces cardiomyocyte injury through calcium-sensing receptor . DB01373 -sensing receptor ( P41180 ) belongs to the family C of G-protein coupled receptors . We have previously demonstrated that P41180 could induce apoptosis of cultured neonatal rat ventricular cardiomyocytes in simulated ischemia/reperfusion . It remains unknown whether the P41180 has function in lipopolysaccharide ( LPS ) -induced myocardial injure . The aim of this study was to investigate whether the P41180 plays a role in LPS-induced myocardial injury . Cultured neonatal rat cardiomyocytes were treated with LPS , with or without pretreatment with the P41180 -specific agonist gadolinium chloride ( GdCl3 ) or the P41180 -specific antagonist NPS2390 . Release of P01375 -α and P05231 from cardiomyocytes was observed . Levels of malonaldehyde ( MDA ) , lactate dehydrogenase ( LDH ) , and activity of superoxide dismutase ( SOD ) were measured . In addition , apoptosis of the cardiomyocytes , [Ca(2+)]i and level of P41180 expression were determined . The results showed that LPS increased cardiomyocytes apoptosis , [Ca(2+)]i , MDA , LDH , P01375 -α , P05231 release , and P41180 protein expression . Compared with LPS treatment alone , pretreatment with GdCl3 further increased apoptosis of cardiomyocytes , MDA , LDH , P01375 -α , P05231 release , [Ca(2+)]i , and the expression of the P41180 protein . Conversely , pretreatment with NPS2390 decreased apoptosis of cardiomyocytes , MDA , LDH , P01375 -α , P05231 release , [Ca(2+)]i and the expression of the P41180 protein . These results demonstrate that LPS could induce cardiomyocyte injury . Moreover , LPS-induced cardiomyocyte injury was related to P41180 -mediated cardiomyocytes apoptosis , P01375 -α , P05231 release , and increase of intracellular calcium . The influence of mast cell mediators on migration of SW756 cervical carcinoma cells . The role of mast cell mediators on cervical cancer cell migration was assessed using an in vitro assay of scratch wound healing onto monolayers of HPV18-positive cervical carcinoma cells ( SW756 ) . Migration of SW756 cells was accelerated by co-culture with the mast cell line LAD2 . This effect was inhibited by the P35367 antagonist DB06691 and the cannabinoid agonists 2-arachidonylglycerol ( 2AG ) and Win 55,212-2 . Therefore , the specific effects of histamine and cannabinoids on SW756 migration and LAD2 activation were analyzed . DB11320 added to the in vitro assay of scratch wound healing either increased or inhibited SW756 migration rate by acting either on P35367 or Q9H3N8 , respectively . Cannabinoids acted on P21554 receptors to inhibit SW756 migration . Supernatants from SW756 cells stimulated LAD2 cell degranulation , which in turn was inhibited by cannabinoids acting via CB2 receptors . RT-PCR showed that SW756 expressed mRNA for P21554 , CB2 , P35367 , P25021 , and Q9H3N8 . On the other hand , LAD2 expressed mRNA for all four HRs and CB2 . The results suggest that mast cells could be contributing to cervical cancer cell invasion and spreading by the release of histamine and cannabinoids . Therefore , therapeutic modulation of specific mast cell mediators may be beneficial for cervical cancer treatment . Further characterization of a somatic cell hybrid panel : ten new assignments to the bovine genome . Thirty-six partially characterized hamster-bovine hybrid cell lines were used for the determination of synteny groups . Sixteen additional reference loci , selected for their coverage of the bovine genome , were analysed on these hybrid cells . This increases to 25 the number of synteny groups detected . This panel was then used to make synteny assignments for 10 additional loci , eight by Southern blotting ( P02452 , P08123 , FAS , P07858 , P07711 , P07510 , P07686 and P08908 ) and two by polymerase chain reaction ( PCR ) amplification ( P35367 and ETH1112 ) . These loci were assigned to international synteny groups U12 ( P35367 ) , U13 ( P08123 ) , U17 ( P07510 ) , U21 ( P02452 , FAS ) , U29 ( ETH1112 ) , to chromosome 20 ( U14 or U25 ) for P07686 and P08908 , and to the same local synteny group ( A ) , which is probably U18 , for P07858 and P07711 . For three loci already mapped in humans ( P02452 , P08123 and P07510 ) , the present results are in accordance with the predictions based on comparative mapping between the human and bovine species . Dual ligands targeting dopamine D2 and serotonin P08908 receptors as new antipsychotical or anti-Parkinsonian agents . Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson 's disease are associated with poly-factorial pathogenic mechanisms , with several neurotransmitter systems closely involved . In addition to the cerebral dopaminergic ( DA ) system , the serotoninergic ( 5-HT ) system also plays a crucial role in regulating psychoemotional , cognitive and motor functions in the central nervous system ( CNS ) . Among the large 5-HT receptor family , accumulating data have revealed new insights into the therapeutic benefit of the P08908 receptor in treating various CNS disorders , especially schizophrenia and Parkinson 's disease . The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin P08908 receptors in the treatment of these diseases . Aripiprazole was the only marketed drug with dual D2 and P08908 profile . It is a partial D2 and P08908 receptor agonist and has been prescribed as an atypical antipsychotical drug . Two other drugs DB06016 and Pardoprunox are being investigated in clinic . Most of the other candidate compounds , including DB04888 , Sarizotan , Mazapertine succinate , PF-217830 , and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy . Although much effort has been done to highlight the advantages of the P08908 and D2 dual approach , it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and P08908 receptors . In this regard , ' pure ' compounds exclusively acting on the D2 and P08908 receptors are highly needed to further validate this approach . Meanwhile , safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early . Behind the curtain : cellular mechanisms for allosteric modulation of calcium-sensing receptors . DB01373 -sensing receptors ( P41180 ) are integral to regulation of systemic Ca(2+) homeostasis . Altered expression levels or mutations in P41180 cause Ca(2+) handling diseases . P41180 is regulated by both endogenous allosteric modulators and allosteric drugs , including the first Food and Drug Administration-approved allosteric agonist , DB01012 HCl ( Sensipar® ) . Recent studies suggest that allosteric modulators not only alter function of plasma membrane-localized P41180 , but regulate P41180 stability at the endoplasmic reticulum . This brief review summarizes our current understanding of the role of membrane-permeant allosteric agonists in cotranslational stabilization of P41180 , and highlights additional , indirect , signalling-dependent role(s) for membrane-impermeant allosteric drugs . Overall , these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function , and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to P41180 abundance and signalling . Genetic mechanism of aspirin-induced urticaria/angioedema . PURPOSE OF REVIEW : DB00945 -induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma . Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin-induced urticaria/angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema . A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 -activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( -1708A > G ) and Q9Y271 ( -634C > T ) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine-related genes , did not find any significant associations with aspirin-induced urticaria/angioedema for the genes P50135 ( encoding histamine N-methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high-affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin-induced urticaria/angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition . Lactobacillus acidophilus L-92 Cells Activate Expression of Immunomodulatory Genes in THP-1 Cells . To understand the immunomodulatory effects of Lactobacillus acidophilus L-92 cells suggested from our previous study of in vivo anti-allergy and anti-virus effects , host immune responses in macrophage-like THP-1 cells after 4 h ( the early phase ) and 24 h ( the late phase ) of cocultivation with L-92 cells were investigated by transcriptome analysis . In the early phase of L-92 treatment , various transcription regulator genes , such as , NFkB1 , NFkB2 , P05412 , P31629 and Q01201 , and genes encoding chemokines and cytokines , such as P13236 , O14625 , P10147 and P01375 , were upregulated . Two transmembrane receptor genes , Q9NYK1 and P05362 , were also upregulated in the early phase of treatment . In contrast , many transmembrane receptor genes , such as P16871 , P33681 , Q9HC73 , P42081 , P06127 , HLA-DQA1 , P01589 , Q13261 and P15509 , and some cytokine genes , including P05231 , Q9NPF7 and O00626 , were significantly upregulated in the late phase after L-92 exposure . Some genes encoding cytokines , such as P01583 , P01584 and P10145 , and the enzyme P14902 were upregulated at both the early and the late phases of treatment . These results suggest that probiotic L-92 might promote Th1 and regulatory T-cell responses by activation of the MAPK signaling pathway , followed by the NOD-like receptor signaling pathway in THP-1 cells . Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 -mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) -derived DCs ( BM-DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 -mediated signaling . The crosstalk of P35367 -mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 -α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 -α and P05231 production of BM-DCs . P35367 -specific agonists were able to enhance P01375 -α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 -α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 -mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 -mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation . Experimental Staphylococcus aureus infection of the mammary gland induces region-specific changes in innate immune gene expression . Staphylococcus aureus is a prolific mastitis-causing bacterium that resides naturally in the environment of the dairy cow . The aim of this study was to profile immune gene expression in tissue from the alveolar , ductal , gland cistern and teat canal regions of the bovine mammary gland following intramammary infection with S. aureus . Quantitative real-time PCR ( qPCR ) was used to profile expression of innate immune genes including pattern recognition receptors ( PRRs ) , cytokines , antimicrobial peptides ( AMPs ) and acute phase proteins ( APPs ) . Consistent expression of Toll-like receptors ( TLRs ) 1-10 and NOD-like receptors ( NODs ) 1-2 was detected in all four tissue regions . Pro-inflammatory cytokines ( P05231 , Q16552 and P10145 ) and anti-inflammatory cytokine ( P22301 ) were induced in all 4 tissues . P05067 ( SAA3 and HP ) and AMP ( DEFB4 and Q8NG35 ) genes showed the greatest induction throughout the mammary gland in response to S. aureus , with particularly high expression in alveolar tissue ( SAA3 and HP > 133- and > 80-fold respectively , P < 0.05 ; DEFB4 and Q8NG35 > 9- and > 27-fold respectively , P < 0.05 ) . Collectively , our data show both sentinel and effector immune functions throughout the mammary gland in response to S. aureus challenge . P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders . The cannabinoid P21554 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats . Cannabinoid P21554 receptor agonists , including DB00470 ( Delta 9-THC ) ( the main psychoactive ingredient in marijuana ) have been shown to increase feeding in rats and humans . Conversely , it has been reported that acute administration of the P21554 receptor antagonist SR 141716A reduces food intake in rats . Based upon this observation , it has been suggested that P21554 antagonists could be useful as appetite suppressant drugs . The present studies were designed to provide a detailed examination of the effects of P21554 antagonists on food intake across a range of paradigms . Two P21554 antagonists ( SR 141716A and AM 251 ) were administered to rats trained on fixed-ratio schedules with two different ratio requirements ( fixed-ratio 1 and fixed-ratio 5 ) . Both drugs produced a dose-dependent decrease in lever pressing , and had a relatively long duration of action ( T1/2 : SR 141716A , 15.1 h ; AM 251 , 22.0 h ) . Furthermore , intake of three diets with differing macronutrient composition ( lab chow , high fat , high carbohydrate ) was studied . Both drugs significantly suppressed intake of all three foods , and there were no significant interactions between drug dose and diet type . These findings support the hypothesis that P21554 receptor antagonists could be useful pharmacological tools for the suppression of appetite . 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 . Neuroprotective effects of huperzine A . A natural cholinesterase inhibitor for the treatment of Alzheimer 's disease . DB04864 ( HupA ) , isolated from Chinese herb Huperzia serrata , is a potent , highly specific and reversible inhibitor of acetylcholinesterase . It has been found to reverse or attenuate cognitive deficits in a broad range of animal models . Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects , patients with benign senescent forgetfulness , Alzheimer 's disease ( AD ) and vascular dementia ( VD ) , with minimal peripheral cholinergic side effects compared with other AChEIs in use . HupA possesses the ability to protect cells against hydrogen peroxide , beta-amyloid protein ( or peptide ) , glutamate , ischemia and staurosporine-induced cytotoxicity and apoptosis . These protective effects are related to its ability to attenuate oxidative stress , regulate the expression of apoptotic proteins Bcl-2 , Bax , P04637 and caspase-3 , protect mitochondria , and interfere with P05067 metabolism . Antagonizing effects on DB01221 receptors and potassium currents may contribute to the neuroprotection as well . It is also possible that the non-catalytic function of P22303 is involved in neuroprotective effects of HupA . The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism . Serotonin via P34969 receptors activates p38 mitogen-activated protein kinase and protein kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5-hydroxytryptamine ( 5-HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5-HT may induce interleukin ( IL ) -6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5-HT dose- and time-dependently induced P05231 protein synthesis . We identified several 5-HT receptors to be expressed on U373 MG cells , including the P28221 , 5- Q13049 , 5- Q9H205 and P34969 receptors . In this report , we show that the 5-HT-induced P05231 release is mediated by the P34969 receptor based on several agonist/antagonists that were used . 5-HT-induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5-HT-induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO-31-8425 , respectively ) blocked 5-HT-induced P05231 synthesis . Furthermore , 5-HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 /44 MAPKs , however , were not involved in 5-HT-induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .