interacts_with DB00277?
Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . The trace amine-associated receptor 1 ( Q96RJ0 ) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to DB01576 or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine-induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants . That methamphetamine-but not morphine-induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling . c-Jun N-terminal kinase and Akt signalling pathways regulating tumour necrosis factor-α-induced interleukin-32 expression in human lung fibroblasts : implications in airway inflammation . Airway inflammatory diseases such as chronic obstructive pulmonary disease ( P48444 ) and asthma are associated with elevated expression of interleukin-32 ( P24001 ) , a recently described cytokine that appears to play a critical role in inflammation . However , so far , the regulation of pulmonary P24001 production has not been fully established . We examined the expression of P24001 by tumour necrosis factor-α ( P01375 -α ) in primary human lung fibroblasts . Human lung fibroblasts were cultured in the presence or absence of P01375 -α and/or other cytokines/Toll-like receptor ( TLR ) ligands or various signalling molecule inhibitors to analyse the expression of P24001 by quantitative RT-PCR and ELISA . Next , activation of Akt and c-Jun N-terminal kinase ( JNK ) signalling pathways was investigated by Western blot . P24001 mRNA of four spliced isoforms ( α , β , γ and δ ) was up-regulated upon P01375 -α stimulation , which was associated with a significant P24001 protein release from P01375 -α-activated human lung fibroblasts . The combination of interferon-γ and P01375 -α induced enhanced P24001 release in human lung fibroblasts , whereas P05112 , Q16552 , Q8TAD2 and TLR ligands did not alter P24001 release in human lung fibroblasts either alone , or in combination with P01375 -α . Furthermore , the activation of Akt and JNK pathways regulated P01375 -α-induced P24001 expression in human lung fibroblasts , and inhibition of the Akt and JNK pathways was able to suppress the increased release of P24001 to nearly the basal level . These data suggest that P01375 -α may be involved in airway inflammation via the induction of P24001 by activating Akt and JNK signalling pathways . Therefore , the P01375 -α/ P24001 axis may be a potential therapeutic target for airway inflammatory diseases . DB09222 binding to P05362 promotes P00533 -dependent mucin production in human airway epithelial cells . Mucous hypersecretion is a serious feature of chronic airway diseases such as asthma , chronic obstructive pulmonary disease ( P48444 ) , and cystic fibrosis . Although mucins are produced via activation of an P01133 receptor ( P00533 ) signaling cascade , the mechanisms leading to exaggerated mucin production in mucous hypersecretory diseases are unknown . Because expression of P05362 and of the P05362 ligand fibrinogen is increased in the airways of subjects with mucous hypersecretory diseases , we hypothesized that fibrinogen binding to P05362 could increase P00533 -dependent mucin production in human airway ( NCI-H292 ) epithelial cells . Consistent with this hypothesis , we found that an P05362 neutralizing antibody and an P05362 (8-22) peptide that binds fibrinogen decreased mucin production induced by the P00533 ligand transforming growth factor ( TGF ) -alpha dose-dependently . Exogenous fibrinogen and a fibrinogen(117-133) peptide that binds P05362 rescued mucin production in cells treated with the P05362 (8-22) peptide . Surprisingly , the P05362 (8-22) peptide increased P00533 phosphotyrosine and phospho- P27361 /2 in cells treated with TGF-alpha . The P05362 (8-22) peptide-induced increases in P00533 phosphotyrosine and phospho- P27361 /2 were prevented by exogenous fibrinogen , by the fibrinogen(117-133) peptide , and by selective inhibitors of phospholipase C ( P98160 ) , protein kinase C ( PKC ) -alpha/beta , and metalloproteases . These results suggest that fibrinogen binding to P05362 promotes mucin production by decreasing TGF-alpha-induced P00533 and P27361 /2 activation and that the fibrinogen- P05362 -dependent decrease in P00533 and P27361 /2 activation occurs via inhibition of an early positive feedback pathway involving P98160 - and P17252 /beta-dependent metalloprotease activation and subsequent metalloprotease-dependent P00533 reactivation . Prospective analysis of adrenal function in patients with acute exacerbations of P48444 : the Reduction in the Use of Corticosteroids in Exacerbated P48444 ( REDUCE ) trial . OBJECTIVE : To analyze prospectively the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis and clinical outcome in patients treated with prednisone for exacerbated chronic obstructive pulmonary disease ( P48444 ) . DESIGN : Prospective observational study . SUBJECTS AND METHODS : Patients presenting to the emergency department were randomized to receive 40 mg prednisone daily for 5 or 14 days in a placebo-controlled manner . The Q9Y251 axis was longitudinally assessed with the 1 μg corticotropin test and a clinical hypocortisolism score at baseline , on day 6 before blinded treatment , at hospital discharge , and for up to 180 days of follow-up . DB00635 was stopped abruptly , irrespective of the test results . Patients discharged with pathological test results received instructions about emergency hydrocortisone treatment . RESULTS : A total of 311 patients were included in the analysis . Mean basal and stimulated serum total cortisol levels were highest on admission ( 496±398 and 816±413 nmol/l respectively ) and lowest on day 6 ( 235±174 and 453±178 nmol/l respectively ) . Pathological stimulation tests were found in 63 , 38 , 9 , 3 , and 2 % of patients on day 6 , at discharge , and on days 30 , 90 , and 180 respectively , without significant difference between treatment groups . Clinical indicators of hypocortisolism did not correlate with stimulation test results , but cortisol levels were inversely associated with re-exacerbation risk . There were no hospitalizations or deaths as a result of adrenal crisis . CONCLUSION : Dynamic changes in the Q9Y251 axis occur during and after the treatment of acute exacerbations of P48444 . In hypocortisolemic patients who were provided with instructions about stress prophylaxis , the abrupt termination of prednisone appeared safe . TLR and P26718 signaling pathways mediate CS-induced pulmonary pathologies . Long-term exposure to cigarette smoke ( CS ) can have deleterious effects on lung epithelial cells including cell death and the initiation of inflammatory responses . CS-induced cell injury can elaborate cell surface signals and cellular byproducts that stimulate immune system surveillance . Our previous work has shown that the expression of ligands for the cytotoxic lymphocyte activating receptor P26718 is enhanced in patients with P48444 and that the induction of these ligands in a mouse model can replicate P48444 pathologies . Here , we extend these findings to demonstrate a role for the P26718 receptor in CS-induced pathophysiology and provide evidence linking nucleic acid-sensing endosomal toll-like receptor ( TLR ) signaling to P48444 pathology through P26718 activation . Specifically , we show that mice deficient in P26718 exhibit attenuated pulmonary inflammation and airspace enlargement in a model of CS-induced emphysema . Additionally , we show that CS exposure induces the release of free nucleic acids in the bronchoalveolar lavage and that direct exposure of mouse lung epithelial cells to cigarette smoke extract similarly induces functional nucleic acids as assessed by O15455 , 7 , and 9 reporter cell lines . We demonstrate that exposure of mouse lung epithelial cells to TLR ligands stimulates the surface expression of RAET1 , a ligand for P26718 , and that mice deficient in O15455 /7/9 receptor signaling do not exhibit CS-induced NK cell hyperresponsiveness and airspace enlargement . The findings indicate that CS-induced airway injury stimulates TLR signaling by endogenous nucleic acids leading to elevated P26718 ligand expression . Activation of these pathways plays a major role in the altered NK cell function , pulmonary inflammation and remodeling related to long-term CS exposure . Decreased exercise-induced expression of nuclear factor-κB-regulated genes in muscle of patients with P48444 . BACKGROUND : Nuclear factor ( NF ) -κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with P48444 . Therefore , we investigated NF-κB activity and expression of NF-κB-regulated genes in muscle of patients with P48444 and control subjects before and after exercise . METHODS : Quadriceps specimens were obtained before , immediately after , and 2 h after a submaximal cycle ergometry test from seven patients with P48444 ( 50.6 ± 5.7 SEM Q99581 (1) of patients with P48444 ) and seven age-matched control subjects . NF-κB DNA-binding activity in muscle and peripheral blood mononuclear cells ( PBMCs ) was determined using electrophoretic mobility shift assay and enzyme-linked immunosorbent assay , respectively . mRNA expression and protein carbonylation were measured by real-time polymerase chain reaction and Western blot , respectively . RESULTS : In control subjects , P05231 , IκBα , tumor necrosis factor-α , IL-1β , superoxide dismutase , thioredoxin , heme oxygenase 1 , and heat shock protein-70 were upregulated in muscle after exercise , whereas in patients with P48444 only P05231 mRNA was increased . Exercise-induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with P48444 compared with control subjects . Basal muscle protein oxidation was higher in patients with P48444 than in control subjects , but attenuated in response to exercise . No exercise-induced changes in NF-κB DNA-binding activity in muscle and PBMCs of either group were detected . CONCLUSIONS : Skeletal muscle of patients with P48444 is characterized by an impaired response to exercise of NF-κB-regulated genes encoding inflammatory cytokines , antioxidants , stress proteins , and survival factors . 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 . Histone deacetylase-2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase-2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor-kappaB-activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant-activated phosphoinositide-3-kinase-delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid-resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers . 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 . How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor-kappaB and activator protein-1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase-2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti-inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases . DB02546 decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington 's disease . Huntington 's disease ( HD ) is a progressive neurological disorder for which there are no disease-modifying treatments . Transcriptional dysregulation is a major molecular feature of HD , which significantly contributes to disease progression . Therefore , the development of histone deacetylase ( HDAC ) inhibitors as therapeutics for HD has been energetically pursued . DB02546 ( DB02546 ) - a class I HDAC as well an Q9UBN7 inhibitor , improved motor impairment in the R6/2 mouse model of HD . Recently it has been found that DB02546 can also promote the degradation of P56524 and possibly other class IIa HDACs at the protein level in various cancer cell lines . To elucidate whether DB02546 is a potent modifier of HDAC protein levels in vivo , we performed two independent mouse trials . Both WT and R6/2 mice were chronically treated with DB02546 and vehicle . We found that prolonged DB02546 treatment causes the degradation of P56524 in cortex and brain stem , but not hippocampus , without affecting its transcript levels in vivo . Similarly , DB02546 also decreased Q92769 levels without modifying the expression of its mRNA . Consistent with our previous data , DB02546 treatment diminishes Hdac7 transcript levels in both wild type and R6/2 brains and unexpectedly was found to decrease Hdac11 in R6/2 but not wild type . We investigated the effects of DB02546 administration on well-characterised molecular readouts of disease progression . We found that DB02546 reduces SDS-insoluble aggregate load in the cortex and brain stem but not in the hippocampus of the R6/2 brains , and that this was accompanied by restoration of Bdnf cortical transcript levels . Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells . OBJECTIVE : Activation of the endothelium by oxidized low-density lipoprotein ( oxLDL ) has been implicated in the development of atherosclerosis . Histone modifications impact on the transcriptional activity state of genes . We tested the hypothesis that oxLDL-induced inflammatory gene expression is regulated by histone modifications and experienced the effect of statins on these alterations . METHODS AND RESULTS : OxLDL-related interleukin-8 ( P10145 ) and monocyte-chemoattractant protein-1 ( P13500 ) secretion in endothelial cells was reduced by statins but enhanced by histone deacetylase inhibitors . OxLDL induced lectin-like oxidized P01130 -1 ( P78380 ) and extracellular regulated kinases ( P27361 /2 ) -dependent acetylation of histone H3 and H4 as well as phosphorylation of histone H3 , both globally and on the promoters of il8 and mcp1 . Pretreatment of oxLDL-exposed cells with statins reduced the above mentioned histone modification , as well as recruitment of CREB binding protein ( CBP ) 300 , NF-kappaB , and of RNA polymerase II but prevented loss of binding of histone deacetylase ( HDAC ) -1 and -2 at the il8 and mcp1 gene promoters . OxLDL reduced Q13547 and 2 expression , and statins partly restored global HDAC-activity . Statin-related effects were reverted with mevalonate . In situ experiments indicated decreased expression of Q92769 in endothelial cells in atherosclerotic plaques of human coronary arteries . CONCLUSIONS : Histone modifications seem to play an important role in atherosclerosis . Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase-2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide-3-kinase-delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant-activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid-resistant inflammation . Genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm . BACKGROUND : Previous studies suggested an association between abdominal aortic aneurysm ( AAA ) and hyperhomocysteinaemia , a complex trait determined by genetic and environmental factors . Our hypothesis was that polymorphisms in genes directly or indirectly involved in methionine metabolism may contribute to AAA susceptibility . METHOD : We studied 56 polymorphisms in P42898 , Q99707 , Q9UBK8 , P35520 , P11586 , P41440 , P40261 , P20062 , P23526 , Q93088 , Q9H2M3 , Q04609 , P04818 , Q7L5Y1 , P34896 , P27169 , Q15165 genes according to their demonstrated/putative function , localisation in promoter or regulatory and coding regions and/or heterozygosity values > 0.300 . Polymorphisms were evaluated by using a primer extension based microarray technology in 423 AAA patients and 423 matched controls . RESULTS : All polymorphisms resulted in Hardy-Weinberg equilibrium in patients and controls . At the multiple logistic regression analysis adjusted for traditional cardiovascular risk factors ( sex , age , hypertension , smoking habit , dyslipidaemia , diabetes ) and chronic obstructive pulmonary disease ( P48444 ) , rs8003379 P11586 ( odds ratio ( OR ) 0.41 , 95 % confidence interval ( CI ) 0.26 to 0.65 ) and rs326118 Q9UBK8 ( OR 0.47 , 95 % CI 0.29 to 0.77 ) polymorphisms resulted in independent susceptibility factor for AAA . CONCLUSIONS : After haplotype reconstruction , logistic regression analyses adjusted for traditional risk factors and P48444 showed a significant association among AAA and P23526 , Q04609 , P11586 , Q99707 , P40261 , P27169 and P04818 haplotypes . Our findings offer new insights into the pathogenesis of AAA . Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4-methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol-HRP-H2O2 based CL ) . KEY FINDINGS : DB11320 , 4-methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner . On the other hand , only VUF8430 was able to inhibit PMA-activated whole blood CL . DB00863 , but not JNJ10191584 , completely reduced the effects of histamine , 4-methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to P25021 . DB11320 reduces susceptibility to natural killer cells via down-regulation of P26718 ligands on human monocytic leukaemia THP-1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry . Interferon-γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2-pyridylethylamine and P25021 agonist dimaprit down-regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine-induced down-regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription-PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down-regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down-regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity . These results suggest that histamine down-regulates P26718 ligands through the activation of an P35367 - and P25021 -mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells . 5- Q9H205 - and P28335 -antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5- Q9H205 - and P28335 -receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5- Q9H205 - and/or P28335 -mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5- Q9H205 -dependent contraction of the isolated guinea-pig ileum and bradycardic responses in the rat and ( ii ) P28335 -dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea-pig ileum , cyamemazine potently and competitively antagonized 5-HT-dependent contractions ( pA2 = 7.52 +/- 0.08 ; n = 5 ) . In this test , cyamemazine was 5-7 times more potent ( pIC50 = 6.75 +/- 0.13 ) than tropisetron ( pIC50 = 6.02 +/- 0.04 ) . In rats , cyamemazine i.v. antagonized 5-HT-dependent bradycardic responses with ID50 % = 3.2 +/- 1.5 mg/kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 -dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5- Q9H205 - and P28335 -receptors , which compares well with reference compounds . These 5- Q9H205 - and P28335 -antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders . DB00175 -induced changes in receptor-mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . DB00175 treatment significantly reduced plasma levels of total cholesterol and LDL-cholesterol by 15.6 mg/dl ( 38.8 % ) and 12.7 mg/dl ( 42.9 % ) , respectively . We investigated the metabolism of LDL in pravastatin-treated and untreated guinea pigs using the simultaneous intravenous injection of 131I-labeled LDL and 125I-labeled , galactose-treated LDL to quantify the P01130 pathway . DB00175 increased the fractional catabolic rate ( FCR ) of the P01130 -dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 -independent pathway . The FCR of the P01130 -dependent pathway was higher for LDL isolated from pravastatin-treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 -mediated pathway . 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 . Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 ) -axis and the serotonergic system . The Q9Y251 -axis and serotonergic ( 5-HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5-HTT ) transcription but data also points to the fact that 5-HTT expression is regulated nongenomically via redistribution of 5-HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5-HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL/6N blastocysts . These postmitotic 5-HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 ) resulted in enhanced , dose-dependent 5-HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5-HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5-HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid- P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL/6N mice . Branched N-glycans and their implications for cell adhesion , signaling and clinical applications for cancer biomarkers and in therapeutics . Branched N-glycans are produced by a series of glycosyltransferases including N-acetylglucosaminyltransferases and fucosyltransferases and their corresponding genes . Glycans on specific glycoproteins , which are attached via the action of glycosyltransferases , play key roles in cell adhesion and signaling . Examples of this are adhesion molecules or signaling molecules such as integrin and P12830 , as well as membrane receptors such as the P01133 and TGFβ receptors . These molecules also play pivotal roles in the underlying mechanism of a variety of disease such as cancer metastasis , diabetes , and chronic obstructive pulmonary disease ( P48444 ) . Alterations in the structures of branched N-glycans are also hall marks and are useful for cancer biomarkers and therapeutics against cancer . This mini-review describes some of our recent studies on a functional glycomics approach to the study of branched N-glycans produced by N-acetylglucosaminyltransferases III , IV , V and IX ( Vb ) ( GnT-III , GnT-IV , V and IX ( Vb ) ) and fucosyltransferase 8 ( Fut8 ) and their patho-physiological significance , with emphasis on the importance of a systems glycobiology approach as a future perspective for glycobiology . Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il-6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . DB00668 inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects . Genetic polymorphisms associated with DB00544 -induced neurotoxicity . BACKGROUND : Encephalopathy is a rare drug toxicity of fluorouracil therapy . Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes , thymidylate synthase and dihydropyrimidine dehydrogenase . METHODS : Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5-fluorouracil-based chemotherapy presented with acute mental change and hyperammonemia . To evaluate the genetic background of the fluorouracil-associated hyperammonemic encephalopathy , analysis of the polymorphisms of the P04818 , Q12882 and P42898 genes was performed . RESULTS : The patients revealed to be P04818 suppressors showing homogenous deletion of 6 bp in the 3'-UTR and 3RC/3RC genotype in the promoter enhancer region ( TSER ) , respectively . CONCLUSION : Genetic polymorphisms of the P04818 gene would contribute to the 5-fluorouracil-associated hyperammonemic encephalopathy . The prospective validation of the clinical implication of P04818 gene polymorphisms is warranted . Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 -R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T. R. , Torti , F. , and Ringold , G. M. ( 1989 ) J. Biol. Chem. 264 , 4583-4589 ) , have reduced ability to release arachidonic acid ( 20:4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20:4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 -resistant cells has revealed that these cells are unable to synthesize 20:4 endogenously because of a defect in delta 6-desaturase , the rate-limiting enzyme of 20:4 biosynthesis . This deficiency leads to a marked decrease in the steady-state levels of 20:4 present in choline-containing phospholipid ( PC ) and ethanolamine-containing phospholipid ( PE ) . The Q96RJ0 -R6 cells , however , are capable of incorporating exogenous 20:4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild-type Q96RJ0 cells .