interacts_with DB00945?
DB00945 -like molecules that covalently inactivate cyclooxygenase-2 . Many of aspirin 's therapeutic effects arise from its acetylation of cyclooxygenase-2 ( P35354 ) , whereas its antithrombotic and ulcerogenic effects result from its acetylation of P23219 . Here , aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate P35354 . The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide ( APHS ) . Relative to aspirin , APHS was 60 times as reactive against P35354 and 100 times as selective for its inhibition ; it also inhibited P35354 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo . Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects . Surfactin exhibits neuroprotective effects by inhibiting amyloid β-mediated microglial activation . Microglial-mediated neuroinflammation and neurotoxicity contribute to the pathogenesis of neurodegenerative diseases including Alzheimer 's disease ; therefore , control of microglial activation and subsequent suppression of neurotoxic pro-inflammatory molecules could provide a potential therapeutic approach for the treatment of such diseases . In this study , we investigated the effects of surfactin , a surfactant from Bacillus subtilis , on oligomeric amyloid β ( Aβ ) -induced microglial activation and neurotoxicity . Surfactin significantly suppressed expression of P14780 , P35228 and P35354 , as well as production of ROS , NO , DB00917 , P01375 -α , IL-1β , P05231 and P13500 in Aβ-stimulated BV-2 microglial cells . Moreover , surfactin markedly inhibited Aβ-induced nuclear translocation and activation of NF-κB as well as phosphorylation of JNK and p38 MAPK . Furthermore , surfactin protected hippocampal HT22 cells from indirect neuronal toxicity mediated by Aβ-treated microglial cells , but had no effect on Aβ-induced direct toxicity to HT22 cells . These results suggest that surfactin impairs the Aβ-induced inflammatory response of microglial cells and confers protection against indirect neurotoxicity to hippocampal cells . Our findings indicate that surfactin may have therapeutic potential for ameliorating Alzheimer 's disease as well as other neurodegenerative disorders which involve neuroinflammation . Nonsteroidal anti-Inflammatory drugs and cardiovascular risk . Nonsteroidal anti-inflammatory drugs ( NSAID ) inhibit cyclooxygenase ( P36551 ) enzymes , which exist in at least two isoforms , P23219 and P35354 . DB00945 and older agents in this class are nonselective inhibitors of both P23219 and P35354 . Newer agents termed " coxibs " are selective inhibitors of P35354 . Among the NSAID , only aspirin has been proven to significantly reduce cardiovascular risk , primarily through inhibition of P23219 -mediated platelet aggregation . It has been suggested that other nonselective agents , especially naproxen , may provide some lesser degree of cardioprotection , but conclusive evidence is lacking . Conversely , there are concerns that the P35354 inhibitors may increase cardiovascular risk . However , mechanisms for this potentially adverse cardiovascular effect are unknown , and it is becoming increasingly clear that our understanding of the role of P35354 in cardiovascular function is incomplete . Some studies have demonstrated a potentially beneficial effect of P35354 on cardiovascular function that could be negated by P35354 inhibition , while other studies have reported improved endothelial function with P35354 inhibitors . Additionally , the impact of combined therapy with aspirin and other P36551 inhibitors is not yet clear . This article will review the studies that have examined these issues . Analgesics . DB00945 and other non-steroidal anti-inflammatory drugs ( NSAIDs ) are often incriminated in hypersensitivity reactions leading to anaphylaxis . Two populations are at the high risk of developing such reactions : patients with asthma and those with urticaria . In a subset of asthmatics , NSAIDs that inhibit cyclooxygenase-1 ( P23219 ) precipitate non-allergic , hypersensitivity reactions , characterized by violent attacks of dyspnea . These patients suffer from a distinct clinical syndrome , called aspirin induced asthma ( AIA ) , which includes chronic eosinophilic rhinusinusitis and persistent asthma . Inpatients with chronic idiopathic urticaria , and less commonly in patients without chronic urticaria , NSAIDs usually acting through inhibition of P23219 can induce or exacerbate skin eruptions . While alterations in eicosanoid biosynthesis characterized both AIA and aspirin-triggered urticaria , other patients may rarely manifest IgE-mediated reactions . DB00945 resistance : clinical significance and genetic polymorphism . OBJECTIVE : To determine the prevalence , clinical implications and underlying mechanism of aspirin resistance in Chinese patients . METHODS : Platelet aggregation was determined by light transmission aggregometry ( P01374 ) using four different inducers . Patients were divided into aspirin-resistant ( AR ) , aspirin semi responder ( ASR ) and aspirin-sensitive ( AS ) groups , according to their P01374 results . DB00945 resistance was assessed by thrombo elastography ( TEG , with arachidonic acid [ AA ] or adenosine diphosphate as inducers ) , serum/urinary 11-dehydrothromboxane B2 ( P28845 -TXB2 ) assay , platelet function analyser-100 assay and P16109 assay . Polymorphisms in the prostaglandin endoperoxide synthase 1 ( P23219 ) gene ( A842G , C50T , C22T , G128A , C644A and C714A ) , the P35354 gene ( G765C ) and the integrin β3 ( P05106 ) gene ( C196T ) were examined . RESULTS : The study included 360 aspirin-treated patients and 314 healthy controls . AS patients had significantly lower levels of P28845 -TXB2 than AR and ASR patients , and significantly lower levels of P16109 than AR patients . TEG-AA was more sensitive , specific and consistent than P16109 in detecting aspirin resistance . The frequency of the P35354 G765C mutation was significantly higher in the AR/ASR groups versus the AS group . CONCLUSIONS : TEG-AA was more sensitive , specific and consistent than the P16109 assay for detecting aspirin resistance , and the P35354 G765C mutation may be related to aspirin resistance . Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate . The pharmacological action of salicylate can not be explained by its inhibition of cyclooxygenase ( P36551 ) activity . In this report , the effects of aspirin and sodium salicylate on P35354 expressions in human umbilical vein endothelial cells and foreskin fibroblasts were evaluated . DB00945 and sodium salicylate at therapeutic concentrations equipotently blocked P35354 mRNA and protein levels induced by interleukin-1beta and phorbol 12-myristate 13-acetate . The suppressing effect was more pronounced in cultured cells deprived of fetal bovine serum for 24 h , suggesting that it may be cell cycle related . Salicylate inhibited nascent P35354 transcript synthesis but had no effect on P35354 mRNA stability . It inhibited P35354 promoter activity in a concentration-dependent manner . In mice pretreated with aspirin ( 10 and 30 mg/kg ) , followed by challenge with lipopolysaccharide , P35354 mRNA expression in peritoneal macrophages was markedly suppressed . These findings suggest that salicylate exerts its antiinflammatory action in part by suppressing P35354 induction , thereby reducing the synthesis of proinflammatory prostaglandins . P35354 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice . Cyclooxygenase ( P36551 ) 2 is expressed in atherosclerotic lesions . We have previously reported that selective inhibition of P35354 reduces early atherosclerosis in P01130 deficient mice . To examine the role of P35354 in atherosclerosis in other mouse models , we studied the effects of selective P35354 inhibition ( by rofecoxib and NS-398 ) and nonselective P36551 inhibition ( by indomethacin ) on early atherosclerotic lesion formation in apolipoprotein E-deficient ( apoE(-/-) ) mice . Selective P35354 and nonselective P36551 inhibition reduced atherosclerosis in female apoE(-/-) mice by 35-38 % and 38-51 % in the proximal and en face aortas , respectively . Next we investigated the role of macrophage P35354 by transplanting P35354 (-/-) fetal liver cells into C57BL/6 mice and challenging the mice with an atherogenic diet . Genetic deletion of P35354 from hematopoietic cells reduced atherosclerosis by 51 % . In addition , LPS activated P35354 (-/-) macrophages had decreased expression of monocyte chemoattractant protein-1 ( P13500 ) and tumor necrosis factor-alpha ( TNFalpha ) . The results demonstrate that selective inhibition of P35354 and elimination of P35354 from macrophages significantly reduces early atherosclerotic lesion formation in apoE-deficient and C57BL/6 mice . These results are compatible with P35354 expression by macrophages having a proatherogenic role , and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis . RE : DB00945 and P35354 Inhibitor Use in Patients With Stage III Colon Cancer . The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity-mortality of the illness . DB08815 is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5- Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . DB08815 was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents . TLR-2-mediated cytokine and chemokine secretion in human keratinocytes . The human epidermis provides a first line of defense against exogenous pathogens . Resistance to bacterial skin infections , e.g. with Staphylococcus aureus ( S. aureus ) , is based on the function of intact innate immune mechanisms in the epidermis , mainly provided by keratinocytes . They establish the local cytokine and chemokine milieu which is necessary for attracting other cells participating in an immune response . Toll-like receptor ( TLR ) -2 recognizes components of S. aureus and is known to be expressed on keratinocytes . The aim of this study was to investigate TLR-2-mediated chemokine and cytokine secretion on human primary keratinocytes ( HPKs ) both on mRNA and on protein level . As there is no selective TLR-2 ligand known so far , we chose Pam3Cys that acts via TLR-2/TLR-1 heterodimers , lipoteichoic acid ( P01374 ) that acts via TLR-2/TLR-6 and peptidoglycan ( Q9UQ90 ) which acts via TLR-2 and Nod . Pam3Cys stimulation yielded in an enhanced secretion of P78556 , P13500 , P14780 and P10145 in HPK , whereas stimulation with Q9UQ90 or P01374 showed no or solely slight effects . Our findings show evidence for a functional TLR-2/TLR-1 signalling profile in HPKs upon stimulation with Pam3Cys contributing to the defense against bacterial skin infections . DB04946 binding to human and rat dopamine and 5-HT receptors . DB04946 ( DB04946 ; 1- [ 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 displays affinity for dopamine D2 receptors and for 5- Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5- Q13049 and P28335 receptors and rat P50406 and P34969 receptors . DB04946 displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 displayed high affinity for the P50406 and P34969 receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5- Q13049 ( Ki = 5.6 nM ) than for the P28335 receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds . Effects of combined octreotide and aspirin on the growth of gastric cancer . OBJECTIVE : To investigate the effects of the combination of octreotide and aspirin on the growth of gastric cancer . METHODS : Proliferation of gastric cancer cell lines treated with octreotide or aspirin was determined by (3)H-thymidine incorporation . After xenografts of human gastric cancer were implanted orthotopically in the stomach of nude mice , they were administered octreotide plus aspirin for 8 weeks . The mRNA of somatostatin receptor in the tissues of gastric carcinoma was detected by reverse transcription polymerase chain reaction ( RT-PCR ) . P35354 in gastric cancer tissues was measured by immunohistochemistry . RESULTS : Both octreotide and aspirin significantly reduced the (3)H-thymidine incorporation of gastric cancer cells . Xenografts in situ were found in all stomachs of nude mice except for two in the combination group . Either size or weight of tumors treated by octreotide , aspirin or in combination was significantly reduced as compared with that of controls . The inhibition rate for tumor was 60.6 % ( octreotide ) , 39.3 % ( aspirin ) , and 85.6 % ( in combination ) respectively . No severe side effects were observed in any treated groups . Somatostatin receptor-2 and -3 were expressed in the transplanted gastric adenocarcinomas . DB00945 could down-regulate the strong expression of cyclooxygenase-2 in the tissue of gastric adenocarcinomas of nude mice . CONCLUSION : A combination of octreotide and aspirin significantly inhibited proliferation of gastric cancer through mediation of somatostatin receptors and suppression of cyclooxygenase-2 . Mitogen-inducible prostaglandin G/H synthase is expressed in canine mastocytoma cells . A mitogen-inducible prostaglandin G/H synthase ( P35354 or cyclooxygenase-2 ) has recently been cloned from chicken and mouse fibroblasts . This protein is distinct from classic prostaglandin G/H synthase ( P23219 or cyclooxygenase-1 ) but has a similar enzymatic activity . Because P23219 is a rate-limiting enzyme in the synthesis of prostaglandins , P35354 may also play an important role in prostaglandin production . To examine whether P35354 is induced by phorbol ester in mast cells , we studied mRNA expression of P35354 and also measured prostaglandin D2 ( PGD2 ) production when canine mastocytoma cells were incubated with phorbol myristate acetate ( PMA ) . P35354 mRNA was induced by PMA , with a maximal induction after 4 h of incubation with 10 nM PMA . There was concentration-dependent production of PGD2 after incubation with PMA . In contrast , P23219 mRNA was expressed in resting cells , and the expression of P23219 mRNA was down-regulated by PMA . Dexamethasone inhibited PMA-induced mRNA expression of P35354 and PGD2 production . DB00945 had no effect on mRNA expression of P35354 but inhibited PGD2 production . In conclusion , P35354 is induced by phorbol ester in canine mast cells . We speculate that P35354 may be important in airway inflammation in which mast cells are activated . Green tea polyphenols in the prevention of colon cancer . Several plant-based nutrients and non-nutrients that can inhibit mutagenesis and proliferation have been identified . Some of the most promising nutrients identified as chemopreventive agents in colon cancer prevention include isoflavones , curcumin , calcium , vitamin D and more recently Green tea polyphenols ( GTP ) . In addition to inhibiting mutagenesis and proliferation , these compounds are relatively non-toxic , are of low cost and can be taken orally or as a part of the daily diet . Epidemiological and laboratory studies have identified epigallocatechin gallate ( EGCG ) in green tea polyphenols ( GTP ) , as the most potent chemopreventive agent that can induce apoptosis , suppress the formation and growth of human cancers including colorectal cancers ( CRC ) . It is only logical then , that future clinical studies should focus on examining the efficacy of phytochemicals such as EGCG in cancer chemoprevention as an alternative to pharmacological agents , especially in populations where administration of P35354 inhibitors , DB00945 and NSAIDS is contraindicated . The goal of this review is to provide the rationale , and discuss the use of EGCG in GTP as a chemopreventive agent for prevention of colon carcinogenesis and present evidence for the efficacy and safety of these agents based on epidemiological , animal , in vitro studies and Phase I clinical trials . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . Possible mechanisms of drug-induced aspirin and clopidogrel resistance . DB00945 ( ASA ) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events . DB00945 irreversibly inhibits the cyclooxygenase-1 ( P23219 ) enzyme , whereas non-steroidal anti-inflammatory drugs ( NSAIDs ) reversibly inhibit the P23219 enzyme . An analysis of the literature revealed a statistically significant decrease in clinical benefit of ASA with concomitant administration of ibuprofen . Another NSAID , diclofenac , showed minimal effect on the inhibition of platelet aggregation when administered with ASA . Furthermore , the selective P35354 inhibitor , rofecoxib , was not shown to influence the effect of ASA . DB00758 is metabolized to an active thiol metabolite by the CYP 3A4 enzyme . Some HMG DB01992 reductase inhibitors have the ability to inhibit the CYP 3A4 enzyme , which can result in a possible interaction if administered concomitantly with clopidogrel . Studies have demonstrated clopidogrel 's platelet inhibition being significantly attenuated by atorvastatin . However in a post-hoc analysis , it was demonstrated that there was no difference in clinical outcomes between patients taking clopidogrel and P04035 inhibitors metabolized by and not metabolized by CYP 3A4 . Data suggest that the interaction observed involving clopidogrel and P04035 inhibitors appears to be significant in-vitro . Therefore , practitioners should advise patients receiving chronic aspirin therapy to limit the use of ibuprofen and may consider concomitant administration of clopidogrel with P04035 inhibitors without regard for the drug interaction . The intent of this paper is to review the literature discussing possible mechanisms of drug-induced aspirin and clopidogrel resistance and discuss whether the interactions translate into clinical effects . Protective effect of treatment with low-dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa- DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) /reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription-polymerase chain reaction ( RT-PCR ) and western blotting respectively . DB01120 was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson׳s test , and the cerebral infarction volume was visualized with TTC staining . We found up-regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8-12h after a 2-hour ischemia . The treatment with low-dose of gliclazide reduced the total number of TUNEL-positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 -regulated NCCa- DB00171 channel may be associated with MCAO/reperfusion injury and the infarct-reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia-reperfusion brain . DB00945 triggers formation of anti-inflammatory mediators : New mechanism for an old drug . Extract : DB00945 is a widely used non-steroidal anti-inflammatory drug ( NSAID ) . It is well documented that aspirin irreversibly inhibits cyclooxygenase ( P36551 ) by acetylation of an amino acid serine residue , and thus blocks the subsequent biosynthesis of prostaglandins and thromboxane . P36551 has at least two forms , P23219 and P35354 . P23219 is the main form present in mature platelets in the blood , where it transforms arachidonic acid to the intermediates PG-G/H , which are subsequently converted to thromboxane A2 . Thromboxane A2 is a vasoconstrictor and potent platelet activator . Thus , inhibition of thromboxane A2 formation explains aspirin 's anti-thrombotic properties . In the early 1990s , a second form of P36551 was identified , namely P35354 . P35354 was initially conceptualized as an " inducible " P36551 that is elevated in its quantity by a wide range of agents that stimulate inflammation or cell division and seems to be responsible for local formation during inflammation and cancer . DB00945 inhibits Chlamydia pneumoniae-induced NF-kappa B activation , cyclo-oxygenase-2 expression and prostaglandin E2 synthesis and attenuates chlamydial growth . Infection with Chlamydia pneumoniae has been implicated as a potential risk factor for atherosclerosis . This study was designed to investigate the mechanisms of the anti-chlamydial activity of aspirin . A reporter gene assay for NF-kappa B activity , immunoblot analysis for cyclo-oxygenase ( P36551 ) -2 and radioimmunoassay for prostaglandin E(2) ( PGE(2) ) were performed . Following infection of HEp-2 cells with C. pneumoniae , NF-kappa B was activated , P35354 was induced and PGE(2) was elevated . DB00945 inhibited NF-kappa B activation at a concentration of 0.1 mM , partially inhibited P35354 induction and blocked PGE(2) synthesis completely . In addition , high doses of aspirin ( 1 and 2 mM ) inhibited chlamydial growth in HEp-2 cells , decreasing the number and size of inclusion bodies ; this effect could be overcome by adding tryptophan to the culture . Indomethacin also blocked the synthesis of PGE(2) , but had no effect on P35354 expression or chlamydial growth . These results indicate that aspirin not only has an anti-inflammatory activity through prevention of NF-kappa B activation but also has anti-chlamydial activity at high doses , possibly through depletion of tryptophan in HEp-2 cells . Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin . BACKGROUND : Patients treated with aspirin may have a reduced sensitivity to its antiplatelet effect . The mechanism accounting for such a reduced sensitivity might involve an impaired interaction of aspirin with cyclooxygenase-1 ( P36551 ) -1 . OBJECTIVE : We sought to investigate whether platelets from patients under chronic treatment with aspirin still produce TxA2 and whether there is any relationship between the eventual persistent TxA2 formation and platelet aggregation . Finally , whether platelet-derived TxA2 can be inhibited by in vitro addition of aspirin . METHODS : Collagen-induced platelet aggregation and thromboxane-A2 ( TxA2 ) were measured in 196 patients treated with aspirin ( 100-330 mg day(-1) ) because of previous vascular events or presence of risk factors of atherosclerosis . RESULTS : Collagen-induced TxA2 production of the entire cohort was 128.7 +/- 21.6 pg 10(-8) cells , and was significantly correlated with platelet aggregation ( Spearman 's correlation coefficient = 0.44 ; P < 0.0001 ) . Patients in the highest quartile of TxA2 showed higher platelet response to collagen ( P < 0.0001 ) when compared with those in the lowest quartile . In a subgroup of 96 patients , platelets were treated in vitro with a TxA2 receptor antagonist ( 13-azaprostanoic acid ) or aspirin before stimulation with collagen . 13-APA acid significantly inhibited platelet aggregation . DB00945 reduced ( -72.9 % ) TxA2 production in patients with TxA2 values above the median but it was ineffective in those with TxA2 values below the median . CONCLUSION : In some patients chronically treated with aspirin platelet production of TxA2 may persist and account for enhanced platelet aggregation . Incomplete inhibition of P23219 seems to be implicated in persistent TxA2 production . 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 . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . DB05039 inhibits tumor cell invasiveness and P14780 expression by suppressing IKK/NF-κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra-long-acting inhaled β2-agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β-arrestin-2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α ( P01375 -α ) -induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα , thereby decreasing NF-κB nuclear translocation and the expression of P14780 , an NF-κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 -α/NF-κB-induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner , preventing further lung damage and improving lung function in P48444 patients . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . The lipoxygenase-cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit . DB04725 is an analogue of arachidonic acid that inhibits P09917 ( P28300 ) , cyclooxygenase ( P36551 ) -1 and P35354 . We investigated the effects of licofelone on cardiovascular derangements and production of thromboxane (Tx)A(2) induced by the inflammatory agonist n-formyl-methionyl-leucyl-phenylalanine ( fMLP ) in the rabbit , in comparison with those of aspirin or rofecoxib , inhibitors of P23219 and P35354 , respectively . In control rabbits , injection of fMLP ( 30 nmol/kg ) in the jugular vein evokes ischemic electrocardiographic ( ECG ) changes in the first 1-5 min , i.e. a profound depression of the ST segment and inversion of the T wave . Simultaneously , fMLP induces bradycardia and hypotension and increases TxB(2) blood levels . All changes are transient . DB04725 ( 60 mg/kg/5 days , p.os ) prevented fMLP-induced ECG ischemic changes in all treated animals , reverted bradycardia and hypotension , and significantly reduced TxB(2) . DB00945 ( 10 mg/kg/5 days , p.os ) prevented ischemic ECG alterations in 2 out of 5 treated animals and did not modify either bradycardia or hypotension . One rabbit died two min after fMLP . In 2 rabbits , aspirin reduced TxB(2) levels by more than 80 % respect to mean control values ; the remaining two rabbits produced an amount of TxB(2) similar to controls . These two rabbits also showed ischemic ECG changes . DB00533 ( 10 mg/kg/5 days , p.os ) did not prevent fMLP-induced ischemic ECG alteration , bradycardia and hypotension , and did not significantly modify the increase of TxB(2) . These results indicate that the capacity of licofelone to efficiently suppress TxA(2) production , is responsible for the protection from the cardiovascular derangement triggered by an inflammatory stimulus . Oral aspirin challenges in patients with a history of intolerance to single non-steroidal anti-inflammatory drugs . Summary Background In the clinical practice patients with a history of acute urticaria induced by a single non-steroidal anti-inflammatory drug ( NSAID ) and seeking for safe alternative drugs generally undergo tolerance tests with alternative NSAIDs that have little or no cyclooxygenase-1 ( P23219 ) enzyme inhibitory activity . This practice does not allow for the detection of single NSAID reactors and may lead to unnecessary avoidance of many potentially useful NSAIDs . OBJECTIVE : Evaluate aspirin challenge as a means to distinguish single from multiple NSAID intolerance in patients with a clinical history of acute urticaria induced by a single NSAID . Methods One hundred and seventeen otherwise normal subjects with a history of acute urticaria following the ingestion of a single NSAID ( pyrazolones ( n=58 ) , nimesulide ( n=17 ) , propionic acid derivatives ( n=13 ) , aryl acetic acid derivatives ( n=14 ) , acetaminophen ( n=9 ) , piroxicam ( n=5 ) , and indometacin ( n=1 ) ) underwent single-blind placebo-controlled oral challenges with aspirin . DB00945 -intolerant subjects underwent further tolerance tests drugs exerting little or no inhibitory activity on P23219 enzyme ( including paracetamol , nimesulide , rofecoxib , tramadol , and floctafenine ) . Results DB00945 induced urticaria in 28/117 ( 24 % ) patients . Five out of 28 ( 18 % ) aspirin reactors did not tolerate alternative NSAID on subsequent oral challenges . Conclusion In subjects with a history of urticaria induced by a single NSAID ( other than aspirin ) the diagnostic workup should start with an aspirin challenge in order to detect single/multiple NSAID reactors . Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy donors . 1. Cyclo-oxygenase ( P36551 ) and lipoxygenase ( LO ) share a common substrate , arachidonic acid . DB00945 and related drugs inhibit P36551 activity . In a subset of patients with asthma aspirin induces clinical symptoms associated with increased levels of certain LO products , a phenomenon known as aspirin-sensitive asthma . The pharmacological pathways regulating such responses are not known . 2 . Here P23219 and LO activity were measured respectively by the formation of thromboxane B(2) ( TXB(2) ) or leukotrienes ( LT ) C(4) , D(4) and E(4) in whole blood stimulated with A23187 . P35354 activity was measured by the formation of prostaglandin E(2) ( PGE(2) ) in blood stimulated with lipopolysaccharide ( LPS ) for 18 h . 3 . No differences in the levels of P23219 , P35354 or LO products or the potency of drugs were found in blood from aspirin sensitive vs aspirin tolerant patients . DB00945 , indomethacin and nimesulide inhibited P23219 activity , without altering LO activity . Indomethacin , nimesulide and the P35354 selective inhibitor DB00677 [ 5,5-dimethyl-3-(2-isopropoxy)-4-(4-methanesulfonylphenyl)-2(5H)-furanone ] inhibited P35354 activity . NO-aspirin , like aspirin inhibited P23219 activity in blood from both groups . However , NO-aspirin also reduced LO activity in the blood from both patient groups . Sodium salicylate was an ineffective inhibitor of P23219 , P35354 or LO activity in blood from both aspirin-sensitive and tolerant patients . 4 . Thus , when P36551 activity in the blood of aspirin-sensitive asthmatics is blocked there is no associated increase in LO products . Moreover , NO-aspirin , unlike other NSAIDs tested , inhibited LO activity in the blood from both aspirin sensitive and aspirin tolerant individuals . This suggests that NO-aspirin may be better tolerated than aspirin by aspirin-sensitive asthmatics . DB00945 resistance in coronary artery disease is correlated to elevated markers for oxidative stress but not to the expression of cyclooxygenase ( P36551 ) 1/2 , a novel P23219 polymorphism or the PlA(1/2) polymorphism . DB00945 resistance ( AR ) is estimated to be present in 5-75 % of patients and is related to increased cardiovascular mortality . However , the underlying mechanisms are mostly unknown . In the present study , AR was detected in 14 out of 55 patients ( 25 % ) with coronary artery disease . The presence of concomitant anti-inflammatory drugs did not affect AR . Plasma levels of thromboxane B(2) as well as the markers for oxidative stress and known platelet activators 8-isoprostane and lipid peroxidation products were significantly higher in aspirin-resistant individuals ( 349.3 pg/ml , 53.9 pg/ml , and 538 micromol/l ) compared to controls ( 113.7 pg/ml , 10.3 pg/ml , and 32.2 micromol/l ; P < 0.05 , respectively ) . Platelet cyclooxygenase-1 ( P23219 ) and P35354 mRNA and protein expression were without significant differences between the two groups . DNA sequencing detected a novel platelet P23219 single nucleotide polymorphism ( SNP ) resulting in amino acid exchange at position 8 ( Arg8/Trp8 ) . The wild-type as well as the heterozygous and homozygous SNP were present in both patient groups without significant differences . The aspirin binding ( Arg120 ) and acetylation site ( Ser529 ) were unaffected in the samples tested . Neither was AR related to the platelet integrin PlA(1)/A(2) polymorphism . In conclusion , AR appears to be unrelated to differences in platelet P23219 and P35354 expression or to a novel platelet P23219 SNP and the PlA(1)/A(2) SNP . However , a correlation exists to elevated eicosanoids generated by oxidative stress indicating P23219 -independent pathways for the generation of platelet activating molecules represent a potential cause for AR . Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . [ The concept of aspirin " resistance " : mechanisms and clinical relevance ] . DB00945 , a 110-year-old molecule , is a cornerstone in the treatment of atherothrombotic patients . The concept of aspirin " resistance " emerged approximately 15 years ago and is of growing interest . DB00945 resistance , defined as a lack of inhibition of cyclo-oxygenase-1 ( P23219 ) , is a rare phenomenon and its clinical relevance can hardly be studied . On the contrary , residual platelet hyperactivity is more common and affects 20 to 30 % of aspirin-treated patients . This latter phenomenon corresponds to sustained platelet reactivity despite a proper inhibition of P23219 by aspirin . Several meta-analyses suggest that residual platelet hyperactivity could be a risk factor for the recurrence of ischemic events in aspirin-treated patients . Causes of biological non-responsiveness to aspirin are discussed , including the role of compliance , drug-drug interactions , genetic polymorphisms and diabetes mellitus . Ongoing studies are designed to find out the mechanisms of residual platelet hyperactivity , determine its potential clinical relevance and delineate the more appropriate assays in order to identify patients who may benefit of a tailored antiplatelet therapy . [ DB00945 -- the prodigious panacea ? Molecular mechanisms of the action of acetylsalicylic acid in the organism ] . DB00945 ( acetylsalicylic acid ) is a commonly used non-steroidal anti-inflammatory drug capable of acetylating proteins in the course of a simple , non-enzymatic chemical reaction . Its main physiological effect is inhibiting prostanoid synthesis . Cyclooxygenases , P23219 and P35354 , are crucial in the metabolic pathway leading to the generation of prostanoids . Both enzymes are major cellular targets for aspirin . The physiological spectrum of the biological activity of the prostanoids is very broad , and underlies the high clinical effectiveness of aspirin as an anti-inflammatory , antipyretic , and analgesic drug . Apart from the inhibition of prostanoid synthesis aspirin shows a variety of pharmacological activities , including reduction of DB00171 storage pools , increased extracellular adenosine , lowered inducible nitric oxide synthase activity , modulation of mitogen-activated protein kinases , and the expression of a plethora of genes induced under conditions of cell stress via the regulation of transcription factor NFkappaB activity . Such multipotent action explains its wide use in clinical practice . Regardless of the accumulated evidence on the molecular mechanisms of aspirin 's action , the rationale of the appropriate dosing and monitoring of aspirin therapy and prophylaxis remains obscure . Hence , an evaluation and reasonable weighing of the cost/benefit ratio of aspirin therapy in various diseases seems appropriate . Effects of aspirin on atherosclerosis and the cyclooxygenase-2 expression in atherosclerotic rabbits . BACKGROUND : Atherosclerosis is a complex vascular inflammatory disease . DB00945 is a mainstay in the prevention of vascular complications of atherosclerosis . In this study , the effectiveness of aspirin in suppressing atherosclerosis and the inflammation process was evaluated in rabbits fed with a high fat diet . METHODS : Eighteen male New Zealand rabbits were randomly divided into 3 groups : control group , untreated cholesterol-fed group , aspirin treated cholesterol-fed group , which were fed for 12 weeks . After 12 weeks , the aorta was harvested for pathologic morphology observation . Immunohistochemical analysis of cyclooxygenase-2 ( P35354 ) , macrophage and vascular smooth muscle cell ( VSMC ) was performed . The statistical analysis was performed by the statistical program SPSS10.0 . RESULTS : The aorta plaque/intima size ( P/I ) by pathologic morphology observation was 0 % , ( 59.6 +/- 13.7 ) % and ( 36.3 +/- 16.5 ) % in the control , untreated cholesterol-fed group and aspirin treated group , respectively . The maximum plaque thickness , the degree of artery stenosis and the proportion of the intimal circumference occupied by atheroma of the 3 groups were significantly different from each other ( P < 0.01 ) . The expression of P35354 and macrophage in plaque of the aspirin treated group were decreased compared with that in untreated cholesterol-fed group . However , no difference was found in the expression of VSMC between the aspirin treated and the untreated cholesterol-fed group . CONCLUSION : The mechanism of atherosclerosis suppression by aspirin in cholesterol-fed rabbits is related to the inhibition of P35354 expression together with the reduced inflammation followed by , but not related to the hypolipidemic effects . Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via P01375 suppression . Leukocyte adhesion to the diabetic retinal vasculature results in blood-retinal barrier breakdown , capillary nonperfusion , and endothelial cell injury and death . Intercellular adhesion molecule-1 ( P05362 ) and the leukocyte integrin P05107 are required for these processes . Diabetes was induced in Long Evans rats , resulting in a two- to threefold increase in retinal leukocyte adhesion . Following one week of diabetes , neutrophil CD11a , CD11b , and P05107 expression was increased significantly , as were retinal P05362 levels . Animals were treated with aspirin , a cyclooxygenase 2 ( P35354 ) inhibitor ( meloxicam ) , or a soluble tumor necrosis factor alpha ( P01375 ) receptor/Fc construct ( TNFR-Fc , etanercept ) . High-dose aspirin , etanercept , and high-dose meloxicam each reduced leukocyte adhesion and suppressed blood-retinal barrier breakdown . High-dose aspirin also reduced the expression of CD11a , CD11b , and P05107 , whereas meloxicam and etanercept did not . High-dose aspirin , etanercept , and high-dose meloxicam each reduced retinal P05362 expression . DB00945 and meloxicam both lowered retinal P01375 levels . Notably , aspirin , meloxicam , and etanercept did not change retinal vascular endothelial growth factor levels . High-dose aspirin , etanercept and high-dose meloxicam , each suppressed the retinal expression of P29474 and the DNA-binding capacity of retinal nuclear factor-kappaB . High-dose aspirin also suppressed Erk kinase activity , which is involved in P05107 up-regulation . Taken together , these data identify P35354 and P01375 as operative in the early signature pathologies of diabetic retinopathy , a newly recognized inflammatory disease . Clinical pharmacology of cyclooxygenase inhibition and pharmacodynamic interaction with aspirin by floctafenine in Thai healthy subjects . DB08976 , a hydroxyquinoline derivative with analgesic properties , is widely used in Thailand and many other countries . The objectives of this study were to evaluate in Thai healthy volunteers : i ) the inhibition of whole blood cyclooxygenase( P36551 )-2 and P23219 activity by floctafenine and its metabolite floctafenic acid in vitro and ex vivo after dosing with floctafenine ; ii ) the possible interference of floctafenine administration with aspirin antiplatelet effects . We performed an open-label , cross-over , 3-period study , on 11 healthy Thai volunteers , who received consecutively floctafenine(200mg/TID) , low-dose aspirin(81mg/daily) or their combination for 4 days , separated by washout periods . DB08976 and floctafenic acid resulted potent inhibitors of P23219 and P35354 in vitro ( floctafenic acid was more potent than floctafenine ) showing a slight preference for P23219 . After dosing with floctafenine alone , whole blood P23219 and P35354 activities were inhibited ex vivo in a time-dependent fashion which paralleled floctafenic acid plasma concentrations . DB00945 alone inhibited profoundly and persistently platelet P23219 activity and AA-induced platelet aggregation throughout 24-h dosing interval which was affected by the co-administration of floctafenine . At 24 h after dosing with aspirin and floctafenine , the inhibition of platelet thromboxane(TX)B2 generation and aggregation were significantly ( P less than 0.05 ) lower than that caused by aspirin alone . Therapeutic dosing with floctafenine profoundly inhibited prostanoid biosynthesis through the rapid conversion to floctafenic acid . DB08976 interfered with the antiplatelet effect of aspirin . Our results suggest that floctafenine should be avoided in patients with cardiovascular disease under treatment with low-dose aspirin . Update on aspirin desensitization for chronic rhinosinusitis with polyps in aspirin-exacerbated respiratory disease ( AERD ) . DB00945 -exacerbated respiratory disease ( AERD ) is a clinical condition which results in adverse upper and lower respiratory symptoms , particularly rhinitis , conjunctivitis , bronchospasm , and/or laryngospasm , following exposure to cyclooxygenase-1 ( P23219 ) inhibiting drugs , namely aspirin or nonsteroidal anti-inflammatory drugs ( NSAIDs ) . A provocative aspirin challenge is the gold standard for diagnosis of AERD . DB00945 desensitization and continuous aspirin therapy has been highly efficacious in those patients with suboptimal control of their disease on current available pharmacotherapy or those with other underlying conditions ( i.e. , cardiovascular disease ) who may require frequent treatment with aspirin or NSAIDs . This review article focuses on aspirin desensitization and the management of patients with AERD with a particular emphasis on outcomes in those patients with chronic rhinosinusitis and nasal polyposis . The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells . Celecoxib ( DB00482 ) is a cyclooxygenase-2 ( P35354 ) selective inhibitor and gefitinib ( DB00317 (R) , ZD1839 ) is a selective epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor for human non-small cell lung cancer ( NSCLC ) . The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated . The Rad51 protein is essential for homologous recombination repair , and is overexpressed in chemo- or radioresistant carcinomas . In this study , we characterize the role of celecoxib in the cytotoxicity , P27361 /2 activation and Rad51 expression affected by gefitinib in NSCLC cells . We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells . Treatment with celecoxib alone has no effect on the P27361 /2 activation , Rad51 mRNA and protein levels , however , combined treatment with gefitinib results in a significant reduction of phospho- P27361 /2 and Rad51 protein levels , and triggers the degradation of Rad51 via a 26S proteasome-dependent pathway . Expression of constitutively active Q02750 /2 vectors ( Q02750 /2-CA ) significantly rescues the decreased P27361 /2 activity , and restores Rad51 protein levels and cell survival under co-treatment with gefitinib and celecoxib . Furthermore , blocking P27361 /2 activation by U0126 ( Q02750 /2 inhibitor ) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib . DB00758 and aspirin in cardiovascular medicine : responders or not -- current best available evidence . Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease . It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions . DB00758 effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane . DB00945 works by irreversibly acetylating the cyclooxygenase ( P23219 ) enzyme , thus suppressing the production of thromboxane A(2) ( TxA(2) ) and inhibiting platelet activation and aggregation . Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel . The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed . DB00758 and aspirin responsiveness as they are measured in the laboratory by various techniques ( platelet aggregometry and point-of-care assays such as platelet function analyzer [ PFA-100 ] and rapid platelet function assay [ RPFA ] ) are evaluated . The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical , cellular and genetic factors are defined . DB00945 and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction , stroke or death . The therapeutic interventions to deal with nonresponsiveness are reported , although specific recommendations are not clearly established . In the future , routine measurement of platelet function in patients with cardiovascular disease may become the standard of care . Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient . Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5- Q13049 receptors . Signaling pathways responsible for serotonin ( 5-HT ) -mediated induction of early response genes prostaglandin G/H synthase-2 ( P35354 , cyclooxygenase-2 ) and egr-1 were investigated in rat mesangial cells . Gene induction by 5-HT was dependent on 5- Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family . Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C ( P98160 ) and release of Ca2+ from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5-HT signaling . Instead , inhibition of phosphatidylcholine-specific P98160 interfered with P35354 and egr-1 mRNA induction , suggesting this enzyme as a link between 5- Q13049 receptors and protein kinase C , an essential part of 5-HT-mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr-1 mRNA expression by itself , but strongly inhibited 5-HT-mediated mRNA induction . P35354 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA , suggesting involvement of Ca2+-dependent enzymes . In contrast , egr-1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps . Activation of the Gq-coupled 5- Q13049 receptor thus leads to the expression of the early response genes P35354 and egr-1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively . DB00945 -triggered lipoxin in patients treated with aspirin and selective vs. nonselective P35354 inhibitors . AIMS : Cyclooxygenase ( P36551 ) -2 inhibition has been reported to suppress the biosynthesis of the gastroprotective lipoxygenase metabolite 15(R)-epi-lipoxin A(4) , also termed ' aspirin-triggered lipoxin ' ( ATL ) . We tested the hypothesis that the co-administration of aspirin with either the selective P35354 inhibitor celecoxib or the nonselective P36551 inhibitor ibuprofen reduces ATL biosynthesis . METHODS : We measured the urinary excretion of ATL in 24 patients with both ischaemic heart disease and osteoarthritis , chronically treated with aspirin and co-administered celecoxib 200 mg b.i.d. , ibuprofen 600 mg t.i.d. , or placebo for 7 days . RESULTS : Baseline ATL was comparable in the three groups . On days 1 and 7 , 4 h after co-administration of celecoxib or ibuprofen , ATL levels did not show significant variations ( day 1 : 0.24 +/- 0.33 , 0.26 +/- 0.21 and 0.37 +/- 0.22 ng mg(-1) creatinine , respectively ; day 7 : 0.21 +/- 0.13 , 0.35 +/- 0.15 and 0.23 +/- 0.18 ng mg(-1) creatinine , respectively ) . CONCLUSIONS : Neither selective nor nonselective P35354 inhibition appreciably interferes with ATL biosynthesis , suggesting that this mediator is not involved in exacerbating gastrotoxicity by the association of aspirin with P35354 inhibitors . Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene-related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS-19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency-dependent decreases in DBP . The infusions of AS-19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous α- P80511 . This inhibition by AS-19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 /2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically-induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 -dependent K(+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS-19-induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 -dependent K(+) channels . Pharmacogenetics of aspirin resistance : a comprehensive systematic review . AIMS : The aim was to perform a systematic review of all candidate gene association studies in aspirin resistance . METHODS : Electronic databases were searched up until 1 December 2007 for all studies investigating any candidate gene for aspirin resistance in humans . DB00945 resistance was required to have been measured by a standardized laboratory technique to be included in the analysis . RESULTS : Within 31 studies , 50 polymorphisms in 11 genes were investigated in 2834 subjects . The PlA1/A2 polymorphism in the P05106 platelet receptor was the most frequently investigated , with 19 studies in 1389 subjects . The PlA1/A2 variant was significantly associated with aspirin resistance when measured in healthy subjects [ odds ratio ( OR ) 2.36 , 95 % confidence interval ( CI ) 1.24 , 4.49 ; P = 0.009 ] . Combining genetic data from all studies ( comprising both healthy subjects and those with cardiovascular disease ) reduced the observed effect size ( OR 1.14 , 95 % CI 0.84 , 1.54 ; P = 0.40 ) . Moreover , the observed effect of PlA1/A2 genotype varied depending on the methodology used for determining aspirin sensitivity/resistance . No significant association was found with aspirin resistance in four other investigated polymorphisms in the P23219 , GPla , P47900 or Q9H244 genes . CONCLUSIONS : Our data support a genetic association between the PlA1/A2 molecular variant and aspirin resistance in healthy subjects , with the effect diminishing in the presence of cardiovascular disease . The laboratory methodology used influences the detection of aspirin resistance . However , as heterogeneity was significant and our results are based on a limited number of studies , further studies are required to confirm our findings . Frequency , risk factors , prognosis , and genetic polymorphism of the cyclooxygenase-1 gene for aspirin resistance in elderly Chinese patients with cardiovascular disease . BACKGROUND : Cardiovascular disease ( CVD ) is an important cause of mortality in elderly patients worldwide . DB00945 resistance has been well reported in CVD . OBJECTIVE : The frequency , risk factors , prognosis , and genetic polymorphism of the cyclooxygenase-1 ( P23219 ) gene for aspirin resistance have not been reported in elderly patients with CVD . We therefore undertook this study to evaluate these associations among elderly Chinese patients with CVD . METHODS : Four hundred thirty-one elderly Chinese patients with CVD receiving daily aspirin therapy ( ≥75 mg ) over 1 month were enrolled . Platelet aggregation was measured by light transmission aggregometry ( P01374 ) and thromboelastography platelet mapping assay ( TEG ) using arachidonic acid ( AA ) as a stimulus . The median follow-up was 1.8 years . RESULTS : After the median follow-up , aspirin-resistant patients were at an increased risk of the composite endpoint compared to nonresistant patients by LTAAA + TEGAA ( 23.7 vs. 9.2 % , p = 0.025 ) . Additionally , Cox proportional hazards regression modeling demonstrated that aspirin resistance and cerebrovascular disease were associated with major adverse long-term outcomes ( HR for aspirin resistance = 2.31 , 95 % CI 1.11-4.81 , p = 0.026 ) . The variant G-allele of P23219 rs1330344 ( -1676 A/G ) significantly increased the risk of aspirin resistance defined by LTAAA + TEGAA ( OR = 1.82 , 95 % CI 1.13- 2.92 , p = 0.01 ) . CONCLUSIONS : DB00945 resistance , evaluated by LTAAA + TEGAA , is associated with an increased risk of adverse clinical events in elderly Chinese patients with CVD . The variant G-allele of P23219 rs1330344 is significantly associated with aspirin resistance defined by LTAAA + TEGAA . Regulatory regions of growth-related genes can activate an exogenous gene of the alpha-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase-2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha-fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer-linked AFP promoter even in high-AFP-producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer/promoter in intermediate-AFP-producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth-related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity . Thromboxane A(2) generation , in the absence of platelet P23219 activity , in patients with and without atherothrombotic myocardial infarction . BACKGROUND : DB00945 's therapeutic action is via inhibition of platelet cyclooxygenase 1 ( P23219 ) thromboxane A2 ( TxA2 ) production . The aim of this study was to evaluate TxA2 production , in the absence of platelet P23219 activity , in coronary atherosclerotic heart disease patients with and without atherothrombotic myocardial infarction ( MI ) . METHODS AND RESULTS : TxA2 production , in the absence of platelet P23219 activity , was evaluated in 44 patients taking aspirin on 3 commercially available assays that detect metabolites of TxA2 in the urine . Two assays measure urine 11-dehydro-thromboxane B2 ( TxB2 ) alone and 1 measures urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 . Platelet P23219 inhibition was confirmed on < 10 % platelet aggregation in response to ≥1 mmol/L arachidonic acid . Median urine 11-dehydro-TxB2 was no different in those with and without a diagnosis of atherothrombotic MI ( 325 vs. 311 pg/mg creatinine , P=0.59 via polyclonal ELISA ) and ( 312 vs. 244 pg/mg creatinine , P=0.11 via LC-MS/MS ) . Median urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 , however , was higher in those with vs. those without a diagnosis of atherothrombotic MI ( 1,035 vs. 606 pg/mg creatinine , P=0.03 via monoclonal ELISA ) . CONCLUSIONS : Differences in TxA2 production , in the absence of platelet P23219 activity , between those with vs. without atherothrombotic MI were not observed when TxA2 generation was assessed on 11-dehydro-TxB2 production alone ( polyclonal ELISA or LC-MS/MS ) , but differences were observed when TxA2 generation was assessed using 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 ( monoclonal ELISA ) . These findings highlight important differences between different commercially available assays for TxA2 generation and suggest that 11-dehydro-2,3-dinor-TxB2 may be critical to the biology of atherothrombosis . Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague-Dawley rats were used . DB04630 ( 200 microg/day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0.02 mEq/day ) , and the experimental group was supplied with a higher sodium diet ( 2. /day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real-time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape . DB00945 activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer . Substantial evidence indicates that aspirin has antitumour activity against large bowel cancer and modulation of the NF-kappaB ( NF-kappaB ) signalling pathway has been identified as a key mechanism in this effect . However , studies examining how aspirin affects the NF-kappaB pathway to promote apoptosis have been restricted to in vitro analysis in tissue culture systems and have produced contrasting results . Here , we employed two animal models of human colorectal cancer to determine aspirin effects on the NF-kappaB pathway in colorectal neoplasia in vivo , and the relationship of such effects to the induction of apoptosis . We demonstrate that aspirin induces phosphorylation and degradation of cytoplasmic P25963 in xenografted HT-29 tumours and in adenomas from P25054 (Min+/-) mice . Furthermore , we show that this response occurs in a time-dependent manner and is paralleled by nuclear translocation of p65 and caspase activation . Using high performance liquid chromatography analysis , we demonstrate that > 0.5 mM salicylate levels are achievable in xenografted tumours after low-dose aspirin ( 40 mg/kg ) treatment and that these levels , which are pharmacologically relevant to humans , are sufficient to stimulate an NF-kappaB and apoptotic response . We demonstrate that activation of the NF-kappaB pathway is associated with increased apoptosis in neoplastic epithelial cells , but found that aspirin has a minimal effect on nuclear p65 and apoptosis in normal intestinal mucosa from P25054 (Min+/-) mice . These in vivo findings further establish that aspirin induces activation of the NF-kappaB pathway in neoplastic epithelial cells and provide further support that this effect is important for the antitumour activity of the agent . These data have considerable relevance to cancer prevention and therapy . Altered apoptosis of inflammatory neutrophils in P14780 -deficient mice is due to lower expression and activity of caspase-3 . Matrix metalloproteinase 9 ( P14780 ) is a Zn(2+)-dependent endopeptidase that degrades some of the components of basement membranes and extracellular matrix and thus participates in leukocyte infiltration during inflammation . In a model of zymosan peritonitis , neutrophil infiltration in MMP-deficient ( P14780 (-/-) ) mice was significantly weaker at the time of their maximal influx in wild-type mice ( 6h ) . However , during the late stages of peritonitis ( 24h ) an extended accumulation of neutrophils was observed in P14780 (-/-)versus the wild-type mice . Recently , we reported that the ratio of apoptosis of inflammatory leukocytes is impaired in P14780 (-/-) mice during late peritonitis and the process depends on P23219 -driven PGE(2) . Here we scrutinized the alterations in apoptotic mechanisms by comparisons between P14780 (-/-) and the wild-type mice . Altered apoptosis occurred only during late ( 24h ) peritonitis and concerned only neutrophils , and not macrophages , mast cells or lymphocytes . Furthermore , expression and activity of caspases was altered in P14780 (-/-) animals , delayed for caspase-8 and -9 , and decreased in the case of caspase-3 . Also the expression of Bax/Bcl-2 proteins was changed in P14780 (-/-) mice . These changes , and in particular the impaired neutrophil apoptosis and weaker caspase-3 activity , were restored by the selective P23219 inhibition . We conclude that in mice lacking P14780 the enhanced P23219 -PGE(2) decreases caspase-3 expression and activity leading to impaired apoptosis of inflammatory neutrophils resulting in abnormal accumulation of the cells at the inflammatory focus . The data also reinforce the notion that P14780 is a key enzyme in neutrophil biology . DB00945 minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating Q9BUP3 in hepatocellular carcinoma . BACKGROUND AIMS : We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma ( HCC ) , which is mediated by down-regulation of tumor suppressor Q9BUP3 . The aim of the present study was to determine whether aspirin minimizes this effect and improves survival . METHODS : The effects of sorafenib , aspirin , and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice . Tumor growth , intrahepatic metastasis ( IHM ) , lung metastasis , and survival were assessed . Polymerase chain reaction ( PCR ) array , real-time ( RT ) -PCR , and Western blotting were used to examine gene expression . The anti-invasion and anti-metastasis effects of aspirin were studied in Q9BUP3 -knockdown and Q9BUP3 -overexpressing HCC cell lines . The molecular mechanism of Q9BUP3 regulation by aspirin was explored . RESULTS : DB00945 suppressed the pro-invasion and pro-metastasis effects of sorafenib in HCC and up-regulated Q9BUP3 expression . DB00945 did not inhibit the proliferation of HCC cells , but it decreased the invasiveness of HCC with lower expression of Q9BUP3 and increased expression of a set of markers , indicating a mesenchymal-to-epithelial transition in tumor cells . The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase ( P36551 ) 2 expression . CONCLUSIONS : DB00945 minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor Q9BUP3 ; this mechanism is mediated through inhibition of P35354 . Nonsteroidal antiinflammatory drugs and cyclooxygenase inhibition in the gastrointestinal tract : a trip from peptic ulcer to colon cancer . DB00945 was commercialized more than a 100 years ago . Today , this compound is still widely prescribed , and new mechanisms of action and indications are being tested . Inhibition of cyclooxygenase ( P36551 ) -1 and P35354 by aspirin or its related compounds , nonsteroidal antiinflammatory drugs ( NSAIDs ) , has been associated with both adverse and beneficial effects in the gastrointestinal ( GI ) tract . Inhibition of P23219 has been linked to GI adverse effects . Adverse effects of NSAIDs and aspirin in the upper GI tract include esophagitis , peptic ulcer , peptic ulcer complications , and death . Effective preventive therapies are available that have been associated with a progressive decline in the rate of hospitalization due to upper GI complications . NSAIDs and aspirin can also damage the small bowel and the colon . NSAID enteropathy is frequent and in most cases subclinical ( increased mucosal permeability , inflammation , erosion , ulcer ) . However , more serious clinical outcomes such as anemia , bleeding , perforation , obstruction , diverticulitis , and deaths have also been described . Prevention therapy of NSAID damage to the lower GI tract is not well defined . Inhibition of P35354 by NSAIDs , coxibs , or aspirin seems to provide beneficial effects to the GI tract . Observational studies show that these compounds reduce the risk of both upper and lower GI cancers . Randomized controlled trials have shown that aspirin and coxibs reduce the recurrence rate of colonic polyps , and long-term cohort studies have shown that aspirin reduces the risk of colon cancer time and dose dependently . New studies will have to define the appropriate population that may benefit with these therapies . The effect of cilostazol and aspirin pre-treatment against subsequent transient focal cerebral ischemia in rat . OBJECTIVES : Among several anti-platelet drugs to prevent recurrent stroke , cilostazol has shown various effects besides its anti-platelet activity . We examined whether 7 days of oral administration of cilostazol protects against subsequent cerebral ischemia , and whether or not the effect of combination therapy with aspirin is more protective . METHODS : We used Sprague-Dawley ( SD ) rats and assigned them to four groups : vehicle , aspirin , cilostazol , and aspirin plus cilostazol combination therapy . After oral administration of anti-platelets for 7 days , we performed transient middle cerebral artery occlusion ( MCAO ) for 90 minutes , and examined infarct volume , neurological symptoms , and regional cerebral blood flow ( rCBF ) . Immunostaining of Bax , Bcl-2 , TUNEL , 4-HNE , 8-OHdG , and P35354 was performed 24 hours after ischemia . RESULTS : The cilostazol group and the combination therapy group showed significant decreases of infarct volume and significant improvements of rCBF during ischemia , compared with the vehicle or aspirin group . Significant decreases of Bax , TUNEL , 8-OHdG , and 4-HNE expression in the combination therapy group , compared with those in the vehicle or aspirin group , were shown in the boundary zone . P35354 expression was unexpectedly increased in the combination therapy group . DISCUSSION : DB00945 co-administration did not inhibit this effect . The addition of the oral administration of cilostazol either alone or with aspirin administration may be beneficial for subsequent cerebral ischemic damage in terms of reducing infarct volume , improving rCBF during ischemia , inhibiting the apoptotic pathway , and reducing oxidative stress . Selective cyclooxygenase-2 inhibitor cross-reactivity in aspirin-exacerbated respiratory disease . DB00945 -induced asthma ( AIA ) is a severe and difficult-to-treat allergic disease in which acute asthma attacks are induced by nonsteroidal anti-inflammatory drugs . Patients with AIA rarely experience asthma attacks when taking celecoxib , a specific inhibitor of cyclooxygenase ( P36551 ) 2 . A 33-year-old woman had a severe asthma attack with hypoxia and lost consciousness after oral provocation testing with 15 mg of aspirin and also with 50 mg of celecoxib . After 2 months of treatment with 10 mg/day of oral prednisolone , 1600 μg/day of inhaled fluticasone propionate , montelukast as a leukotriene receptor antagonist ( LTRA ) , and long-term beta-agonist , we again challenged her with a provocation test with up to 200 mg of celecoxib ; this time there were neither allergic symptoms nor decrease in forced expiratory volume in 1 second . Patients with severe or poorly controlled asthma may experience asthma attacks even if using selective P35354 inhibitors . However , treatment with steroids and an LTRAs may inhibit asthma attacks induced by celecoxib . Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L. cv. Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 ) , a well-known BER protein . The plant P18887 lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H(2)O(2) or UV-B . DB00290 also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system . Short-term/low-dose aspirin-induced duodenal erosions are not dependent on Helicobacter pylori infection , cyclooxygenase expression and prostaglandin E2 levels . OBJECTIVE : The mechanisms of interaction between Helicobacter pylori infection and low-dose aspirin in the induction of duodenal erosions are not fully understood . The aim of this study was to investigate the effects of low-dose aspirin on the induction of duodenal erosions , the expression of cyclooxygenases and prostaglandin ( PG ) -E(2) levels in healthy subjects according to their H. pylori status . MATERIAL AND METHODS : Twenty healthy volunteers ( H. pylori-negative n=10 , H. pylori-positive n=10 ) received 100 mg aspirin/day for 1 week . During esophagogastroduodenoscopy , duodenal biopsies were taken before and at days 1 , 3 , and 7 of medication . P23219 and -2 expressions were analyzed by reverse transcriptase-polymerase chain reaction ( RT-PCR ) , and immunohistochemistry ; mucosal PGE(2) levels were determined by ELISA . Three months after successful eradication of infection , nine H. pylori-positive subjects repeated the protocol . RESULTS : DB00945 -induced duodenal erosions occurred independently of whether H. pylori infection was present or not . There was no difference in duodenal P23219 and P35354 expression among the groups and expression was not affected by aspirin . Basal duodenal PGE(2) levels were similar among the different groups ( H. pylori-negative 4.3+/-4.2 , H. pylori-positive 5.2+/-1.3 , following H. pylori eradication 5.2+/-1.4 ng/microg protein ) and were not affected by low-dose aspirin . CONCLUSIONS : In healthy subjects , low-dose aspirin-induced duodenal erosions are not influenced by H. pylori status . Low-dose aspirin medication for one week does not affect either cyclooxygenase expression or duodenal PGE(2) levels and therefore is likely to induce duodenal damage mainly through topical toxicity . In vivo effects of meloxicam and aspirin on blood , gastric mucosal , and synovial fluid prostanoid synthesis in dogs . OBJECTIVE : To evaluate in vivo activity in dogs of meloxicam or aspirin , previously shown in vitro to be a selective cyclooxygenase-2 ( P35354 ) inhibitor ( P23219 sparing drug ) , or a nonselective P36551 inhibitor , respectively . ANIMALS : 12 male dogs with unilateral osteoarthritis of the stifle joint . PROCEDURE : Each dog was treated in a crossover design with aspirin or meloxicam for 21 days . DB00917 ( DB00917 ) concentrations were measured at days 0 ( baseline ) , 7 , and 21 of each treatment period in lipopolysaccharide ( LPS ) -stimulated blood , synovial fluid collected by arthrocentesis , and endoscopic gastric mucosal biopsy specimens . Thromboxane B2 ( TXB2 ) was evaluated in blood on days 0 , 7 , and 21 of each treatment period . RESULTS : DB00945 administration significantly suppressed DB00917 concentrations in blood , gastric mucosa , synovial fluid , and suppressed TXB2 concentration in blood at days 7 and 21 . Meloxicam administration significantly suppressed DB00917 concentrations in blood and synovial fluid at days 7 and 21 , but had no effect on concentrations of TXB2 in blood or DB00917 in gastric mucosa . Suppression of LPS-stimulated DB00917 concentrations in blood and synovial fluid by aspirin and meloxicam administration is consistent with activity against the P35354 isoenzyme . Suppression of concentrations of DB00917 in the gastric mucosa and TXB2 in blood by aspirin administration is consistent with activity against P23219 . Meloxicam , in contrast , had a minimal effect on functions mediated by P23219 . CONCLUSIONS AND CLINICAL RELEVANCE : Meloxicam acts in vivo in dogs as a P23219 sparing drug on target tissues by sparing gastric DB00917 synthesis while retaining antiprostaglandin effects within inflamed joints . DB00945 and age-related macular degeneration : positives versus negatives . The anti-inflammatory , analgesic , antipyretic and antithrombotic activities of aspirin confer its wide therapeutic application . The three former activities require higher doses of aspirin , whereas the latter can be achieved through a lower , thus safer dose of the drug . Low-dose , long-term aspirin is used as an antithrombotic therapy to prevent cardiovascular disease . Such therapy is used by millions of people worldwide , including those suffering from age-related macular degeneration ( AMD ) ; thus , questions have arisen as to whether such treatment has any impact on the development and course of AMD . This editorial addresses the important issue of possible beneficial and adverse effects of long-term , low-dose aspirin treatment of AMD patients . Special emphasis is given to the ability of aspirin to acetylate cyclooxygenases ( especially P35354 ) and thus to initiate a biochemical pathway leading to the generation of anti-inflammatory pro-resolving mediators synthesized from both ω-3 and ω-6 long-chain polyunsaturated fatty acids . Such mediators ( e.g. , resolvins , lipoxins ) may be of therapeutic value in retarding the development of dry form AMD . P35354 promotes early atherosclerotic lesion formation in P01130 -deficient mice . BACKGROUND : Atherosclerosis has features of an inflammatory disease . Because cyclooxygenase ( P36551 ) -2 is expressed in atherosclerotic lesions and promotes inflammation , we tested the hypotheses that selective P35354 inhibition would reduce early lesion formation in P01130 -deficient ( P01130 -/- ) mice and that macrophage P35354 expression contributes to atherogenesis in P01130 -/- mice . METHODS AND RESULTS : Treatment of male P01130 -/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta ( 25 % and 37 % ) and in the aorta en face ( 58 % and 57 % ) , respectively . DB00533 treatment did not inhibit platelet thromboxane production , a P23219 -mediated process , but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1alpha . Fetal liver cell transplantation was used to generate P01130 -/- mice null for expression of the P35354 gene by macrophages . After 8 weeks on the Western diet , P35354 -/- --> P01130 -/- mice developed significantly less ( 33 % to 39 % ) atherosclerosis than control P35354 +/+ --> P01130 -/- mice . In both the inhibitor studies and the transplant studies , serum lipids did not differ significantly between groups . CONCLUSIONS : The present studies provide strong pharmacological and genetic evidence that P35354 promotes early atherosclerotic lesion formation in P01130 -/- mice in vivo . These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis . [ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1. carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 , etc. ) , 2 . DNA repair enzymes ( O15527 , P18887 , P18074 , etc. ) , 3 . DNA synthesis and methylation ( P42898 , MS , etc. ) , 4. cytokines and inflammation-related enzymes ( IL-1B , P01375 -A , P05164 , etc. ) , and 5. sex hormone metabolizing enzymes and the receptors ( P11511 , P31213 , ER , etc. ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene-environment interaction ) , opens the door to genotype applications for disease prevention practice . Serotonin provides an accessory signal to enhance T-cell activation by signaling through the P34969 receptor . Although typically considered a neurotransmitter , there is substantial evidence that serotonin ( 5-HT ) plays an important role in the pathogenesis of inflammatory disorders . Despite these findings , the precise role of 5-HT in modulating immune function , particularly T-cell function , remains elusive . We report that naive T cells predominantly express the type 7 5-HT receptor ( 5-HTR ) , and expression of this protein is substantially enhanced on T-cell activation . In addition , T-cell activation leads to expression of the 5-HT(1B) and 5-HT(2A) receptors . Significantly , exogenous 5-HT induces rapid phosphorylation of extracellular signal-regulated kinase-1 and -2 ( P27361 /2 ) and P25963 in naive T cells . 5-HT-induced activation of P27361 /2 and NFkappaB is inhibited by preincubation with a specific 5-HT(7) receptor antagonist . Thus , 5-HT signaling via the 5-HT(7) receptor may contribute to early T-cell activation . In turn , 5-HT synthesized by T cells may act as an autocrine factor . Consistent with this hypothesis , we found that inhibition of 5-HT synthesis with parachlorophenylalanine ( PCPA ) impairs T-cell activation and proliferation . Combined , these data demonstrate a fundamental role for 5-HT as an intrinsic cofactor in T-cell activation and function and suggest an alternative mechanism through which immune function may be regulated by indoleamine 2,3-dioxygenase-mediated catabolism of tryptophan . [ Cyclooxygenase ( P36551 ) -2 selective inhibitors : aspirin , a dual P23219 / P35354 inhibitor , to P35354 selective inhibitors ] . DB00945 was developed as a non-steroidal anti-inflammatory drug ( NSAID ) in 1899 . During the century after that , aspirin has been found to show its anti-inflammatory , analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase ( P36551 ) ; and then P36551 was found to be constituted of two isoforms , constitutive P23219 and inducible P35354 . Currently , novel NSAIDs , acting through selective inhibition of P35354 , that have efficacy as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries , but not in Japan . Physiological and pathophysiological roles of P23219 and P35354 have been explained from studies in experimental animals , but there are many differences in species and diseases between animals and humans . Thus , physiological and pathophysiological roles of P35354 were considered from the standpoint of clinical effects of the two latest P35354 selective inhibitors , celecoxib and rofecoxib , on inflammation , pain , fever and colorectal cancer together with their adverse effects on gastrointestinal , renal and platelet functions ; and the usefulness and limits of P35354 -selective inhibitors were discussed with the trends of new NSAIDs development . [ DB00707 sodium ( Photofrin-II ) ] . DB00707 sodium ( DB00707 ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . DB00707 sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84.8 % , 50.0 % , 90.0 % , 87.5 % and 94.4 % , respectively . The major side effects were cutaneous symptoms e.g. photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .