Structure of the human cyclo-oxygenase-2 gene.
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ABSTRACT:
SUBMITTER: Appleby SB
PROVIDER: S-EPMC1137291 | biostudies-other | 1994 Sep
REPOSITORIES: biostudies-other
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Project description:AIMS: To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors. METHODS: A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes. RESULTS: Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the 'low risk' haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the 'high risk' haplotype (one or two copies of GT). CONCLUSIONS: We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the 'low risk' haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.
| S-EPMC3195745 | biostudies-literature
Project description:IntroductionElevated circulating soluble FLT1 (sFLT1) levels seen in preeclampsia may play a role in its development. Aspirin is recommended for prevention of preeclampsia. We hypothesized that aspirin may inhibit the production of sFlt1.MethodsPlacentas from women with and without preeclampsia were collected. Primary cytotrophoblasts (CTBs) were cultured from normal placentas and treated with aspirin, sc-560, a COX1 inhibitor or celecoxib, a COX2 inhibitor. The expression of sFLT1, FLT1, COX1 and COX2 was studied. The effect of aspirin on sFlt1 expression was also studied in HEK293 cells and in HTR-8/SVNeo cells.ResultsThe expression of sFLT1 was increased in preeclamptic placentas compared to control placentas and the expression and release of sFLT1 increased in CTBs exposed to 2% O2 compared to controls. Aspirin at 3 and 12 mM concentration reduced the expression and release of sFLT1 in CTBs. Aspirin also inhibited sFlt1 expression from HTR-8/SVNeo and HEK293 cells. Sc-560, but not celecoxib, reduced sFLT1 expression and release from CTBs. Aspirin and sc-560 also reduced hypoxia-induced FLT1 mRNA expression and inhibited COX1 mRNA in CTBs.DiscussionThis study confirms that sFLT1 expression is increased in preeclamptic placentas and in CTBs exposed to hypoxia. Aspirin inhibits the production sFLT1 in CTBs and in HTR-8/SVNeo. Sc-560 recapitulated the effects of aspirin on sFLT1 expression and release in CTBs suggesting that the aspirin effect may be mediated via inhibition of COX1. The study increases our understanding of the mechanisms regulating sFlt1 expression and provides a plausible explanation for the effect of aspirin to prevent preeclampsia.
| S-EPMC4359945 | biostudies-literature
Project description:Platelet mixed membrane fractions can be separated into discrete vesicle subpopulations of surface and intracellular origin. Intracellular membrane vesicles are the predominant site of phospholipid-modifying enzymes that liberate arachidonic acid. We report the selective enrichment in intracellular membranes of cyclo-oxygenase and thromboxane synthetase activities. Surface membrane fractions show no such enrichment. These results suggest that a sequence of activities leading to the biosynthesis of thromboxane from arachidonate is associated with the intracellular membrane elements known as dense tubular membranes.
| S-EPMC1158429 | biostudies-other
Project description:In the title compound, 5-(4-chloro-phen-yl)-1-(4-methoxy-phen-yl)-3-(trifluoro-meth-yl)-1H-pyrazole (SC-560), C(17)H(12)ClF(3)N(2)O, a COX-1-selective inhibitor, the dihedral angles between the heterocycle and the chlorobenzene and methoxybenzene rings are 41.66?(6) and 43.08?(7)°, respectively. The dihedral angle between the two phenyl rings is 59.94?(6)°. No classic hydrogen bonds are possible in the crystal, and intermolecular interactions must be mainly of the dispersion type. This information may aid the identification of dosage formulations with improved oral bioavailability.
| S-EPMC2968361 | biostudies-other
Project description:Carbamates are a widely used class of insecticides and herbicides. They were tested for their ability to affect human blood platelet aggregation and arachidonic acid metabolism in platelets. (1) The herbicides of the carbamate type have no, or only little, influence up to a concentration of 100 microM; the carbamate insecticides, however, inhibit both aggregation and arachidonic acid metabolism in a dose- and time-dependent manner. (2) Carbaryl, the most effective compound, inhibits platelet aggregation and cyclo-oxygenase activity completely at 10 microM. The liberation of arachidonic acid from phospholipids and the lipoxygenase pathway are not affected, whereas the products of the cyclo-oxygenase pathway are drastically decreased. (3) By using [14C]carbaryl labelled in the carbamyl or in the ring moiety, it could be proved that the carbamyl residue binds covalently to platelet proteins. In contrast with acetylsalicylic acid, which acetylates only one protein, carbaryl carbamylates a multitude of platelet proteins. (4) One of the carbamylated proteins was found to be the platelet cyclo-oxygenase, indicating that carbaryl resembles in this respect acetylsalicylic acid, which is known to inhibit this enzyme specifically by acetylation.
| S-EPMC1148821 | biostudies-other
Project description:It is increasingly recognized that the tumor microenvironment plays a critical role in the initiation and progression of lung cancer. In particular interaction of cancer cells, macrophages, and inflammatory response in the tumor microenvironment has been shown to facilitate cancer cell invasion and metastasis. The specific molecular pathways in macrophages that immunoedit tumor growth are not well defined. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on a select group of myeloid cells mainly monocyte/macrophages. Recent studies suggest that expression of TREM-1 in tumors may predict cancer aggressiveness and disease outcomes in liver and lung cancer however the mechanism of TREM-1 expression in the setting of cancer is not defined. In this study we demonstrate that tumor tissue from patients with non-small cell lung cancer show an increased expression of TREM-1 and PGE2. Immunohistochemistry and immunofluorescence confirmed that the expression of TREM-1 was selectively seen in CD68 positive macrophages. By employing an in vitro model we confirmed that expression of TREM-1 is increased in macrophages that are co-cultured with human lung cancer cells. Studies with COX-2 inhibitors and siCOX-2 showed that expression of TREM-1 in macrophages in tumor microenvironment is dependent on COX-2 signaling. These studies for the first time define a link between tumor COX-2 induction, PGE2 production and expression of TREM-1 in macrophages in tumor microenvironment and suggest that TREM-1 might be a novel target for tumor immunomodulation.
| S-EPMC4026315 | biostudies-literature
Project description:BackgroundIt has been proved that cyclo-oxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known whether overexpression of COX-2 in the liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis.AimTo investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice.MethodsTG mice that overexpress the human COX-2 gene in the liver using the liver-specific transthyretin promoter and non-TG littermates were derived and fed the normal diet for up to 12 months. Hepatic prostaglandin E(2) (PGE(2)) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-kappaB) activation by electrophoretic mobility shift assays, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling and proliferation by Ki-67 immunohistochemistry.ResultsCOX-2 TG mice exhibited strongly increased COX-2 and PGE(2), elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-kappaB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-alpha (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1beta (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fold) and chemokine macrophage inflammatory protein-2 (3.2-fold). The inflammatory response of the COX-2 TG mice was associated with infiltration macrophages and lymphocytes, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal.ConclusionEnhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating NF-kappaB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.
| S-EPMC1994375 | biostudies-literature
Project description:BackgroundLeukotriene (LT) B4 concentrations are increased and prostaglandin (PG) E2 concentrations are decreased in exhaled breath condensate (EBC) in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate the short term effects of cyclo-oxygenase (COX) inhibition on exhaled LTB4 and PGE2 concentrations in patients with COPD and to identify the COX isoform responsible for exhaled PGE2 production.MethodsTwo studies were performed. A double blind, crossover, randomised, placebo controlled study with ibuprofen (400 mg qid for 2 days), a non-selective COX inhibitor, was undertaken in 14 patients with stable COPD, and an open label study with oral rofecoxib (25 mg once a day for 5 days), a selective COX-2 inhibitor, was undertaken in a different group of 16 COPD patients. EBC was collected before and after drug treatment. Exhaled LTB4 and PGE2 concentrations were measured with specific immunoassays.ResultsAll patients complied with treatment as indicated by a reduction in ex vivo serum thromboxane B2 concentrations (ibuprofen) and a reduction in lipopolysaccharide induced increase in ex vivo plasma PGE2 values (rofecoxib) of more than 80%. Exhaled LTB4 was increased after ibuprofen (median 175.5 (interquartile range 128.8-231.5) pg/ml v 84.0 (70.0-98.5) pg/ml, p < 0.001) and exhaled PGE2 was reduced (93.5 (84.0-105-5) pg/ml v 22.0 (15.0-25.5) pg/ml, p < 0.0001). Rofecoxib had no effect on exhaled LTB4 (p = 0.53) or PGE2 (p = 0.23).ConclusionsNon-selective COX inhibition decreases PGE2 and increases LTB4 in EBC, whereas selective COX-2 inhibition has no effect on these eicosanoids. PGE2 in EBC is primarily derived from COX-1 activity, and COX inhibition may redirect arachidonic acid metabolism towards the 5-lipoxygenase pathway.
| S-EPMC1747215 | biostudies-literature
Project description:The role of Rho proteins in lysophosphatidic acid (LPA)-mediated induction of cyclo-oxygenase-2 (Cox-2) was investigated in renal mesangial cells. Previous studies had shown that toxin B, an inhibitor of Rho, Rac and Cdc42, suppressed Cox-2 induction. A role for RhoA in pertussis toxin-sensitive LPA signalling was excluded with C3 transferase from Clostridium limosum, used as the fusion toxin C2IN-C3 (where C2IN is part of the C2I toxin of C. botulinum). Incubation of the cells with C2IN-C3 disrupted cytosolic actin stress fibres, but had no effect on Cox-2 induction. Similarly, activation of p42/44 mitogen-activated protein kinase (MAP kinase), an upstream step in Cox-2 induction, was inhibited by toxin B, but not affected by C2IN-C3. Upon treatment with toxin B, focal adhesion kinase and paxillin were dephosphorylated at tyrosine residues and the actin cytoskeleton was completely destroyed. An intact cytoskeleton, however, was not required for p42/44 MAP-kinase activation or Cox-2 induction, as shown by the actin-depolymerizing agent cytochalasin D. Toxin B did not influence functionality of LPA receptors, because G(i)-mediated Ca(2+) release from intracellular stores remained unchanged. Within 1 h, toxin B inactivated and translocated RhoA and Cdc42 to the cellular membranes. Within the same time frame, monoglucosylated Rac1 was degraded. Direct stimulation of Rho proteins by cytotoxic necrotizing factor type 1 (CNF1) induced Cox-2 expression, which was sensitive to inhibition of the MAP-kinase pathway by PD98059, but not to an inhibitor of RhoA kinase. By exclusion of RhoA and non-specific cytoskeletal effects, the results in the present study indicate an important role for Rac and/or Cdc42 in pertussis toxin-sensitive LPA-mediated Cox-2 induction.
| S-EPMC1222357 | biostudies-other
Project description:BackgroundThe adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs.Methodology/principal findingsImmunoblotting studies showed that leptin increased cyclo-oxygenase-2 (COX-2) expression (but not COX-1) in cultured human umbilical vein ECs (HUVEC) through pathways that depend upon activation of both p38 mitogen-activated protein kinase (p38(MAPK)) and Akt, and stimulated rapid phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) on Tyr(1175). Phosphorylation of VEGFR2, p38(MAPK) and Akt, and COX-2 induction in cells challenged with leptin were blocked by a specific leptin peptide receptor antagonist. Pharmacological inhibitors of COX-2, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and p38(MAPK) abrogated leptin-induced EC proliferation (assessed by quantifying 5-bromo-2'-deoxyuridine incorporation, calcein fluorescence and propidium iodide staining), slowed the increased migration rate of leptin-stimulated cells (in vitro wound healing assay) and inhibited leptin-induced capillary-like tube formation by HUVEC on Matrigel. Inhibition of VEGFR2 tyrosine kinase activity reduced leptin-stimulated p38(MAPK) and Akt activation, COX-2 induction, and pro-angiogenic EC responses, and blockade of VEGFR2 or COX-2 activities abolished leptin-driven neo-angiogenesis in a chick chorioallantoic membrane vascularisation assay in vivo.Conclusions/significanceWe conclude that a functional endothelial p38(MAPK)/Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals.
| S-EPMC3078934 | biostudies-literature