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Results for “Cyclooxygenase 2”

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At least 19 recordsLinked to original sources

PubMed2026

Supplementations of docosahexaenoic acid and blueberry suppress a high-fat breakfast-induced postprandial inflammation but only docosahexaenoic acid improves endothelial function in healthy adults: a randomized, double-blind, placebo-controlled crossover intervention study.

Blueberries and n - 3 polyunsaturated fatty acids each can provide protection against inflammation and cardiometabolic disorders. However, the underlying mechanisms are not fully understood. We hypothesized that blueberry and docosahexaenoic acid (DHA) can suppress high fat (HF) meal-induced postprandial inflammation and improve endothelial function. Sixty-two healthy participants (age: 26.8 ± 1.2 y; BMI: 22.1 ± 1.2 kg/m²) consumed an isoenergetic breakfast (850 kcal) containing 34.7 g mostly animal fat (36% kcal), 25.3 g protein, and 111 g carbohydrate, with or without either 42.2 g blueberry powder (BBP) or 1.76 g DHA in a randomized, double-blind, placebo-controlled crossover intervention study. Blood samples were collected before and 1 h, 3 h and 6 h after breakfast. Monocyte activation, proinflammatory gene expression, cytokine production and endothelial function were assessed. Compared with the placebo control, DHA supplementation suppressed the HF breakfast-induced: expression of IL-1β by 21.6% (P < .01) and prostaglandin-endoperoxide synthase 2 (PTGS2, i.e., cyclooxygenase 2) by 22.8% (P < .01) at 6 h; plasma IL-1β production by 40.1 to 49.8% (P < .01) at 1-6 h; lipoprotein lipase (LPL)-treated blood IL-1β production by 40.9% (P < .0001) at 6 h; and total cholesterol/HDL cholesterol ratio by 2.2% (P < .01) at 3 h and 3.5% (P < .0001) at 6 h. BBP supplementation suppressed LPL-treated blood IL-1β production by 23.1% (P < .05) at 6 h. BBP and DHA also induced postprandial increases in reactive hyperemia index (RHI) scores relative to the fasting baselines, with DHA producing a 13.3% increase compared with placebo at 6 h (P < .05). In conclusion, supplementation with BBP or DHA suppressed the HF meal-induced postprandial inflammation but only DHA improved postprandial endothelial function. This study was registered at clinicaltrails.gov (NCT02472171).

Blueberry↗

PubMed2026

Integrated Bulk and Single-Cell RNA-Seq Analysis Reveals Transcriptional Activation of PTGS2 by FOS in Progression From T2DM to T2DM-Associated NAFLD.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) frequently coexist, exacerbating disease burden. However, the molecular mechanisms underlying the progression from T2DM to T2DM-associated NAFLD remain unclear. This study investigated the regulatory function of FOS-mediated PTGS2 activation in this transition. We integrated bulk RNA-seq data from GEO, single-cell transcriptomic data and transcriptomes from patients with T2DM-associated NAFLD. Differentially expressed genes were identified using the limma package, and T2DM-related gene modules were defined by weighted gene co-expression network analysis. LASSO regression and random forest identified 14 candidate genes, with PTGS2 and FOS prioritised. Single-cell analysis showed increased FOS and PTGS2 expression in monocytes, CD8+ T cells and Kupffer cells. Transcription factor prediction and dual-luciferase assays confirmed that FOS directly binds the PTGS2 promoter and drives its transcription. In vitro, FOS silencing decreased PTGS2 expression, cytokine secretion and apoptosis under high-glucose and free fatty acid conditions, whereas PTGS2 overexpression exacerbated inflammation and apoptosis independently of FOS expression. These findings demonstrate that FOS transcriptionally activates PTGS2, contributing to hepatic inflammation and apoptosis during the progression from T2DM to NAFLD. PTGS2 may serve as a promising biomarker and therapeutic target for T2DM-associated NAFLD.

Single-Cell Gene Expression Analysis↗

PubMed2026

Effects of phenylephrine and norepinephrine with restrictive infusion on oxygenation during one-lung ventilation for lung surgery: a randomized controlled trial.

OBJECTIVE: This study compared the effects of norepinephrine or phenylephrine combined with restrictive infusion on the oxygenation during thoracoscopic one-lung ventilation (OLV). METHODS: Ninety patients were randomly divided into three groups: the norepinephrine group (Group N), the phenylephrine group (Group P), and the control group (Group C). Arterial partial pressure of oxygen (PaO2) and intrapulmonary shunt fraction (Qs/Qt) were measured with patients in lateral positions during two-lung ventilation (TLV) at 10 min (T1), and during OLV at 15 min (T2) and 45 min (T3). Lung tissue samples were analyzed for endothelin and COX-2 levels after surgery. RESULTS: At T3, Group P had significantly higher PaO2 and lower Qs/Qt than Groups N and C (all p < 0.05), with no significant differences between Groups N and C (all p > 0.05). Compared to T1, Groups N and C showed significantly lower PaO2 and higher Qs/Qt at T2 and T3 (all p < 0.05), with no significant differences in PaO2 and Qs/Qt at T3 compared with T2 (all p > 0.05). Group P patients had lower PaO2 and higher Qs/Qt at T2 and T3 compared to T1 (all p < 0.05), but at T3, PaO2 increased and Qs/Qt decreased compared to T2 (all p < 0.05). Lung tissue levels of endothelin and COX-2 were significantly elevated in group P compared to groups N and C (all p < 0.05). CONCLUSION: Combining phenylephrine with restrictive infusion during OLV improved oxygenation by increasing PaO2, decreasing Qs/Qt, and raising endothelin and COX-2 levels in lung tissue, thereby enhancing the HPV effect.

Humans↗

PubMed2004

A cyclooxygenase-2 homologue encoded by rhesus cytomegalovirus is a determinant for endothelial cell tropism.

Cyclooxygenase-2 (COX-2) is a cellular enzyme in the eicosanoid synthetic pathway that mediates the synthesis of prostaglandins from arachidonic acid. The eicosanoids function as critical regulators of a number of cellular processes, including the acute and chronic inflammatory response, hemostasis, and the innate immune response. Human cytomegalovirus (HCMV), which does not encode a viral COX-2 isoform, has been shown to induce cellular COX-2 expression. Importantly, although the precise role of COX-2 in CMV replication is unknown, COX-2 induction was shown to be critical for normal HCMV replication. In an earlier study, we identified an open reading frame (Rh10) within the rhesus cytomegalovirus (RhCMV) genome that encoded a putative protein (designated vCOX-2) with high homology to cellular COX-2. In the current study, we show that vCOX-2 is expressed with early-gene kinetics during RhCMV infection, resulting in production of a 70-kDa protein. Consistent with the expression of a viral COX-2 isoform, cellular COX-2 expression was not induced during RhCMV infection. Finally, analysis of growth of recombinant RhCMV with vCOX-2 deleted identified vCOX-2 as a critical determinant for replication in endothelial cells.

Amino Acid Sequence↗

PubMed1978

Inhibition of platelet prostaglandin synthetase by oral aspirin.

Aspirin inhibits platelet function by permanently acetylating the cyclooxygenase that forms prostaglandins. We determined the sensitivity of platelets to aspirin in normal subjects by measuring [3H-acetyl]aspirin-susceptible cyclooxygenase in washed platelets obtained at various times after aspirin ingestion. A single 325-mg aspirin dose inactivated 89% of platelet cyclooxygenase. The inhibition persisted for 2 days suggesting that oral aspirin also inactivated megakaryocyte cyclooxygenase. Thereafter, active enzyme returned with a time-course reflecting platelet turnover (life-span 8.2+/-2 days). Single doses of 20-650 mg aspirin resulted in 34- greater than 95% inhibition after 24 h. Daily doses of 20-325 mg aspirin for brief periods produced 61- greater than 95% inactivation when measured 24 h after cessation of the drug. Platelet cyclooxygenase is more sensitive to inactivation by aspirin than enzyme in sheep seminal vesicles.

Acetylation↗

PubMed1979

Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin.

Endothelial cells synthesize prostacyclin (PGI(2)), an unstable prostaglandin that inhibits platelet aggregation and serotonin release. Because cyclooxygenase, which is necessary for synthesis of PGI(2), is inactivated by aspirin, we examined the effect of aspirin on PGI(2) production by cultured human endothelial cells. Endothelial cells synthesize PGI(2) (20.1+/-7.2 ng/10(6) cells, mean+/-SD) when stimulated with 20 muM sodium arachidonate for 2 min. PGI(2) production is inhibited by low-dose aspirin (5 muM); the t((1/2)) of inactivation is 6.0+/-1.3 min (mean+/-SEM, n = 3). Thus, endothelial cell cyclooxygenase is as sensitive to aspirin as the enzyme in platelets. After 1 h incubation with aspirin, endothelial cell PGI(2) production was inhibited 50% by 2.1+/-0.4 muM aspirin and was inhibited 90% by 6.2+/-0.9 muM aspirin (mean+/-SEM, n = 4). When endothelial cells were incubated with 100 muM aspirin, washed, and recultured, their ability to synthesize PGI(2) returned to control levels in 35.6+/-1.0 h (mean+/-SEM, n = 4). Recovery of endothelial PGI(2) production after aspirin depended on de novo protein synthesis because treatment with cycloheximide (3 mug/ml) inhibited recovery by 92%.These results indicate that although endothelial cell cyclooxygenase in vitro is inhibited by low concentrations of aspirin, endothelial cells rapidly resynthesize their cyclooxygenase after the aspirin is removed. This rapid resynthesis of cyclooxygenase lessens the likelihood that aspirin used in clinical doses promotes thrombosis.

Aspirin↗

PubMed1978

Cardiac and renal prostaglandin I2. Biosynthesis and biological effects in isolated perfused rabbit tissues.

Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I(2). The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI(2), 6-keto-PGF(1alpha), in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH(2), but not dihomo-gamma-linolenic acid and its endoperoxide PGH(1), serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI(2) but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE(2); while the heart converts endogenous arachidonate primarily into PGI(2). Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI(2) by the heart, and of PGE(2) by the kidney. Cardiac PGI(2) administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH(2) causes an increase in coronary resistance without apparent cardiac conversion to PGI(2). The perfused heart rapidly degrades most of the exogenous endoperoxide probably into PGE(2), while exogenous PGI(2) traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH(2) in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI(2) synthetase, whereas the more lipid soluble precursor arachidonic acid (exogenous or endogenous) penetrated to the cyclooxygenase, which apparently is tightly coupled to the PGI(2) synthetase.

Animals↗

PubMed1979

Conformational requirements at the prostaglandin cyclooxygenase receptor site.

When space-filling models of the peroxy radical precursor of PGG were compared with models of 2(S)-(3-chloro-4-cyclohexylphenyl)propionic acid and other acidic cyclooxygenase inhibitors several common structural features were revealed. This led us to propose a template for synthesising non-steroidal anti-inflammatory drugs (NSAIS's) based on the geometry of the peroxy radical immediately prior to its cyclisation to PGG.

Anti-Inflammatory Agents↗

PubMed1979

Conformational requirements at the prostaglandin cyclooxygenase receptor site: a template for designing non-steroidal anti-inflammatory drugs.

When space-filling models of the peroxy radical precursor of PGG were compared with models of 2(S)-(3-chloro-4-cyclohexylphenyl) propionic acid and other acidic cyclooxygenase inhibitors several common structural features were revealed. This led us to propose a template for designing non-steroidal anti-inflammatory drugs (NSAID's) based on the conformation of the peroxy radical immediately prior to its cyclisation to PGG. The template can be equated with a complementary cyclooxygenase receptor site.

Anti-Inflammatory Agents↗

PubMed1978

Lipoxygenation activity of purified prostaglandin-forming cyclooxygenase.

Purified cyclooxygenase, a single enzyme which catalyzes the formation of endoperoxide from arachidonic acid (20:4) in a bis(dioxygenase) reaction, is capable of oxygenating eicosadienoic acid (20:2) at C-11 in a single dioxygenase reaction. The partial oxygenation of 20:2 resembles the formation of prostaglandin from 20:4, with both oxygenation reactions exhibiting similar pH optima, substrate Km values, and cofactor effects including a need for peroxide and an absolute requirement for heme. In addition, those processes known to destroy 20:4 oxygenase activity, such as heat inactivation, inactivation with anti-inflammatory drugs, and turnover-mediated inactivation, have equally destructive effects on 20:2 oxygenase activity. Thus, both oxygenations are catalyzed by one enzyme. All of the above similarities for 20:2 and 20:4 oxygenation demonstrate that C-11 oxygenation is an integral rate-limiting step of cyclooxygenase action rather than a separate reaction resembling that of plant lipoxygenase.

Animals↗

PubMed1979

Rapid inactivation of cyclooxygenase activity after stimulation of intact platelets.

Trypsin, thrombin, and ionophore A23187 activate phospholipid breakdown of platelets that have been labeled with [(14)C]arachidonate, releasing their cyclooxygenase and lipoxygenase products. Intact platelets can also very effectively directly degrade low concentrations of exogenous, free [(14)C]arachidonate. Pretreatment of platelets with trypsin, thrombin, or ionophore A23187 for a minimum time of 30 sec leads to complete inactivation of cyclooxygenase activity, as demonstrated by subsequent exposure to [(14)C]arachidonate. Lipoxygenase activity is lost after 5 min. The thrombin-induced inactivation of cyclooxygenase and lipoxygenase is prevented by cyclic AMP (which inhibits the stimulated activity of phospholipase A(2)), although cyclic AMP does not affect the degradation of exogenous [(14)C]arachidonate. Exposure of platelets labeled with [(14)C]arachidonate to unlabeled arachidonate under conditions that lead to use of the latter also results in a similarly rapid inhibition of cyclooxygenase activity, as determined by subsequent challenge with thrombin. Under these conditions lipoxygenase activity is much less markedly inactivated. The arachidonate-induced inhibition of cyclooxygenase activity is not prevented by cyclic AMP. Trypsin does not induce platelet aggregation, and platelets whose cyclooxygenase activity has been inactivated are intact insofar as they are still able to undergo aggregation. These studies demonstrate that operation in intact platelets of the cyclooxygenase pathway, through use of endogenous or exogenous substrate, leads to a very rapid, irreversible inactivation of this enzyme. The lipoxygenase pathway is also progressively impaired, but much less rapidly than the cyclooxygenase enzyme and much less markedly on use of exogenous compared to endogenous substrate. The possible consequences of these physiological processes of spontaneous inactivation are considered.

Animals↗

PubMed1979

Stimulation of phosphatidic acid production in platelets precedes the formation of arachidonate and parallels the release of serotonin.

Thrombin rapidly induces the formation of labeled phosphatidic acid from platelets prelabeled with [17C]arachidonate or 32PO34- and specifically decreases by 50--75% the content of phosphatidylinositol. Ionophore A23187 also stimulates phosphatidate labeling, but less effectively than thrombin. This effect on phosphatidic acid is blocked by increasing the levels of cyclic AMP by preincubation with dibutyryl cyclic AMP, cyclic AMP-phosphodiesterase inhibitors or prostacyclin. Indomethacin and eicosatetraynoic acid do not alter the production of phosphatidate, indicating independence from cyclooxygenase or lipoxygenase products. Increased turnover of [14C]- or [32P]phosphatidate occurs within 2--5 s after platelet activation by thrombin and is observed before endogenous, 14C-labeled arachidonate can be detected. The rate of phosphatidate formation parallels the induced rate of serotonin release. Release of [3H]serotonin is not affected by eicosatetraynoic acid. Phosphatidate production reflects the generation of diacylglycerol by C-type phospholipase degradation of phosphatidylinositol. Diacylglycerol and phosphatidic acid may participate in the membrane modification related to the early changes in platelet shape, release reactions or aggregation which occur on stimulation.

Animals↗

PubMed1977

Decreased prostaglandin synthetase activity during kidney regeneration after folic acid or 2,4,5-triamino-6-styrylpyrimidine application.

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Animals↗

PubMed1979

Triene prostaglandins: prostaglandin D3 and icosapentaenoic acid as potential antithrombotic substances.

Addition of the 3-series fatty acid precursor (icosapentaenoic acid, IPA), its endoperoxide [prostaglandin (PG)H(3)], or thromboxane A(3) to human platelet-rich plasma (PRP) does not result in aggregation of the platelets. In fact, preincubation of human PRP with exogenous PGH(3) actually inhibited aggregation by increasing platelet cyclic AMP concentrations. PGH(3) undergoes rapid spontaneous degradation to PGD(3) in human PRP. The PGD(3) so formed is adequate to account for the increase of platelet cAMP and inhibition of aggregation. Furthermore, addition of PGD-specific antisera to human PRP blocked the platelet inhibitory activity of exogenous PGH(3). PGD(3) has considerable potential as a circulating antithrombotic agent. Pretreatment of human PRP with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine blocked the increase of platelet cyclic AMP and the inhibition of aggregation normally produced by PGI(2), PGE(1), PGD(2), PGH(3), and PGD(3). Furthermore, the dideoxyadenosine unmasked a direct but moderate reversible aggregatory effect in response to the subsequent addition of PGH(3). Similarly, the dideoxyadenosine markedly enhanced the aggregation produced by exogenous PGH(2). IPA is readily incorporated into tissue lipids but proved to be a poor substrate for kidney, blood vessel, or heart cyclooxygenase. IPA was previously shown to be a poor substrate for platelet cyclooxygenase. IPA is readily deacylated from the renal phospholipid pool in response to bradykinin, a substance that also stimulates the release of arachidonic acid. A diet that relies primarily on cold-water fish, as in the case of the Greenland Eskimos, lowers endogenous arachidonic acid and markedly increases the IPA content of tissue lipids. Thus, because IPA has the potential to act as an antagonist with arachidonic acid for platelet cyclooxygenase and lipoxygenase, the simultaneous release of IPA could suppress any residual arachidonic acid conversion to its aggregatory metabolites.

Adenosine↗

PubMed1978

Low concentrations of indomethacin inhibit phospholipase A2 of rabbit polymorphonuclear leukocytes.

Inhibition of prostaglandin synthesis by indomethacin, a drug with anti-inflammatory properties, has been attributed to its action on fatty acid cyclooxygenase. However, prostaglandin synthesis would also be inhibited if precursor fatty acids were not supplied. We find that indomethacin inhibits phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) of rabbit polymorphonuclear leukocytes in dose-dependent fashion. Inhibition is immediate and readily detected at 1 micrometer. The extent of inhibition is the same over a 10-fold range of substrate concentration and over a 500-fold range of enzyme purification. Inhibition is of the noncompetitive type, with an apparent Ki of 12 micrometer. Four other phospholipases A2--from venoms of Russell viper, Crotalus adamanteus, and bee, and from pig pancreas--are unaffected by 50 micrometer indomethacin, which inhibits leukocyte phospholipase A2 by 70%. This inhibition at low concentrations may well be important in the effects of the drug on protaglandin synthesis and inflammatory responses.

Animals↗

PubMed1978

Effect of inhibitors of prostaglandin synthesis and prostaglandins E2 and F2alpha on the immunologic release of mediators of inflammation from actively sensitized guinea-pig lung.

Histamine and slow reacting substance of anaphylaxis (SRS-A) were released from actively sensitized guinea-pig chopped lung fragments (100 mg) in a concentration dependent manner by 0.2 to 100 microgram/ml of antigen. Individual variation between lungs in the proportion of the total histamine released by antigen (20 microgram/ml) showed a normal frequency distribution (n = 95). The effect of inhibitors of prostaglandin (PG) synthesis on the release of histamine and SRS-A was examined. Indomethacin (0.03--13 micrometer), racemic 6-chloro-alpha-methylcarbazole-2-acetic acid (0.03--3 micrometer) and sodium salicylate (0.8--8 micrometer) stimulated histamine release by high concentrations of antigen (more than 10 microgram/ml) but had no effect at low concentrations of antigen. These agents stimulated the release of SRS-A at all antigen concentrations tested. In contrast, 5,8,11,14-eicosatetraynoic acid (0.04--42 micrometer) had no effect on the release of histamine but inhibited the release of SRS-A. Histamine release was stimulated by exogenous PGF2alpha (0.01--1 micrometer) in lungs which had control releases in the 25th percentile of the frequency distribution, but was unaffected by exogenous PGE2 (0.01--10 micrometer). In the presence of blockade of PG synthesis by indomethacin (13 micrometer), the stimulatory effect of PGF2alpha was enhanced while PGE2 antagonized the stimulatory effect of indomethacin. These results suggest that 1) histamine and SRS-A release from guinea-pig lung is regulated in part by the de novo synthesis of prostaglandins and 2) that SRS-A synthesis and release is influenced by a metabolite of arachidonic acid produced by a metabolic pathway other than cyclooxygenase.

Animals↗

PubMed1977

Inhibition of prostaglandin endoperoxide synthetase by thiol analogues of prostaglandin.

A variety of thiol compounds inhibited the enzymatic bis-oxygenation of 8,11,14-eicosatrienoic acid to prostaglandin G1, as examined with a purified preparation of prostaglandin endoperoxide synthetase (prostaglandin synthase; 8,11,14-eicosatrienoate, hydrogen-donor:oxygen oxidoreductase; EC 1.14.99.1) from bovine vesicular gland. The hydroperoxide cleavage of prostaglandin G1 producing prostaglandin H1 was not affected by these thiol compounds. Several prostaglandin analogues with a thiol group (9,11-dihydroxy-15S- or 15R-mercaptoprosta-5,13-dienoic acid, 1-mercapto-9,11,15-trihydroxyprosta-5,13-diene, and 1-mercapto-9-oxo-11,15-dihydroxyprosta-5,13-diene) were most potent inhibitors, showing almost complete inhibition at concentrations on the order of 1 muM. Other thiol compounds, such as 2,3-dimercaptopropanol, dithiotherreitol, and dihydrolipoic acid, were also inhibitory but were much less effective. The inhibition, as examined with 9,11-dihydroxy-15S-mercaptoprosta-5,13-dienoic acid and 2,3-dimercaptopropanol, was noncompetitive.

8,11,14-Eicosatrienoic Acid↗

PubMed1978

Redistribution of intrarenal blood flow following ADH administration: lack of inhibition by blockade of prostaglandin in cyclooxygenase.

The effect of prostaglandin synthesis inhibition on the redistribution of renal cortical blood flow in response to antidiuretic hormone (ADH) was examined using radioactive microspheres in water loaded, thiopental-anesthetized dogs. Microsphere injections were made during a control and an ADH infusion period (0.35 mU/kg/min following a 20 mU/kg bolus) both before and after indomethacin pretreatment (8 mg/kg intravenously). Urinary prostaglandin E2 (PGE2) excretion in each period was measured by gas chromatography-mass spectrometry. ADH caused a marked redistribution of flow toward inner cortical zones from 19 +/- 1 to 25 +/- 2 ml/min (mean +/- SE, p less than 0.01). Fractional flow to inner zones was also significantly increased. Indomethacin pretreatment had no effect on the ADH-induced redistribution (17 +/- 2 vs. 24 +/- 2 ml/min, p less than 0.01), although urinary PGE2 excretion was suppressed by indomethacin by 60%. It is concluded that prostaglandins do not mediate the redistribution of intrarenal blood flow accompanying ADH administration.

Animals↗