Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The superoxide anion-generating effect of celecoxib (4-[5-(4-methylpheny)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); SC58633), a selective cyclooxygenase-2 inhibitor, on human neutrophils was evaluated in this study. Celecoxib induced superoxide anion generation in a concentration-dependent manner in human neutrophils. The EC50 value of celecoxib on superoxide anion generation was 15.5+/-2.5 microM. A NADPH oxidase inhibitor, diphenyliodonium (20 microM), and superoxide dismutase (150 U/ml) completely inhibited the free radical generation caused by celecoxib, indicating that the respiratory burst was activated by celecoxib. 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM;10 microM) and staurosporine (200 nM) completely inhibited the superoxide anion release caused by celecoxib, respectively. These data indicated that celecoxib increased superoxide anion release by increasing intracellular calcium and protein kinase C activation. Moreover, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-C)-carbazole (Go-6976; 1 microM) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide, methane sulfate (Ro-31-8220; 0.5 microM), specific inhibitors of conventional protein kinase C isotypes (alpha, beta(I) and beta(II)), significantly inhibited superoxide anion release caused by celecoxib. Rottlerin (5 microM), a protein kinase C delta inhibitor, did not affect the free radical generation caused by celecoxib. Celecoxib caused translocation of protein kinase C alpha, beta(I) and beta(II) from the cytosol to the cellular membrane. 2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one (PD98059; 20 microM) and wortmannin (100 nM) did not decrease the superoxide anion generation caused by celecoxib, indicating that Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3 kinase) were not involved in the respiratory burst induced by celecoxib. Pertussis toxin (2 microg/ml), a Gi-protein sensitive inhibitor, significantly inhibited superoxide anion release. Moreover, pertussis toxin significantly inhibited intracellular calcium mobilization and protein kinase C alpha, beta(I) and beta(II) translocation from the cytosol to the membrane. Celecoxib increased beta(2)-integrin expression on human neutrophils and this effect was inhibited by BAPTA/AM (10 microM), superoxide dismutase (150 U/ml), genistein (25 microM) and PD98059 (20 microM). This information indicated that intracellular calcium, superoxide anion, tyrosine kinase and MAP kinase are involved in beta(2)-integrin expression. Furthermore, BAPTA/AM, superoxide dismutase and genistein inhibited celecoxib-increased MAP kinase activity, indicating that MAP kinase is a downstream signal for beta(2)-integrin expression. In conclusion, celecoxib stimulates superoxide anion release from human neutrophils by activating pertussis toxin sensitive G-protein. An increase in intracellular calcium and protein kinase C alpha, beta(I) and beta(II) is involved in this process. Celecoxib also regulates beta(2)-integrin expression through superoxide anion release, tyrosine kinase and p42/p44 MAP kinase on human neutrophils.
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PMID:Celecoxib simulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for beta 2-integrin expression on human neutrophils. 1472 79

We determined the roles of reactive oxygen species (ROS) in the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated microglia. LPS treatment increased intracellular ROS in rat microglia dose-dependently. Pre-treatment with superoxide dismutase (SOD)/catalase, or SOD/catalase mimetics that can scavenge intracellular ROS, significantly attenuated LPS-induced release in PGE2. Diphenylene iodonium (DPI), a non-specific NADPH oxidase inhibitor, decreased LPS-induced PGE2 production. In addition, microglia from NADPH oxidase-deficient mice produced less PGE2 than those from wild-type mice following LPS treatment. Furthermore, LPS-stimulated expression of COX-2 (determined by RT-PCR analysis of COX-2 mRNA and western blot for its protein) was significantly reduced by pre-treatment with SOD/catalase or SOD/catalase mimetics. SOD/catalase mimetics were more potent than SOD/catalase in reducing COX-2 expression and PGE2 production. As a comparison, scavenging ROS had no effect on LPS-induced nitric oxide production in microglia. These results suggest that ROS play a regulatory role in the expression of COX-2 and the subsequent production of PGE2 during the activation process of microglia. Thus, inhibiting NADPH oxidase activity and subsequent ROS generation in microglia can reduce COX-2 expression and PGE2 production. These findings suggest a potential therapeutic intervention strategy for the treatment of inflammation-mediated neurodegenerative diseases.
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PMID:Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. 1475 15

Chorioamnionitis (CAM) is one of the causes of preterm labour. A recent study has indicated that NADPH oxidase, a reactive oxygen species (ROS)-producing enzyme, is activated in CAM. CAM is thought to be closely associated with oxidative stress. We have hypothesized that oxidative stress in CAM may induce preterm labour. The purpose of this study is to examine the effect of 4-hydroxy-2-nonenal (HNE), which is a marker of oxidative stress, on human placenta during preterm labour. We initially examined the HNE-modified proteins in human placentas by immunoblotting and immunohistochemistry using anti-HNE antibody. To examine the effect of HNE on human placenta, we stimulated human placental tissue with HNE. The expressions of cyclooxygenase-2 (COX-2) mRNA and protein were observed by RT-PCR and western blot analysis respectively. Furthermore, we measured the peroxidase activity of COX-2 by COX activity assay kit. Prostaglandin E(2) (PGE(2)) in the supernatants of placental tissue was also determined by enzyme-linked immunosorbent assay. Immunoblotting and immunohistochemistry showed that the levels of HNE-modified proteins were increased in the placentas with CAM, compared to the normal placenta. HNE induced the expression of COX-2 mRNA, protein and activity in the placental tissue culture stimulated with HNE. In addition, PGE(2) was also released into the medium in a time-dependent fashion. These findings suggest that HNE-modified proteins, which were increased in the placenta with CAM, play an important role in preterm labour.
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PMID:Effects of 4-hydroxy-2-nonenal, a marker of oxidative stress, on the cyclooxygenase-2 of human placenta in chorioamnionitis. 1498 Nov 43

In the present study we report the preventive effect of apocynin, an active constituent of the Himalayan herb Picrorhiza kurrooa, on cyclooxygenase-2 (Cox-2) synthesis and activity in human adherent monocytes exposed to serum treated zymosan (STZ) and phorbol myristate acetate (PMA). Apocynin markedly decreases the intracellular reduced/oxidized glutathione ratio (GSH/GSSG) and prevents nuclear factor-kappaB (NF-kappaB) activation in stimulated monocytes. Moreover, it reduces intracellular reactive oxygen species (ROS) generation, NADPH oxidase activity in monocyte homogenates and translocation of p47phox subunit in monocyte membranes. p47phox levels are also reduced in lysates of apocynin-treated monocytes. The inhibition of Cox-2 by apocynin is completely abrogated by GSH provision. Results from this study indicate that apocynin inhibits Cox-2 synthesis and activity induced in monocytes by an increased oxidative tone and provide an explanation for the protective effect exerted by this compound in numerous cell and animal models of inflammation. Attenuation of NADPH oxidase derived ROS coupled with GSH/GSSG reduction and suppression of NF-kappaB activation are highlighted as the molecular mechanisms responsible for Cox-2 inhibition.
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PMID:Apocynin prevents cyclooxygenase 2 expression in human monocytes through NADPH oxidase and glutathione redox-dependent mechanisms. 1520 87

Chronic inflammation through foam cells and macrophages is important in atherosclerosis development, and can be considered as therapeutic targets. Cyclooxygenase and NADPH-oxidase were expressed within atherosclerotic lesions. Reactive oxygen species produced by NADPH oxidase were found to trigger the cyclooxygenase-2 expression. The effects of preferential COX-2 inhibitors on ROS produced by Chlamydia-primed human monocytes (THP-1 cells) were evaluated by fluorescence, chemiluminescence, oxymetry, and EPR spin trapping. Fluorescence assays showed an increased production of ROS with Chlamydia versus cells primed by 10(-8)M PMA. COX-2 inhibitors inhibited in a dose-dependent manner the luminol-enhanced CL while ibuprofen and diclofenac increased the chemiluminescence response. By EPR spin trapping, COX-2 inhibitors, ibuprofen, and diclofenac, exhibited a dose-dependent inhibiting effect (10 and 100muM) on the EPR signal appearance. Our cell model combining EPR, chemiluminescence, and oxymetry appeared relevant to study the modulating effects of preferential COX-2 inhibitors on the cell oxidant activity and chronic inflammatory diseases.
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PMID:Effects of COX-2 inhibitors on ROS produced by Chlamydia pneumoniae-primed human promonocytic cells (THP-1). 1555 44

Epidemiological and experimental studies have suggested that high dietary intake of fats is associated with cognitive decline and a significantly increased risk of dementia. Since oxidative stress and inflammation have been speculated to be critical mechanisms underlying neurodegenerative diseases, we hypothesized that a high fat (HF) diet might induce cerebral oxidative stress or neural inflammation and subsequently contribute to the high risk of dementia. To test this hypothesis, male rats were placed on either a HF diet or a low fat (LF) diet starting at 1 month of age and lasting for 5 months. Intracellular reactive oxidative species (ROS) generation in the cerebral cortex was measured by the oxidant-sensitive dye 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA). Cortical tissue concentration of prostaglandin E(2) (PGE(2)) was determined using an enzymatic immunoassay. Expression of NADPH oxidase subunits, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), nuclear transcription factor NF(kappa)-B (NF-kappaB) p65 subunit, Ikappa B(IkappaB), and phospho-Ikappa B(phospho-IkappaB) was evaluated by Western blot analysis. The HF diet significantly increased ROS generation and expression of gp91(phox), p22(phox), p47(phox), and p67(phox) NADPH oxidase subunits in cerebral cortex. Elevated PGE(2) levels and markedly increased COX-2 expression suggested a neural inflammatory response in response to excessive fat intake. These findings were further supported by significantly increased phospho-IkappaB and nuclear NF-kappaB expression that suggested a role of IkappaB phosphorylation in HF diet-induced NF-kappaB translocation. The present study revealed that HF diet induced neural oxidative stress, inflammation, and NF-kappaB activation in rat cerebral cortex, and provided novel evidence regarding the link between high dietary fat and increased risk of dementia.
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PMID:High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. 1564 87

In the vasculature, reactive oxygen species (ROS) generated by both mitochondrial respiration and enzymatic sources serve as integral components of cellular signaling and homeostatic mechanisms. Because ROS are highly reactive biomolecules, the cellular redox milieu is carefully maintained by small-molecule antioxidants and antioxidant enzymes to prevent the deleterious consequences of ROS excess. When this redox balance is perturbed, because of either increased ROS production or decreased antioxidant capacity, oxidant stress is increased in the vessel wall and, if not offset, vascular dysfunction ensues. A number of heritable polymorphisms of pro-oxidant enzymes, including 5-lipoxygenase, cyclooxygenase-2, nitric oxide synthase-3, and NAD(P)H oxidase, have been identified and found to modulate ROS production and, thereby, the risk of atherothrombotic cardiovascular disease in individuals with these genetic polymorphisms. Similarly, heritable deficiency of the antioxidant enzymes catalase, glutathione peroxidases, glutathione-S-transferases, heme oxygenase, and glucose-6-phosphate dehydrogenase favors ROS accumulation, and has been associated with an increased risk of vascular disease. Individually, each of these polymorphisms imposes a state of uncompensated oxidant stress on the vasculature and collectively comprise the oxidative enzymopathies.
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PMID:Oxidative enzymopathies and vascular disease. 1579 Sep 28

Angiotensin II is an important oxidative stress mediator. Our previous studies have indicated that the potent antioxidative properties of acetylsalicylic acid play an important role in its cardiovascular protective effects. There are some ongoing controversies concerning the use of selective cyclooxygenase-2 inhibitors in cardiovascular disease. The aim of this study was to determine whether the cyclooxygenase-2 selective inhibitors rofecoxib and nimesulide possess antioxidative and cardiovascular protective effects against angiotensin II. Chronic subcutaneous angiotensin II infusion increased cardiovascular but not colonic tissue superoxide production, heart/body weight ratio, and blood pressure. Moreover, angiotensin II selectively increased cardiac cyclooxygenase-2 but not cyclooxygenase-1 expression, which was totally prevented by acetylsalicylic acid treatment. Similar to acetylsalicylic acid, rofecoxib or nimesulide treatments significantly attenuated angiotensin II-induced oxidative stress, hypertension, and cardiac NAD(P)H oxidase subunit p47(phox) expression. Rofecoxib also reduced cardiac hypertrophy. Treatment with nonselective anti-inflammatory drugs ibuprofen, indomethacin, or salicylic acid did not show any effect on angiotensin II-induced superoxide production, hypertension, or cardiac hypertrophy. Although acetylsalicylic acid and salicylic acid inhibited angiotensin II-induced nuclear factor kappaB (NF-kappaB) activation, nimesulide did not modify NF-kappaB activation. In conclusion, cyclooxygenase-2 pathway is implicated in angiotensin II-induced oxidative stress and deleterious cardiovascular changes. Rofecoxib and nimesulide produced significant antioxidative effect by reducing NAD(P)H oxidase-dependent superoxide generation. These effects seem to be independent of NF-kappaB inhibition.
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PMID:Cyclooxygenase-2 inhibitors attenuate angiotensin II-induced oxidative stress, hypertension, and cardiac hypertrophy in rats. 1585 30

Vascular inflammation is involved in the initiation and progression of atherosclerosis, and is also present in hypertension- and diabetes-induced vascular complications. Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of blood pressure and electrolyte homeostasis. There is accumulating evidence to indicate that Ang II is also capable of inducing inflammatory response in the vascular wall. This review summarizes the current understanding of the molecular mechanisms and signal transduction pathways of Ang II-induced vascular inflammation. The roles of modulators of Ang II-induced inflammatory response, such as nitric oxide (NO), bradykinin, cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), and epoxyeicosatrienoic acids (EETs), are also discussed. The current data suggest that Ang II modifies several steps of inflammatory response, such as increase of vascular permeability, leukocyte infiltration, tissue hypertrophy/proliferation, and fibrosis. Ang II, via the type 1 (AT1) receptors, enhances the production of reactive oxygen species (ROS) through stimulation of NAD(P)H oxidase in the vascular wall. Increased oxidative stress contributes to endothelial dysfunction and to vascular inflammation by stimulating the redox-sensitive transcription factors (NF-kappaB) and by upregulating adhesion molecules, cytokines, and chemokines. The pro-inflammatory action of Ang II may help us to understand the molecular mechanisms of hypertension- and diabetes-induced vascular complication as well as the pleiotropic actions of drugs interfering with RAS.
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PMID:Angiotensin II and vascular inflammation. 1591 31

beta-Carotene has shown antioxidant and anti-inflammatory activities; however, its molecular mechanism has not been clearly defined. We examined in vitro and in vivo regulatory function of beta-carotene on the production of nitric oxide (NO) and PGE(2) as well as expression of inducible NO synthase (iNOS), cyclooxygenase-2, TNF-alpha, and IL-1beta. beta-Carotene inhibited the expression and production of these inflammatory mediators in both LPS-stimulated RAW264.7 cells and primary macrophages in a dose-dependent fashion as well as in LPS-administrated mice. Furthermore, this compound suppressed NF-kappaB activation and iNOS promoter activity in RAW264.7 cells stimulated with LPS. beta-Carotene blocked nuclear translocation of NF-kappaB p65 subunit, which correlated with its inhibitory effect on IkappaBalpha phosphorylation and degradation. This compound directly blocked the intracellular accumulation of reactive oxygen species in RAW264.7 cells stimulated with LPS as both the NADPH oxidase inhibitor diphenylene iodonium and antioxidant pyrrolidine dithiocarbamate did. The inhibition of NADPH oxidase also inhibited NO production, iNOS expression, and iNOS promoter activity. These results suggest that beta-carotene possesses anti-inflammatory activity by functioning as a potential inhibitor for redox-based NF-kappaB activation, probably due to its antioxidant activity.
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PMID:beta-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages by suppressing redox-based NF-kappaB activation. 1615 9


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