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

---

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

Nitric oxide provokes vasodilation and inhibits platelet aggregation. We examined the effect of nitric oxide on superoxide anion production by three sources: activated intact neutrophils, xanthine oxidase/hypoxanthine, and the NADPH oxidase. Nitric oxide significantly inhibited the generation of superoxide anion by neutrophils exposed to either FMLP (10(-7)M) or PMA (150 ng/ml) (IC50 = 30 microM). To determine whether the effect of nitric oxide on the respiratory burst was due to simple scavenging of O2+, kinetic studies that compared effects on neutrophils and the cell-free xanthine oxidase system were performed. Nitric oxide inhibited O2+ produced by xanthine oxidase only when added simultaneously with substrate, consistent with the short half-life of NO in oxygenated solution. In contrast, the addition of nitric oxide to neutrophils 20 min before FMLP resulted in the inhibition of O2+ production, which suggests formation of a stable intermediate. The effect of nitric oxide on the cell-free NADPH oxidase superoxide-generating system was also examined: The addition of NO before arachidonate activation (t = -6 min) significantly inhibited superoxide anion production. Nitric oxide did not inhibit O2+ when added at NADPH initiation (t = 0). Treatment of the membrane but not cytosolic component of the oxidase was sufficient to inhibit O2+ generation. The data suggest that nitric oxide inhibits neutrophil O2+ production via direct effects on membrane components of the NADPH oxidase. This action must occur before the assembly of the activated complex.
...
PMID:Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. 132 92

Several types of compound exert their cytotoxicity by generating reactive oxygen species, notably the superoxide anion radical. These include quinoid and nitroaromatic compounds serving as redox cyclers, i.e. producing superoxide at the expense of NADPH and oxygen catalyzed by cellular reductases. In specialized cell-types employed in defense such as granulocytes, eosinophils and macrophages, myeloperoxidase, NADPH oxidase and nitric oxide synthase have been identified as major sources of reactive oxygen species in cell toxicity. These include hypochlorite, singlet oxygen, superoxide, nitric oxide and hydrogen peroxide. The interaction of superoxide and nitric oxide generates further oxidants such as peroxynitrite. Lumino-amplified chemiluminescence generated by Kupffer cells is partially sensitive to inhibitors of NO synthase. Superoxide dismutase has been found to catalyze a novel reaction, the reversible conversion of nitric oxide to the nitroxyl anion, the latter being viewed as another form of EDRF. In the defense against oxidative damage, there are enzymatic and nonenzymatic antioxidants. Regarding compounds used pharmacologically, we have been interested in ebselen, a seleno-organic compound exhibiting GSH peroxidase activity, which protects against reactive oxygen species generated, for example, at reoxygenation following a period of hypoxia. Further, we have studied lipoate and dihydrolipoate as antioxidant redox system and as singlet oxygen quencher, e.g. protecting against damage of deoxyguanosines in plasmid DNA generated by singlet oxygen.
...
PMID:Role of reactive oxygen species in cell toxicity. 133 81

Luminol chemiluminescence in phorbolester-activated cultured rat liver Kupffer cells was strongly inhibited by the selenoorganic compound ebselen (IC50 = 2 mumol/L). Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) also diminished reduction of ferricytochrome c (IC50 = 10 mumol/L), indicating a suppression of superoxide anion formation. Likewise, in lipopolysaccharide-pretreated Kupffer cells, ebselen proved to be a potent inhibitor of the conversion of oxyhemoglobin to methemoglobin (IC50 = 3 mumol/L) as a measure of nitric oxide formation. The sulfur-containing analog (2-phenyl-1,2-benzisothiazol-3[2H]one) and the ebselen derivative, methylselenobenzanilide, were inactive. These results indicate that ebselen is a potent inhibitor of NADPH oxidase in Kupffer cells, as has been reported for other macrophages and granulocytes. In addition, they suggest a novel characteristic of ebselen, namely very effective inhibition of nitric oxide synthase of macrophages. In line with its inhibitory effects on the release of reactive oxygen species by macrophages, complemented by its antioxidant properties, ebselen was potent in the prevention of reoxygenation injury of Kupffer cells (IC50 approximately 5 mumol/L).
...
PMID:Inhibition of superoxide and nitric oxide release and protection from reoxygenation injury by Ebselen in rat Kupffer cells. 137 78

Phorbol 12-myristate 13-acetate-induced luminol chemiluminescence in rat Kupffer cells was doubled by the addition of L-arginine and significantly (up to 70%) inhibited by NG-nitro-L-arginine and NG-monomethyl-L-arginine, competitive inhibitors of L-arginine-dependent nitric oxide (NO) formation. The release of superoxide anion (O2-) by NADPH oxidase was neither affected by L-arginine nor by the inhibitors. Only very slight luminol chemiluminescence was detectable in lipopolysaccharide-pretreated Kupffer cells, a condition in which significant amounts of NO were formed but no O2-. In a cell-free system, significant luminol chemiluminescence only occurred when both authentic NO and the O2-/H2O2- generating system xanthine/xanthine oxidase were present. The results indicate that luminol chemiluminescence in phorbol-ester-activated Kupffer cells largely depends on L-arginine metabolism by NO synthase, requiring the concurrent formation of NO and O2-/H2O2.
...
PMID:Contribution of nitric oxide synthase to luminol-dependent chemiluminescence generated by phorbol-ester-activated Kupffer cells. 171 62

Research over the past year has revealed several interesting advances in the biosynthesis of the superoxide anion and nitric oxide. Highlights include the demonstration that the G protein Rac 2 is required for NADPH oxidase activation, the finding that nitric oxide is a feedback inhibitor of nitric oxide synthase isoforms, and the discovery that the continuous catalytic activity of the immune/inflammatory nitric oxide synthase is due to strong calmodulin binding, which is independent of elevated calcium levels. Interferon-gamma primes neutrophils and macrophages for both O2- and nitric oxide synthesis. However, NADPH oxidase and immune/inflammatory nitric oxide synthase are differentially regulated such that their activities are not simultaneously induced.
...
PMID:Assembly and regulation of NADPH oxidase and nitric oxide synthase. 751 23

We found that ventilation with nitric oxide (NO, 50 ppm) significantly (P < 0.05) reduced capillary leak (as reflected by weight gain and Ficoll retention) in isolated rat lungs perfused for 60 min with N-formyl-methionyl-leucyl-phenylalanine (fMLP; 10(-7) M) and human neutrophils (1,300/microliters). Perfusion with previously heated neutrophils (48 degrees C for 10 min, which inactivates NADPH oxidase) did not cause weight gain or Ficoll retention, indicating that neutrophil-derived oxidants mediated lung leak. Although perfusion with fMLP and neutrophils increased mean pulmonary artery pressures (PAP) from 7 to 11.7 +/- 0.5 mmHg at 10 min, lungs perfused with fMLP and neutrophils in which PAP was maintained at 7 mmHg by reducing perfusion flow rates also developed significant (P < 0.05) weight gain and Ficoll retention. Furthermore, inhaled NO did not reduce (P > 0.05) PAP at 10 min and only modestly reduced PAP at 30 and 60 min of perfusion. Our results suggest that oxidative endothelial damage, and not increased hydrostatic pressure, was the primary cause of the capillary leak, and that the protection provided by inhaled NO was not solely a consequence of vasodilation. We conclude that inhaled NO prevents neutrophil-mediated, oxygen radical-dependent leak in isolated rat lungs, and speculate that inhaled NO has anti-inflammatory properties in addition to its ability to cause pulmonary vasodilation.
...
PMID:Inhaled nitric oxide prevents neutrophil-mediated, oxygen radical-dependent leak in isolated rat lungs. 763 9

The cytokine tumor necrosis factor alpha (TNF alpha) and the growth factor basic fibroblast growth factor (bFGF) are known to induce early response genes such as c-fos and c-jun in various cell types. Activation of AP-1, a heterodimeric complex of Fos and Jun proteins, is required for matrix metalloproteinase production and cell proliferation. However, the signaling pathways by which these two factors influence the expression and activities of AP-1 remain currently poorly characterized. Several studies have shown that cytokines induce reactive oxygen species (ROS) production, but growth factor induction of ROS has not been reported. In the present study we demonstrate that both TNF alpha and bFGF induce ROS production, and that this is a common signaling event involved in the stimulation of c-fos gene expression in chondrocytes. To our knowledge, this is the first report directly demonstrating ROS production upon stimulation with a growth factor. TNF alpha and bFGF induction of ROS production is mediated through flavonoid-containing enzymes such as NADPH oxidase. Moreover, the ROS nitric oxide is not responsible for the induction of c-fos expression by TNF alpha and bFGF. In addition, the inhibitory effects of antioxidants on c-fos expression may account for their protective roles against proliferative and inflammatory diseases such as cancer, cardiovascular diseases, and arthritis.
...
PMID:Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. 774 16

The involvement of NADPH oxidase in hypoxic pulmonary vasoconstriction (HPV) was investigated in buffer-perfused rabbit lungs, employing the inhibitors diphenyleneiodonium (DPI) and apocynin. Responses to the vasoconstrictors U-46619 and angiotensin II (ANG II) were used to test specificity. Lung nitric oxide (NO) generation was assessed by on-line monitoring of NO exhalation (chemiluminescence), and the efficacy of DPI and apocynin on the NADPH oxidase-dependent O2- generation was quantified in alveolar macrophages by fluorescent-activated cell sorter technique. In a concentration range between 1 and 5 mM, apocynin inhibited macrophage respiratory burst and HPV but similarly suppressed U-46619-induced vasoconstrictor responses. DPI inhibited macrophage O2- generation in concentrations > or = 0.5 microM. At doses between 0.5 and 1.5 microM, DPI blocked lung NO generation, thereby increasing HPV. At higher doses (4 microM), in contrast, DPI fully blocked the hypoxia-induced pressor responses, whereas the vasoconstrictor responses to U-46619 and [Asn1, Val5] ANG II were not diminished. In the presence of NG-monomethyl-L-arginine, used to block lung NO generation throughout, DPI exhibited only the monophasic selective inhibition of HPV. We conclude that apocynin lacks specificity for HPV, but DPI, in addition to inhibiting lung NO generation, causes selective blockade of the hypoxia-induced vasoconstriction. This finding supports the hypothesis that an NADPH oxidase is involved in hypoxia sensing or specific signal transduction events underlying HPV.
...
PMID:Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs. 776 77

We investigated the role of endogenous nitric oxide (NO) and superoxide anions in recombinant human interleukin-1 beta (rhIL-1 beta)-induced bronchial hyperresponsiveness (BHR) and neutrophilia in Brown-Norway rats. Aminoguanidine (100 mg/kg/d) administered subcutaneously for 3 d, an inhibitor of inducible NO synthase, L-arginine (100 mg/kg/d administered subcutaneously for 3 d, a specific precursor for the synthesis of NO, and apocynin (5 mg/kg/orally), an inhibitor of superoxide anion (O2-)-generating NADPH oxidase in macrophages and neutrophils, were administered prior to administration of rhIL-1 beta (500 U) intratracheally. Aminoguanidine in addition to another inhibitor of NO synthase, NW-nitro-L-arginine methyl ester (L-NAME) 100 mg kg/d administered subcutaneously for 3 d augmented bronchial responsiveness to inhaled bradykinin (BK) but not to acetylcholine (ACh), an effect reversed by L-arginine. rhIL-1 beta-treated rats also demonstrated BHR to BK but not to ACh, associated with neutrophilia in bronchoalveolar lavage fluid (BALF). rhIL-1 beta-induced BHR and neutrophilia were neither further increased by aminoguanidine nor inhibited by L-arginine. Apocynin, however, significantly inhibited rhIL-1 beta-induced BHR but not the BALF neutrophilia. Suppression of NO generation and generation of O2- from macrophages and infiltrating neutrophils may be important in rhIL-1 beta-induced airway hyperresponsiveness to bradykinin.
...
PMID:Role of nitric oxide and superoxide anions in interleukin-1 beta-induced airway hyperresponsiveness to bradykinin. 792 31

Nitric oxide synthase (NOS) inhibitors have been reported to modulate luminol-dependent chemiluminescence (CL) in rat macrophages, whereas the potent oxidant peroxynitrite (ONOO-) was shown to react with luminol to yield CL in a cell-free system. We evaluated the role of the L-arginine/NOS pathway in luminol CL by phorbol ester-activated human polymorphonuclear (PMN) leukocytes using the NOS inhibitors NG-monomethyl-L-arginine (L-NMMA) and N-iminoethyl-L-ornithine (L-NIO). Nitric oxide (.NO) release was determined by oxidation of oxymyoglobin. In addition, the effect of NOS inhibitors on superoxide anion O2.-) production was measured. Luminol CL was notably diminished by L-NMMA in a dose-dependent manner. Superoxide dismutase (SOD) also decreased luminol CL and L-NMMA potentiated light emission decrease produced by SOD. Nitric oxide and O2.- production was significantly decreased by L-NMMA; moreover, luminol-dependent CL but not O2.- production was attenuated by L-NIO. These data suggest that products of catalytic activity of both .NO synthase and NADPH oxidase are required to elicit maximal luminol CL in this system. These studies demonstrate that the NOS synthase pathway is involved in luminol CL by human PMN, and they suggest that ONOO- would be an unrecognized mediator in this phenomenon.
...
PMID:Nitric oxide synthase inhibitors decrease human polymorphonuclear leukocyte luminol-dependent chemiluminescence. 858 46


1 2 3 4 5 6 7 8 9 10 Next >>

---