Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple enzymes may stimulate ROS production in VSMC and endothelial cells. These include NADH/NADPH oxidase, xanthine oxidase, lipoxygenases, cyclooxygenase, P-450 monooxygenases, and the enzymes of mitochondrial oxidative phosphorylation. In addition to generation of intracellular O2- by these enzymes, extracellular stimuli including lipophilic substrates, membrane permeant oxidants (e.g., H2O2), cytokines, and growth factors may modulate cellular redox state. Both intracellular and extracellular ROS act as second-messengers to activate tyrosine and serine-threonine kinases, such as the MAP kinase family. As discussed in the previous sections, regulation of the MAP kinases is one example of the complexity of ROS-dependent signal transduction. Although the complexity of ROS-mediated signal transduction is daunting, the diversity offers multiple therapeutic targets for pharmacologic intervention.
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PMID:Redox signals that regulate the vascular response to injury. 1060 87

Matrix metalloproteinases (MMPs) play a pivotal role in angiogenesis, atherogenesis, vascular remodeling after vascular injury, and instability of atherosclerotic plaque. The present study was undertaken to investigate the effect of lysophosphatidylcholine, a major component of oxidized low density lipoprotein (LDL), on the regulation of MMPs in cultured bovine aortic endothelial cells (BAECs). Furthermore, we explored the potential role of oxidative stress in the regulation of MMP. LPC increased the secretion of gelatinolytic activity, as well as, protein of MMP-2 from BAECs. The stimulation of BAEC with superoxide increased the production of MMP-2 and it also induced its activation. Electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap agent demonstrated that lysophosphatidycholine (LPC) induced generation of reactive oxygen (ROS) species from BAECs. The inhibition of NADH/NADPH oxidase, one of the potential sources of superoxide in endothelial cells, attenuated the effect of LPC. Our findings suggest that LPC might activate the endothelial NADH/NADPH oxidase to enhance superoxide production, and it might, in turn, enhance MMP-2 induction.
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PMID:Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. 1122 25

Endogenously produced reactive oxygen species are important for intracellular signaling mechanisms leading to vascular smooth muscle cell (VSMC) growth. It is therefore critical to define the potential enzymatic sources of ROS and their regulation by agonists in VSMCs. Previous studies have investigated O2*- production using lucigenin-enhanced chemiluminescence. However, lucigenin has been recently criticized for its ability to redox cycle and its propensity to measure cellular reductase activity independent from O2*-. To perform a definitive characterization of VSMC oxidase activity, we used electron spin resonance trapping of O2*- with DEPMPO. We confirmed that the main source of O2*- from VSMC membranes is an NAD(P)H oxidase and that the O2*- formation from mitochondria, xanthine oxidase, arachidonate-derived enzymes, and nitric oxide synthases in VSMC membranes was minor. The VSMC NAD(P)H oxidase(s) are able to produce more O2*- when NADPH is used as the substrate compared to NADH (the maximal NADPH signal is 2.4- +/- 0.4-fold higher than the NADH signal). The two substrates had similar EC(50)'s ( approximately 10-50 microM). Stimulation with angiotensin II and platelet-derived growth factor also predominantly increased the NADPH-driven signal (101 +/- 8% and 83 +/- 1% increase above control, respectively), with less of an effect on NADH-dependent O2*- (17 +/- 3% and 36 +/- 5% increase, respectively). Moreover, incubation of the cells with diphenylene iodonium inhibited predominantly NADPH-stimulated O2*-. In conclusion, electron spin resonance characterization of VSMC oxidase activity supports a major role for an NAD(P)H oxidase in O2*- production in VSMCs, and provides new evidence concerning the substrate dependency and agonist-stimulated activity of this key enzyme.
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PMID:Electron spin resonance characterization of the NAD(P)H oxidase in vascular smooth muscle cells. 1129 58

We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.
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PMID:The role of metals in site-specific DNA damage with reference to carcinogenesis. 1197 84

Ubiquinone is inhomogenously distributed in subcellular biomembranes. Apart from mitochondria where ubiquinone was demonstrated to exert bioenergetic and pathophysiological functions, unusually high levels of ubiquinone were also reported to exist in Golgi vesicles and lysosomes. In lysosomes the interior differs from other organelles by the low pH-value, which is important not only to arrest proteins but also to ensure optimal activity of hydrolytic enzymes. Since redox-cycling of ubiquinone is associated with the acceptance and release of protons, we assumed that ubiquinone is a part of a redox chain contributing to unilateral proton distribution. A similar function of ubiquinone was earlier suggested by Crane to operate in Golgi vesicles. Support for the involvement of ubiquinone in a presumed couple of redox-carriers came from our observation that almost 70% of total lysosomal ubiquinone was in the divalently reduced state. Further reduction was seen in the presence of external NADH. Analysis of the components involved in the transfer of reducing equivalents from cytosolic NADH to ubiquinone revealed the existence of a FAD-containing NADH-dehydrogenase. The latter was found to reduce ubiquinone by means of a b-type cytochrome. Proton translocation into the interior was linked to the activity of the novel lysosomal redox chain. Oxygen was found to be the terminal electron acceptor, thereby also regulating acidification of the lysosomal matrix. In contrast to mitochondrial respiration, oxygen was only trivalently reduced, giving rise to the release of HO*-radicals. The role of this novel proton-pumping redox chain and the significance of the associated ROS formation has to be elucidated.
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PMID:The bifunctional activity of ubiquinone in lysosomal membranes. 1201 31

This study investigated the effects of the peripheral vasodilator hydralazine on in vitro generation of reactive species of oxygen (ROS), nitrogen (RNS) and prostaglandin (PG) biosynthesis in elicited murine peritoneal macrophages, and on the gene expression and protein synthesis of two key enzymes in the inflammatory process, inducible NO(*) synthase (NOS-2) and inducible cyclooxygenase 2 (COX-2). Hydralazine at 0.1-10 mM inhibited both extracellular and intracellular ROS production by inflammatory macrophages, by a ROS-scavenging mechanism probably affecting superoxide radical (O(2)(*-))-generation by xanthine oxidase (XO) and nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase. Hydralazine at 0.1-10 mM significantly reduced NO(*) generation, and this effect was attributable to an inhibition of NOS-2 gene expression and protein synthesis. At 1-10 mM, hydralazine also effectively blocked COX-2 gene expression which perfectly correlated with a reduction of protein levels and PGE(2) synthesis. These data suggest that hydralazine, at the concentrations tested, show antioxidant properties and strongly attenuates the macrophage activation.
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PMID:Antioxidant activity and inhibitory effects of hydralazine on inducible NOS/COX-2 gene and protein expression in rat peritoneal macrophages. 1499 8

Pyocyanin (1-hydroxy-N-methylphenazine) is a cytotoxic pigment secreted by the bacterial species Pseudomonas aeruginosa, which frequently infects the lungs of immunosuppressed patients as well as those with cystic fibrosis. Pyocyanin toxicity results presumably from the ability of the compound to undergo reduction by NAD(P)H and subsequent generation of superoxide and H2O2 directly in the lungs. We report that in the presence of peroxidase mimics, microperoxidase 11, or hemin, pyocyanin undergoes oxidation by H2O2, as evidenced by loss of the pigment's characteristic absorption spectrum and by EPR detection of a free radical metabolite. The oxidation of pyocyanin is irreversible, suggesting an extensive modification of the pigment's phenazine chromophore. Oxidation of pyocyanin was observed also when exogenous H2O2 was replaced by a H2O2-generating system consisting of NADH and the pigment itself. That the oxidation involves the phenolate group of pyocyanin was verified by the observation that a related pigment, phenazine methosulfate, which is devoid of this group, does not undergo oxidation by microperoxidase 11/H2O2. In contrast to intact pyocyanin, oxidized pyocyanin was less efficient in NADH oxidation and stimulation of interleukin-8 release by human alveolar epithelial A549 cells in vitro, suggesting that oxidation of pyocyanin leads to its inactivation. This study demonstrates that pyocyanin may play a dual role in biological systems, first as an oxidant and ROS generator, and second as a substrate for peroxidases, contributing to H2O2 removal. This latter property may cause pyocyanin degradation and inactivation, which may be of considerable biomedical interest.
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PMID:Oxidation of pyocyanin, a cytotoxic product from Pseudomonas aeruginosa, by microperoxidase 11 and hydrogen peroxide. 1513 82

During the post-hypoxic period, symptoms of oxidative stress and activation of enzymatic and non-enzymatic antioxidant systems were observed in several plant tissues. In the roots, mitochondrial respiratory chain is the main source of ROS. Superoxide anion radical is formed in the mitochondrial electron-transport chain at the level of Complexes I and III. The purpose of this work was to estimate superoxide anion production by the mitochondria isolated after a period of hypoxic treatment. Seedlings of barley (Hordeum vulgare L.) were grown on a nutrient medium flushed for 5d with air (control) or nitrogen (hypoxia) and then transferred for 24h to aerated medium (post-hypoxia). Production of superoxide anion by the mitochondria was measured by SOD-inhibitable oxidation of adrenaline to adrenochrome with NADH as a respiratory substrate. Hypoxic treatment increased mitochondrial activity but decreased mitochondrial superoxide anion appearance outside the mitochondrial membrane as compared to the mitochondria isolated from the roots continuously grown on aerated medium. The result of lower superoxide anion determination is attributed to increased antioxidants concentration during hypoxia. This was confirmed by inhibition of O2- production by exogenous GSH and stimulation by addition of 1-chloro-2,4-dinitrobenzene (CDNB), which depleted endogenous mitochondrial GSH.
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PMID:Factors affecting determination of superoxide anion generated by mitochondria from barley roots after anaerobiosis. 1565 4

Bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I) catalyzed NADH- and ubiquinone-1-dependent oxygen (O2) turnover to hydrogen peroxide that was stimulated by piericidin A and superoxide dismutase (SOD), but was insensitive to antimycin A, myxothiazol, and potassium cyanide. The extent of O2 consumption as a function of ubiquinone-1 did not correlate with piericidin A-sensitive rates of ubiquinone reduction. Decylubiquinone did not stimulate O2 consumption, but did initiate an SOD-sensitive cytochrome c reduction when complex I was isolated away from ubiquinol-cytochrome c oxidoreductase. Rates and extent of O2 turnover (ROS production) and ubiquinone reduction were higher than previously reported for submitochondrial particles (SMP) and isolated complex I. This ROS production was shown to co-isolate with complex I flavin.
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PMID:NADH-Ubiquinone oxidoreductase: substrate-dependent oxygen turnover to superoxide anion as a function of flavin mononucleotide. 1612 Mar 48

Ubiquinone is inhomogenously distributed in subcellular biomembranes. Apart from mitochondria, where ubiquinone has bioenergetic and pathophysiological functions, unusually high levels of ubiquinone have also been reported in Golgi vesicles and lysosomes. In lysosomes, the interior differs from other organelles in its low pH value which is important to ensure optimal activity of hydrolytic enzymes. Since redox-cycling of ubiquinone is associated with the acceptance and release of protons, we assumed that ubiquinone is part of a redox chain contributing to unilateral proton distribution. A similar function of ubiquinone was earlier suggested by Crane to operate in Golgi vesicles. Support for the involvement of ubiquinone in a presumed couple of redox carriers came from our observation that almost 70% of total lysosomal ubiquinone was in the divalently reduced state. Further reduction was seen in the presence of external NADH. Analysis of the components involved in the transfer of reducing equivalents from cytosolic NADH to ubiquinone revealed the existence of an FAD-containing NADH dehydrogenase. The latter was found to reduce ubiquinone by means of a b-type cytochrome. Proton translocation into the interior was linked to the activity of the novel lysosomal redox chain. Oxygen was found to be the terminal electron acceptor, thereby also regulating acidification of the lysosomal matrix. In contrast to mitochondrial respiration, oxygen was only trivalently reduced giving rise to the release of HO radicals. The role of this novel proton-pumping redox chain and the significance of the associated ROS formation has to be elucidated.
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PMID:Lysosomal ROS formation. 1625 87


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