Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chondrocytes stimulated with IL-1 produce high levels of nitric oxide (NO), which inhibits proliferation induced by transforming growth factor-beta or serum. This study analyzes the role of NO and IL-1 in the induction of chondrocyte cell death. NO generated from sodium nitroprusside induced apoptosis in cultured chondrocytes as demonstrated by electron microscopy, 4',6-dianidino-2-phenylindole dihydrochloride staining, FACS analysis, and histochemical detection of DNA fragmentation. Similar results were obtained with two other NO donors, 3-morpholinosynonimide-hydrochloride and s-nitroso-N-acetyl-D-L-penicillamine. In contrast, oxygen radicals generated by hypoxanthine/xanthine oxidase caused necrosis but did not induce chondrocyte apoptosis. To analyze whether endogenously generated NO induces apoptosis, chondrocytes were stimulated with IL-1, but there was no evidence for apoptotic changes. Combinations of NO inducers such as IL-1, lipopolysaccharide, tumor necrosis factor, and interferon-gamma also failed to trigger apoptosis. IL-1-stimulated chondrocytes are known to produce oxygen radicals that react with NO to form products that can induce cell death in other systems. We thus tested IL-1 in combination with the oxygen radical scavengers N-acetyl cysteine, dimethyl sulfoxide, or 5,5'-dimetylpyrroline 1-oxide. Under these conditions IL-1 was able to induce apoptosis, which was inhibited in a dose-dependent manner by the NO synthase inhibitor N-monomethyl L-arginine. Conversely, endogenous oxygen radicals induced by inflammatory mediators caused necrosis under conditions in which the simultaneous production of NO was reduced. These results suggest that NO, but not oxygen radicals, is the primary inducer of apoptosis in human articular chondrocytes.
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PMID:Chondrocyte apoptosis induced by nitric oxide. 785 40

This study examined the effects of inhibiting Cu/Zn superoxide dismutase with diethyldithiocarbamate (DETCA) on the ability of superoxide generating agents such as pyrogallol, hypoxanthine/xanthine oxidase and LY 83583, to influence NANC relaxation of strips of bovine retractor penis (BRP) muscle. Although pyrogallol (100 microM) and hypoxanthine (0.3 mM)/xanthine oxidase (64 mU ml-1) had little effect on NANC relaxation in control strips, both induced almost complete inhibition following treatment with DETCA (3 mM) for 1 h. Inhibition was due to the actions of superoxide anion since it was blocked by the addition of exogenous superoxide dismutase (250 U ml-1). LY 83583 (0.1-30 microM) produced a concentration-dependent inhibition of NANC relaxation even in control strips and this too was blocked by exogenous superoxide dismutase, but sensitivity to inhibition was enhanced 10-fold following treatment with DETCA. The data suggest that under normal circumstances the NANC neurotransmitter is protected by high levels of tissue superoxide dismutase, and inhibition of this enzyme increases its susceptibility to destruction by superoxide anions. An important impediment to accepting free nitric oxide as the NANC neurotransmitter in the BRP on the basis that superoxide anion-generating agents inhibit the actions of authentic nitric oxide but not those of NANC nerve stimulation has thus been removed.
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PMID:NANC neurotransmission in the bovine retractor penis muscle is blocked by superoxide anion following inhibition of superoxide dismutase with diethyldithiocarbamate. 787 Feb 86

Superoxide (O2-.), nitric oxide (.NO), and their reaction product peroxynitrite (ONOO-) have all been shown to independently exert toxic target molecule reactions. Because these reactive species are often generated in excess during diverse inflammatory and other pathologic circumstances, we assessed the influence of .NO on membrane lipid peroxidation induced by O2-., H2O2, and .OH derived from xanthine oxidase (XO) and by ONOO-. Experimental conditions in lipid oxidation systems were adjusted to yield different rates of delivery of .NO, relative to rates of O2-. and H2O2 generation, by infusion of either .NO or via .NO released from S-nitroso-N-acetylpenicillamine or S-nitrosoglutathione. Peroxidation of phosphatidylcholine liposomes was assessed by formation of thiobarbituric acid-reactive products and by liquid chromatography-mass spectrometry. Liposomes exposed to XO-derived reactive species in the presence of .NO exhibited both stimulation and inhibition of lipid peroxidation, depending on the ratio of the rates of reactive oxygen species production and .NO introduction into reaction systems. Nitric oxide alone did not induce lipid peroxidation. Linolenic acid emulsions peroxidized by XO-derived reactive species showed similar dose-dependent regulation of lipid peroxidation by .NO. Mass spectral analysis of oxidation products showed formation of nitrito-, nitro-, nitrosoperoxo-, and/or nitrated lipid oxidation adducts, demonstrating that .NO serves as a potent terminator of radical chain propagation reactions. Electron spin resonance (ESR) analysis of incubation mixtures provided no evidence for formation of paramagnetic iron-lipid-nitric oxide complexes in reaction systems. Peroxynitrite-dependent lipid peroxidation, which predominantly occurs by metal-independent mechanisms, was also inhibited by .NO. Peroxynitrite-mediated benzoate hydroxylation was partially inhibited by .NO, inferring reaction between .NO and ONOOH. It is concluded that .NO can both stimulate O2-./H2O2/.OH-induced lipid oxidation and mediate oxidant-protective reactions in membranes at higher rates of .NO production, with the prooxidant versus antioxidant outcome critically dependent on relative concentrations of individual reactive species. Prooxidant reactions of .NO will occur after O2-. reaction with .NO to yield potent secondary oxidants such as ONOO- and the antioxidant effects of .NO a consequence of direct reaction with alkoxyl and peroxyl radical intermediates during lipid peroxidation, thus terminating lipid radical chain propagation reactions.
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PMID:Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. 792 18

The conditions under which nitric oxide (.NO) may modulate or promote lung injury have not been identified. We hypothesized that .NO-induced injury results from peroxynitrite, formed by the reaction of .NO with superoxide. The simultaneous generation of .NO and superoxide by 3-morpholinosydnonimine (SIN-1, 0.1-2 mM) resulted in oxidation of dihydrorhodamine, a marker of peroxynitrite production, and a dose-dependent decrease in the ability of SP-A to enhance lipid aggregation. Western blot analysis of SIN-1 exposed SP-A samples, overlaid with a polyclonal antibody against nitrotyrosine, were consistent with nitration of SP-A tyrosine residues. Superoxide dismutase (100 U/ml), L-cysteine (5 mM), xanthine oxidase (10 mU/ml) and xanthine (500 microM), or urate (100 microM) prevented the SIN-1-induced dihydrorhodamine oxidation and injury to SP-A. .NO alone, generated by S-nitroso-N-acetylpenicillamine plus 100 microM L-cysteine, or superoxide and hydrogen peroxide, generated by pterin and xanthine oxidase in the absence of iron, did not damage SP-A or oxidize dihydrorhodamine. We concluded that peroxynitrite, but not .NO or superoxide and hydrogen peroxide, in concentrations likely to be encountered in vivo, caused nitrotyrosine formation and decreased the ability of SP-A to aggregate lipids.
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PMID:Concurrent generation of nitric oxide and superoxide damages surfactant protein A. 794 50

Inhaled nitric oxide (NO) decreases pulmonary arterial pressure (Ppa) and improves oxygenation in the adult respiratory distress syndrome. Endogenous NO can modulate the development of acute tissue injury. We investigated the effects of inhaled NO and of inhibition of endogenous NO synthase in oxidant-induced acute lung injury in the isolated buffer-perfused rabbit lung. A rapid (45 min) and a more gradual (3 h) model of oxidant-induced acute lung injury were developed using the production of superoxide free radicals from the reaction of purine with low and high doses of xanthine oxidase, respectively. The effects of rapid injury included increases in Ppa, precapillary pulmonary vascular resistance, capillary filtration coefficient (Kfc), and lung weight. In the gradual-injury model, only lung weight and Kfc increased. Pretreatment with inhaled NO (90-120 ppm) prevented the rise in Ppa and precapillary pulmonary vascular resistance in the rapid-injury model and prevented elevation of Kfc in the gradual-injury model. Pretreatment with an inhibitor of endogenous NO synthase (NG-nitro-L-arginine methyl ester) resulted in increased pulmonary capillary pressure and postcapillary pulmonary vascular resistance in the rapid-injury model and increased peak Ppa, pulmonary capillary pressure, and pulmonary vascular resistance in the gradual-injury model. These data suggest that in oxidant-induced acute lung injury 1) inhaled NO may attenuate increases in capillary permeability and 2) endogenous NO may function as a modulator of pulmonary vascular tone without affecting capillary permeability.
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PMID:Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. 800 78

Recent findings have suggested that nitric oxide (NO) reacts with superoxide anion (O2-) to form a potential oxidant, peroxynitrite anion, which then decays to hydroxyl radical and nitrogen dioxide. In order to ascertain this hypothesis in human polymorphonuclear leukocytes (PMNs) which release both NO and O2-, we studied oxidation of L-cysteine (CYS) and bovine serum albumin (BSA) by PMNs and cell-free O2(-)-generating system of hypoxanthine (HX)-xanthine oxidase (XO) reaction. Oxidation of CYS by HX-XO was equally inhibited by superoxide dismutase (SOD) and catalase (CAT), and that of BSA by HX-XO was inhibited weakly by SOD and strongly by CAT. PMNs stimulated with phorbol 12-myristate 13-acetate increased the oxidation rates of CYS and BSA, and they were inhibited by SOD and CAT almost in a similar way to those by HX-XO. The NO synthase inhibitor, NG-monomethyl-L-arginine (NMMA), was confirmed to have an inhibitory effect on the inhibition of platelet aggregation by PMNs, and L-arginine (ARG) reversed this effect. However, pretreatment of PMNs with either of NMMA, or ARG, or both did not change the oxidation rates of CYS and BSA. We could not confirm the hypothesis at least in human PMNs that interaction of NO with O2- forms powerful oxidants to sulfhydryls of CYS and BSA. These results suggest that oxidation of sulfhydryls of CYS and BSA by PMNs is primarily dependent on reactive oxygen species, and is not modified by NO production.
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PMID:Nitric oxide does not contribute to superoxide-mediated sulfhydryl oxidation in human polymorphonuclear leukocytes. 803 64

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.
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PMID:[Possible significance of free oxygen radicals for reperfusion injury]. 815 62

There is considerable evidence suggesting that reactive oxygen species (ROS) are implicated in the pathogenesis of ischemic, toxic, and immunologically-mediated renal injury. In experimental renal ischemia, ROS sources include the electron transport chain, oxidant enzymes (xanthine oxidase), phagocytes, and auto-oxidation of epinephrine. ROS cause lipid peroxidation of cell and organelle membranes and, hence, disruption of the structural integrity and capacity for cell transport and energy production, especially in the proximal tubule segment. In experimental immune glomerulonephritis, ROS are generated by both infiltrating blood-borne cells (polymorphonuclear leukocytes and monocytes) and resident glomerular cells, mainly mesangial cells. Their formation results in morphologic lesions and in modifications of glomerular permeability to proteins through activation of proteases and reduction of proteoglycan synthesis. Additionally, they promote a reduction in glomerular blood flow and glomerular filtration rate through liberation of vasoconstrictory bioactive lipids (prostaglandins, thromboxane, and platelet activating factor) and, possibly, inactivation of relaxing nitric oxide. Further studies are needed to address the role of ROS in human glomerular diseases.
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PMID:Involvement of reactive oxygen species in kidney damage. 822 Oct 27

Nitric oxide, NO, which is generated by various components of the immune system, has been presumed to be cytotoxic. However, NO has been proposed to be protective against cellular damage resulting during ischemia reperfusion. Along with NO there is often concomitant formation of superoxide/hydrogen peroxide, and hence a synergistic relationship between the cytotoxic effects of nitric oxide and these active oxygen species is frequently assumed. To study more carefully the potential synergy between NO and active oxygen species in mammalian cell cytotoxicity, we utilized either hypoxanthine/xanthine cell cytotoxicity, we utilized either hypoxanthine/xanthine oxidase (a system that generates superoxide/hydrogen peroxide) or hydrogen peroxide itself. NO generation was accomplished by the use of a class of compounds known as "NONOates," which release NO at ambient temperatures without the requirement of enzyme activation or biotransformation. When Chinese hamster lung fibroblasts (V79 cells) were exposed to hypoxanthine/xanthine oxidase for various times or increasing amounts of hydrogen peroxide, there was a dose-dependent decrease in survival of V79 cells as measured by clonogenic assays. However, in the presence of NO released from (C2H5)2N[N(O)NO]-Na+ (DEA/NO), the cytotoxicity resulting from superoxide or hydrogen peroxide was markedly abrogated. Similarly, primary cultures of rat mesencephalic dopaminergic cells exposed either to hydrogen peroxide or to hypoxanthine/xanthine oxidase resulted in the degradation of the dopamine uptake and release mechanism. As was observed in the case of the V79 cells, the presence of NO essentially abrogated this peroxide-mediated cytotoxic effect on mesencephalic cells.
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PMID:Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. 823 17

Reperfusion after global cardiac ischemia may injure coronary artery endothelium and lead to vasospasm and thrombosis. Oxygen-derived radicals have been implicated as mediators of this process, but the precise mechanism of injury is unknown. We hypothesized that oxygen-derived radicals impair coronary endothelial production of nitric oxide, a potent endogenous vasodilator and inhibitor of platelet adhesion. To test this theory, we developed an in vitro model of reperfusion injury in which segments of epicardial canine coronary artery were suspended in organ chambers (physiologic salt solution, 37 degrees C, 95% oxygen and 5% carbon dioxide) and exposed to oxygen-derived radicals (generated by adding xanthine [10(-4) mol/L] and xanthine oxidase [100 mU/ml] to the bathing solution for 70 minutes). After exposure to oxygen-derived radicals, epicardial coronary artery smooth muscle exhibited normal contraction to potassium ions (20 mmol/L) and prostaglandin F2 (4 x 10(-6) mol/L); also, the rings relaxed normally on exposure to isoproterenol and sodium nitroprusside (10(-9) to 10(-4) mol/L) (n = 6). In contrast, endothelium-dependent vasodilatation to receptor-dependent agonists acetylcholine and adenosine diphosphate (10(-9) to 10(-4) mol/L) was impaired as compared with the reaction of control vessels not exposed to oxygen-derived radicals (n = 18, P < 0.001, and n = 10, P < 0.002, respectively). Importantly, receptor-independent, endothelium-dependent relaxation to the calcium ionophore A23187 was normal (n = 6). Further, endothelium-dependent vasodilatation to receptor-dependent agonist bradykinin (non-nitric oxide pathway) was normal after exposure to oxygen-derived radicals. This is the first study to demonstrate that oxygen-derived radicals selectively impair receptor-dependent nitric oxide production by the coronary endothelium. Diminished nitric oxide production is a likely mechanism of vasospasm and thrombosis after reperfusion of the ischemic heart.
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PMID:Oxygen radical-mediated vascular injury selectively inhibits receptor-dependent release of nitric oxide from canine coronary arteries. 830 70


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