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)

Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Three metabolic pathways of ethanol have been described in the human body so far. They involve the following enzymes: alcohol dehydrogenase, microsomal ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals which affect the antioxidant system. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, which results in the production of superoxide. Lipid peroxidation and superoxide production correlate with the amount of cytochrome P450 2E1. MEOS aggravates the oxidative stress directly as well as indirectly by impairing the defense systems. Hydroxyethyl radicals are probably involved in the alkylation of hepatic proteins. Nitric oxide (NO) is one of the key factors contributing to the vessel wall homeostasis, an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metabolites--nitrites and nitrates--were increased in alcoholics (34.3 +/- 2.6 vs. 22.7 +/- 1.2 micromol/l, p < 0.001). High NO concentration could be discussed for its excitotoxicity and may be linked to cytotoxicity in neurons, glia and myelin. Formation of NO has been linked to an increased preference for and tolerance to alcohol in recent studies. Increased NO biosynthesis also via inducible NO synthase (NOS, chronic stimulation) may contribute to platelet and endothelial dysfunctions. Comparison of chronically ethanol-fed rats and controls demonstrates that exposure to ethanol causes a decrease in NADPH diaphorase activity (neuronal NOS) in neurons and fibers of the cerebellar cortex and superior colliculus (stratum griseum superficiale and intermedium) in rats. These changes in the highly organized structure contribute to the motor disturbances, which are associated with alcohol abuse. Antiphospholipid antibodies (APA) in alcoholic patients seem to reflect membrane lesions, impairment of immunological reactivity, liver disease progression, and they correlate significantly with the disease severity. The low-density lipoprotein (LDL) oxidation is supposed to be one of the most important pathogenic mechanisms of atherogenesis, and antibodies against oxidized LDL (oxLDL) are some kind of epiphenomenon of this process. We studied IgG oxLDL and four APA (anticardiolipin, antiphosphatidylserine, antiphosphatidylethanolamine and antiphosphatidylcholine antibodies). The IgG oxLDL (406.4 +/- 52.5 vs. 499.9 +/- 52.5 mU/ml) was not affected in alcoholic patients, but oxLDL was higher (71.6 +/- 4.1 vs. 44.2 +/- 2.7 micromol/l, p < 0.001). The prevalence of studied APA in alcoholics with mildly affected liver function was higher than in controls, but not significantly. On the contrary, changes of autoantibodies to IgG oxLDL revealed a wide range of IgG oxLDL titers in a healthy population. These parameters do not appear to be very promising for the evaluation of the risk of atherosclerosis. Free radicals increase the oxidative modification of LDL. This is one of the most important mechanisms, which increases cardiovascular risk in chronic alcoholic patients. Important enzymatic antioxidant systems - superoxide dismutase and glutathione peroxidase - are decreased in alcoholics. We did not find any changes of serum retinol and tocopherol concentrations in alcoholics, and blood and plasma selenium and copper levels were unchanged as well. Only the zinc concentration was decreased in plasma. It could be related to the impairment of the immune system in alcoholics. Measurement of these parameters in blood compartments does not seem to indicate a possible organ, e.g. liver deficiency.
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PMID:Oxidative stress, metabolism of ethanol and alcohol-related diseases. 1117 77

The hypothesis that the impaired endothelial function seen in streptozotocin (STZ)-induced diabetic rats may result from an increased nitric oxide (NO) metabolism was tested. Acetylcholine (ACh) increased the nitrite NO(2-) and nitrate (NO(3-)) levels in the perfusates from both control and diabetic aortic strips, although the level of NO(2-) was significantly lower in diabetic rats while the NO(3-) level was significantly higher. Both effects (decrease in NO(2-) and increase in NO(3-)) were ameliorated by chronic administration of insulin to diabetic rats but NOx (NO(2-) plus NO(3-)) was increased. The expression of endothelial nitric oxide synthase (eNOS) was significantly increased by chronic administration of insulin to diabetic rats. A decrease in NO(2-) and an increase in NO(3-) occurred following treatment of control aortae with hypoxanthine/xanthine oxidase. Incubating diabetic aortic strips with superoxide dismutase (SOD) normalized the production of both NO(2-) and NO(3-). Both the basal and the ACh-stimulated production of O(2)(-) were significantly higher in diabetic rats than in controls. These results demonstrate that the ACh-induced relaxation of aortic strips was significantly impaired in diabetic rats and that this impairment may be due to an abnormal oxidative metabolism of NO, rather than to a decrease in NOS mRNA and NO production.
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PMID:Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortae from established STZ-induced diabetic rats. 1125 1

We examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, on extracellular potassium ion concentration ([K+]o) and induced hydroxyl free radical (.OH) generation by an in vivo microdialysis technique. A flexibly mounted microdialysis technique was used to detect the generation of .OH in in-vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and tissue was perfused with Ringer's solution through the microdialysis probe at a rate of 1.0 microl/min. To measure the level of .OH, sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). Induction of high-concentration [K+]o (20, 70 and 140 mM) significantly increased formation of .OH trapped as 2,3-DHBA in a concentration-dependent manner. However, the application of L-NAME (50 mg/kg, i.v.) and allopurinol, a xanthine oxidase inhibitor, abolished the [K+]o depolarization-induced .OH generation. Tyramine (1.0 mM) increased the level of 2,3-DHBA. However, the application of L-NAME did not change the level of 2,3-DHBA. On the other hand, pretreatment with allopurinol (10 mg/kg, i.v.) abolished the KCl- or tyramine-induced .OH generation. Moreover, when iron (II) was administered to [K+]o (70 mM)-pretreated animals, there was a marked increased in the level of 2,3-DHBA. However, the application of L-NAME was not related to a Fenton-type reaction via [K+]o depolarization-induced .OH generation. To examine the effect of L-NAME on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion by left anterior descending coronary artery branch (LAD). When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, L-NAME attenuated .OH generation by ischemic/reperfused rat heart. These results suggest that NOS inhibition is associated with a cardioprotective effect due to the suppression of [K+]o depolarization-induced .OH generation.
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PMID:Nitric oxide induces hydroxyl radical generation in rat hearts via depolarization-induced nitric oxide synthase activation. 1148 40

We assessed the distribution and expression of inducible nitric oxide synthase (i-NOS), endothelial nitric oxide synthase (e-NOS), and xanthine oxidase (XAO) in usual interstitial pneumonia, desquamative interstitial pneumonia, and granulomatous diseases. The material consisted of biopsy specimens from 5 healthy subjects (nonsmokers), 9 patients with usual interstitial pneumonia, 11 with desquamative interstitial pneumonia, 14 with sarcoidosis, and 8 with extrinsic allergic alveolitis. i-NOS was expressed intensively in inflammatory but not infibrotic lesions. It was expressed most prominently in alveolar macrophages and alveolar epithelium of all disorders and in the granulomas of sarcoidosis and extrinsic allergic alveolitis. In contrast with i-NOS, e-NOS was expressed prominently in control lung tissue samples but also in granulomas of sarcoidosis and extrinsic allergic alveolitis. Reverse transcription-polymerase chain reaction performed on bronchoalveolar lavage fluid samples from patients with sarcoidosis or usual interstitial pneumonia andfrom healthy subjects indicated positivity for XAO, but immunohistochemical analysis in samples from healthy lung and all parenchymal lung disorders showed no immunoreactivity for XAO. i-NOS has an important role in the pathogenesis of interstitial lung diseases, being up-regulated during the inflammatory but not during the fibrotic disease stage.
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PMID:Inducible nitric oxide synthase, but not xanthine oxidase, is highly expressed in interstitial pneumonias and granulomatous diseases of human lung. 1178 18

Besides NO, neuronal NO synthase (nNOS) also produces superoxide (O(2)(-.) at low levels of L-arginine. Recently, heat shock protein 90 (hsp90) was shown to facilitate NO synthesis from eNOS and nNOS. However, the effect of hsp90 on the O(2)(-.) generation from NOS has not been determined yet. The interrelationship between its effects on O(2)(-.) and NO generation from NOS is also unclear. Therefore, we performed electron paramagnetic resonance measurements of O(2)(-.) generation from nNOS to study the effect of hsp90. Purified rat nNOS generated strong O(2)(-.) signals in the absence of L-arginine. In contrast to its effect on NO synthesis, hsp90 dose-dependently inhibited O(2)(-.) generation from nNOS with an IC(50) of 658 nM. This inhibition was not due to O(2)(-.) scavenging because hsp90 did not affect the O(2)(-.) generated by xanthine oxidase. At lower levels of L-arginine where marked O(2)(-.) generation occurred, hsp90 caused a more dramatic enhancement of NO synthesis from nNOS as compared to that under normal L-arginine. Significant O(2)(-.) production was detected from nNOS even at intracellular levels of L-arginine. Adding hsp90 prevented this O(2)(-.) production, leading to enhanced nNOS activity. Thus, these results demonstrated that hsp90 directly inhibited O(2)(-.) generation from nNOS. Inhibition of O(2)(-.) generation may be an important mechanism by which hsp90 enhances NO synthesis from NOS.
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PMID:Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation. 1218 46

Nitric oxide degradation linked to endothelial dysfunction plays a central role in cardiovascular diseases. Superoxide producing enzymes such as NADPH oxidase and xanthine oxidase are responsible for NO degradation as they generate a variety of reactive oxygen species (ROS). Moreover, superoxide is rapidly degraded by superoxide dismutase to produce hydrogen peroxide leading to the uncoupling of NO synthase and production of increased amount of superoxide. Angiotensin II is an important stimulus of NADPH oxidase. Through its AT(1) receptor, Ang II stimulates the long-term increase of several membrane component of NADPH oxidase such as P(22) phox or nox-1 and causes an increased activity of NADPH oxidase with inactivation of NO leading to impaired endothelium-dependent vasorelaxation, vascular smooth muscle cell hypertrophy, proliferation and migration, extracellular matrix formation, thrombosis, cellular infiltration and inflammatory reaction. Several preclinical and clinical studies have now confirmed the involvement of the AT(1) receptor in endothelial dysfunction. It is proposed that the AT(2) receptor counterbalances the deleterious effect of the Ang II-induced AT(1) receptor stimulation through bradykinin and NOS stimulation. This mechanism could be especially relevant in pathological cases when the NADPH oxidase activity is blocked with an AT(1) receptor antagonist.
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PMID:Angiotensin II and nitric oxide interaction. 1237 20

In addition to nitric oxide (NO) generation from specific NO synthases, NO is also formed during anoxia from nitrite reduction, and xanthine oxidase (XO) catalyzes this process. While in tissues and blood high nitrate levels are present, questions remain regarding whether nitrate is also a source of NO and if XO-mediated nitrate reduction can be an important source of NO in biological systems. To characterize the kinetics, magnitude, and mechanism of XO-mediated nitrate reduction under anaerobic conditions, EPR, chemiluminescence NO-analyzer, and NO-electrode studies were performed. Typical XO reducing substrates, xanthine, NADH, and 2,3-dihydroxybenz-aldehyde, triggered nitrate reduction to nitrite and NO. The rate of nitrite production followed Michaelis-Menten kinetics, while NO generation rates increased linearly following the accumulation of nitrite, suggesting stepwise-reduction of nitrate to nitrite then to NO. The molybdenum-binding XO inhibitor, oxypurinol, inhibited both nitrite and NO production, indicating that nitrate reduction occurs at the molybdenum site. At higher xanthine concentrations, partial inhibition was seen, suggesting formation of a substrate-bound reduced enzyme complex with xanthine blocking the molybdenum site. The pH dependence of nitrite and NO formation indicate that XO-mediated nitrate reduction occurs via an acid-catalyzed mechanism. With conditions occurring during ischemia, myocardial xanthine oxidoreductase and nitrate levels were determined to generate up to 20 microM nitrite within 10-20 min that can be further reduced to NO with rates comparable to those of maximally activated NOS. Thus, XOR catalyzed nitrate reduction to nitrite and NO occurs and can be an important source of NO production in ischemic tissues.
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PMID:Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. 1254 37

Matrix metalloproteinases (MMPs) are responsible for the remodelling of the uterine extracellular matrix during embryo implantation. Nitric oxide (NO) production is increased at the time when implantation begins. Abnormal tissue levels of MMPs are present in diabetes; elevated NO levels in tissues and an increased oxidative stress are also found. The present work evaluates the uterine MMP2 activity and levels during embryo implantation, as well as the influence of nitridergic compounds and reactive oxygen species (ROS) on the MMP2 enzymatic activity in a model of neonatal streptozotocin-induced diabetic rat. Metalloproteinase 2 activity and levels are increased in diabetic tissues compared with controls (P < 0.05 and P < 0.002 respectively). The uterine enzymatic activity in diabetic animals decreases in the presence of the NOS inhibitor NG-nitro-L-arginine methyl ester (P < 0.01) and is enhanced (P < 0.005) when a generating ROS system (xanthine/xanthine oxidase) is added to the incubating medium. It was also found that uterine superoxide dismutase activity is higher in diabetic rats than in control rats on the day of implantation (P < 0.001), suggesting a compensatory antioxidant ability. In conclusion, the results show that the uterine MMP2 activity, which is higher in diabetic animals than in control animals, is modulated positively by NO and ROS during embryo implantation in a model of streptozotocin-induced diabetic rats.
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PMID:Metalloproteinase 2 activity and modulation in uterus from neonatal streptozotocin-induced diabetic rats during embryo implantation. 1261 92

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

In hemorrhagic shock, local hypoxia is present and followed by reoxygenation during the therapeutic process. In endothelium, reactive oxygen species (ROS) have been identified as a cause of inflammatory reactions and tissular lesions in ischemic territory during reoxygenation. This study was designed to identify the enzymatic mechanisms of ROS formation during reoxygenation after hypoxia. Because severe shock, in vivo, can affect both O2 and nutriments, we combined hypoxia at a level close to that found in terminal vessels during shock, with glucose depletion, which induces a relevant additional stress. Human umbilical vein endothelial cells (HUVEC) underwent 2 h of hypoxia (Po2 approximately 20 mmHg) without glucose and 1 h of reoxygenation (Po2 approximately 120 mmHg) with glucose. ROS production was measured by the fluorescent marker 2',7'-dichlorodihydrofluorescein diacetate, and cell death by propidium iodide. After 1 h of reoxygenation, fluorescence had risen by 143 +/- 17%. Cell death was equal to 8.6 +/- 2.4%. Antimycin A and stigmatellin, which inhibits the type III mitochondrial respiratory chain complex, reduced ROS production to values of 61 +/- 10 and 59 +/- 7%, respectively, but inhibitors of other chain complexes did not affect it. In addition, the increase in fluorescence was not affected by inhibition of NADPH oxidase, xanthine oxidase, NOS, cyclooxygenase, cytochrome P-450 monooxygenase, or monoamine oxidase. We did not observe any increase in cell death. These results show that, in HUVEC, mitochondria are responsible for ROS production after hypoxia and reoxygenation and suggest that a ROS release site is activated in the cytochrome b of the type III respiratory chain complex.
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PMID:Reoxygenation after hypoxia and glucose depletion causes reactive oxygen species production by mitochondria in HUVEC. 1520 81


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