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)

NADPH oxidase has been shown to play an important role in cardiovascular biology. The goal of the present study was to determine whether NADPH oxidase activity is important for endothelial cell growth and migration. In proliferation assays, growth factor- or serum-induced DNA synthesis in three different types of human endothelial cells was abrogated by inhibitors of NADPH oxidase, but not by inhibitors of xanthine oxidase or nitric oxide synthase. Moreover, vascular endothelial growth factor-induced migration of human endothelial cells was suppressed in the presence of NADPH oxidase inhibitors. These results support a potential role for NADPH oxidase in mediating angiogenesis.
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PMID:NADPH oxidase activity is required for endothelial cell proliferation and migration. 1111 13

This work tested the hypotheses that splanchnic oxidant generation is important in determining heat tolerance and that inappropriate.NO production may be involved in circulatory dysfunction with heat stroke. We monitored colonic temperature (T(c)), heart rate, mean arterial pressure, and splanchnic blood flow (SBF) in anesthetized rats exposed to 40 degrees C ambient temperature. Heating rate, heating time, and thermal load determined heat tolerance. Portal blood was regularly collected for determination of radical and endotoxin content. Elevating T(c) from 37 to 41.5 degrees C reduced SBF by 40% and stimulated production of the radicals ceruloplasmin, semiquinone, and penta-coordinate iron(II) nitrosyl-heme (heme-.NO). Portal endotoxin concentration rose from 28 to 59 pg/ml (P < 0.05). Compared with heat stress alone, heat plus treatment with the nitric oxide synthase (NOS) antagonist N(omega)-nitro-L-arginine methyl ester (L-NAME) dose dependently depressed heme-.NO production and increased ceruloplasmin and semiquinone levels. L-NAME also significantly reduced lowered SBF, increased portal endotoxin concentration, and reduced heat tolerance (P < 0.05). The NOS II and diamine oxidase antagonist aminoguanidine, the superoxide anion scavenger superoxide dismutase, and the xanthine oxidase antagonist allopurinol slowed the rates of heme-.NO production, decreased ceruloplasmin and semiquinone levels, and preserved SBF. However, only aminoguanidine and allopurinol improved heat tolerance, and only allpourinol eliminated the rise in portal endotoxin content. We conclude that hyperthermia stimulates xanthine oxidase production of reactive oxygen species that activate metals and limit heat tolerance by promoting circulatory and intestinal barrier dysfunction. In addition, intact NOS activity is required for normal stress tolerance, whereas overproduction of.NO may contribute to the nonprogrammed splanchnic dilation that precedes vascular collapse with heat stroke.
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PMID:Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. 1115 46

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

Endothelial function is abnormal in a variety of diseased states such as hypercholesterolemia and atherosclerosis. This may be secondary to decreased synthesis of nitric oxide (NO) and/or increased degradation of NO due to interaction with superoxide anions. More recent experimental observations demonstrate increased production of superoxide in hyperlipidemia, suggesting that endothelial dysfunction in these states is in part secondary to increased NO metabolism. Enzymes proposed to be involved in increased superoxide production may include xanthine oxidase, the NO synthase, and the NAD(P)H oxidase. Superoxide rapidly reacts with NO to form peroxynitrite (ONOO-), a highly reactive intermediate with cytotoxic properties. Despite experimental evidence for the oxidative stress concept in causing endothelial dysfunction, the results of recent randomized trials to test the influence of antioxidants on coronary event rates and prognosis in patients with coronary artery disease were very disappointing. In all of these studies the use of vitamins such as vitamin E failed to improve the prognosis. In contrast, treatment with angiotensin converting enzyme inhibitors or cholesterol- lowering drugs improved endothelial dysfunction, prevented the activation of superoxide-producing enzymes in cholesterol-fed animals, reduced coronary event rates, and improved prognosis in patients with coronary artery disease. Therefore, inhibition of superoxide production at the enzymatic level rather than symptomatic superoxide scavenging may be the better choice of treatment.
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PMID:Antioxidants and endothelial dysfunction in hyperlipidemia. 1117 9

Xanthine oxidase (XO)-catalyzed nitrite reduction with nitric oxide (NO) production has been reported to occur under anaerobic conditions, but questions remain regarding the magnitude, kinetics, and biological importance of this process. To characterize this mechanism and its quantitative importance in biological systems, electron paramagnetic resonance spectroscopy, chemiluminescence NO analyzer, and NO electrode studies were performed. The XO reducing substrates xanthine, NADH, and 2,3-dihydroxybenz-aldehyde triggered nitrite reduction to NO, and the molybdenum-binding XO inhibitor oxypurinol inhibited this NO formation, indicating that nitrite reduction occurs at the molybdenum site. However, at higher xanthine concentrations, partial inhibition was seen, suggesting the formation of a substrate-bound reduced enzyme complex with xanthine blocking the molybdenum site. Studies of the pH dependence of NO formation indicated that XO-mediated nitrite reduction occurred via an acid-catalyzed mechanism. Nitrite and reducing substrate concentrations were important regulators of XO-catalyzed NO generation. The substrate dependence of anaerobic XO-catalyzed nitrite reduction followed Michaelis-Menten kinetics, enabling prediction of the magnitude of NO formation and delineation of the quantitative importance of this process in biological systems. It was determined that under conditions occurring during no-flow ischemia, myocardial XO and nitrite levels are sufficient to generate NO levels comparable to those produced from nitric oxide synthase. Thus, XO-catalyzed nitrite reduction can be an important source of NO generation under ischemic conditions.
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PMID:Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. Evaluation of its role in nitric oxide generation in anoxic tissues. 1131 67

We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.
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PMID:Nitric oxide enhances MPP(+)-induced hydroxyl radical generation via depolarization activated nitric oxide synthase in rat striatum. 1138 16

Oxygen-derived free radicals have been implicated in the pathogenesis of myocardial injury. We therefore investigated the pathophysiology of myocardial injury induced in isolated rat hearts by perfusion with superoxide radical generated by reacting 2.5 mmol/l purine, 0.03 U/ml xanthine oxidase and 300 U/ml catalase. Perfusion with superoxide significantly (P<0.05) increased left ventricular end-diastolic pressure within 15 to 20 min. During the same time period, heart rate and left-ventricular developed pressure significantly declined to 44.6+/-8.2% and 31.0+/-4.9% of control, respectively. Superoxide perfusion also significantly increased production of prostaglandins, nitric oxide (detected as nitrites) and peroxynitrite (detected immunohistochemically as nitrotyrosine). N(G)-nitro-l-arginine (100 micromol/l), a nitric oxide synthase inhibitor, attenuated superoxide-induced generation of peroxynitrite, increased synthesis of prostacyclin, and partially blocked myocardial dysfunction, as did 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 micromol/l), a selective inhibitor of soluble guanylate cyclase, and ONO-3708 (10 micromol/l), a selective thromboxane A(2)receptor antagonist. In contrast, nitroglycerin (4 micromol/l) and sodium nitroprusside (1 micromol/l) each exacerbated the superoxide-induced myocardial dysfunction. These results suggest that nitric oxide and related reactive species contribute to myocardial injury induced by superoxide. Moreover, they suggest that oxidative stress can be delayed or inhibited by reducing levels of nitric oxide, by inhibiting soluble guanylate cyclase, and by blocking thromboxane/prostaglandin receptors.
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PMID:Prostaglandins and nitric oxide mediate superoxide-induced myocardial contractile dysfunction in isolated rat hearts. 1144 16

The activity of matrix metalloproteinase (MMP)-9 was evaluated in placental tissue from healthy subjects (controls) and from patients with gestational and pre-existing diabetes mellitus (GDM and PDM, respectively). Compared with controls, MMP-9 activity was greater in placental tissue from patients with PDM and lower in placental tissue from patients with GDM. The modulatory role of nitric oxide (NO) and reactive oxygen species (ROS) on MMP-9 activity in placental tissue was evaluated. In healthy placenta, NO synthase inhibitors diminished MMP-9 activity, whereas NO donors enhanced it. The addition of xanthine/xanthine oxidase or hydrogen peroxide to placental incubates enhanced MMP-9 activity, while the addition of superoxide dismutase (SOD) diminished it. In placental tissue from patients with PDM, MMP-9 activity was stimulated by NO and by ROS. In placental tissue from patients with PDM, concentrations of nitrates/nitrites and thiobarbituric acid-reactive substances (TBARS) were enhanced, whereas SOD activity was decreased, suggesting that elevated concentrations of NO and ROS may be related to the enhanced MMP-9 concentrations found in these tissues. In placenta from GDM patients, in which a diminished concentration of MMP-9 were detected, nitrate/nitrite concentrations were increased, but placental MMP-9 activity did not change in the presence of either NO donors or inhibitors. The activity of MMP-9 in placental tissue from patients with GDM was stimulated by ROS donor systems and was inhibited by the addition of SOD; however, TBARS and SOD concentrations were unchanged in these tissues compared with controls. These findings demonstrate that placental MMP-9 activity is modulated by NO and ROS and that, in diabetic pathology, NO and ROS may determine changes in MMP-9 activity, which are probably involved in the structural and functional abnormalities of diabetic placental tissue.
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PMID:Membrane-type matrix metalloproteinase-9 activity in placental tissue from patients with pre-existing and gestational diabetes mellitus. 1145 Oct 17

Neuronal nitric oxide-I is constitutively expressed in approximately 2% of cortical interneurons and is co-localized with gamma-amino butric acid, somatostatin or neuropeptide Y. These interneurons additionally express high amounts of glutamate receptors which mediate the glutamate-induced hyperexcitation following cerebral injury, under these conditions nitric oxide production increases contributing to a potentiation of oxidative stress. However, perilesional nitric oxide synthase-I containing neurons are known to be resistant to ischemic and excitotoxic injury. In vitro studies show that nitrosonium and nitroxyl ions inactivate N-methyl-D-aspartate receptors, resulting in neuroprotection. The question remains of how these cells are protected against their own high intracellular nitric oxide production after activation. In this study, we investigated immunocytochemically nitric oxide synthase-I containing cortical neurons in rats after unilateral, cortical photothrombosis. In this model of focal ischemia, perilesional, constitutively nitric oxide synthase-I containing neurons survived and co-expressed antioxidative enzymes, such as manganese- and copper-zinc-dependent superoxide dismutases, heme oxygenase-2 and cytosolic glutathione peroxidase. This enhanced antioxidant expression was accompanied by a strong perinuclear presence of the antiapoptotic Bcl-2 protein. No colocalization was detectable with upregulated heme oxygenase-1 in glia and the superoxide and prostaglandin G(2)-producing cyclooxygenase-2 in neurons. These results suggest that nitric oxide synthase-I containing interneurons are protected against intracellular oxidative damage and apoptosis by Bcl-2 and several potent antioxidative enzymes. Since nitric oxide synthase-I positive neurons do not express superoxide-producing enzymes such as cyclooxygenase-1, xanthine oxidase and cyclooxygenase-2 in response to injury, this may additionally contribute to their resistance by reducing their internal peroxynitrite, H(2)O(2)-formation and caspase activation.
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PMID:Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology. 1152 39

Ciclosporin A (CsA) is the first-choice immunosuppressant universally used in allotransplantation and autoimmune diseases. However, it has been demonstrated that this drug produces negative side effects in several organs and in particular in the lymphoid organs and in the kidney. It has been suggested that the CsA causes deleterious effects because it increases the oxygen free radical production. Here we wanted to test whether antioxidants protect the kidney parenchyma from the toxicity induced by CsA. We used methylene blue (MB), because it inhibits the formation of oxygen free radicals. The study was carried out in four groups of Wistar rats. Group I animals were intraperitoneally injected with MB (1 mg/kg/day) for 21 days; group II animals were subcutaneously injected with CsA (15 mg/kg/day) for 21 days; group III animals were treated with CsA combined with MB at the same doses and for the same periods as groups I and II, and group IV animals were injected subcutaneously with olive oil for 21 days as controls. The kidneys and the thymuses were subsequently removed and examined by conventional morphological staining (hematoxylin-eosin and Masson's trichrome) and enzymatic (NADPH-diaphorase, cytochrome, c oxidase, and superoxide anion production) and immunoenzymatic (inducible nitric oxide synthase--iNOS, endothelial nitric oxide synthase--eNOS) techniques. The thymuses were used to check the persistence of CsA-immunosuppressive effects during MB administration. Group I, III, and IV animals showed a normal kidney architecture and low levels of NADPH-diaphorase and of superoxide anion in all structures studied (proximal and distal tubules, glomeruli and the Henle loops). The cytochrome c oxidase showed a strong activity in proximal tubules, a moderate activity in distal tubules, and a weak activity in glomeruli and in the Henle loops. The expression of iNOS was weak in the proximal tubular epithelial cells and negative in the glomeruli, while eNOS was found to be moderately positive in the glomeruli and in the interstitial arteries, but not in the tubules and in the Henle loops. Degenerative changes with tubulointerstitial injury in the cortex of CsA-treated kidneys (group II) and increases of NADPH-diaphorase levels, iNOS activity, and superoxide staining were found in all structures. The expression of eNOS did not change in group I, III and IV animals. MB combined with CsA prevented the degenerative changes caused by CsA, preserving the structural, enzymatic, and immunoenzymatic integrity of the renal parenchyma. The mechanism by which MB exerts its protective action is not yet clear, but it seems to be due to its ability to inhibit xanthine oxidase and to quench nitric oxide production. Moreover, these data have been also supported by the following: (1) the superoxide anion levels were very high after CsA treatment and reduced after CsA-MB treatment, and (2) the iNOS levels increased in CsA-treated rats and showed normal levels after CsA-MB treatment. Moreover we demonstrated that MB administration did no compromise the CsA immunosuppressive effects, since the thymus showed a cytoarchitecture like that observed in CsA-treated rats.
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PMID:Does methylene blue protect the kidney tissues from damage induced by ciclosporin A treatment? 1159 98


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