Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production/release of superoxide anions from aortic rings was measured by a modified lucigenin-enhanced chemiluminescence (CL) technique. The aortic rings were obtained from control and cholesterol-fed (1% for 12 weeks) rabbits. The CL signal was significantly increased in aortic wall of cholesterol-fed rabbits. Pretreatment with oxypurinol, an inhibitor of xanthine oxidase, had a slight but insignificant effect on the CL response produced by aortic rings from control animals but significantly reduced CL response to aortic rings from cholesterol-fed rabbits. Pretreatment with diethyldithiocarbamate (DETC), an inhibitor of intrinsic superoxide dismutase (SOD), increased the CL signal for both animal groups, but this increase was greatly aggravated in aortic rings from hypercholesterolemic rabbits. Addition of phorbol 12-myristate 13 acetate (PMA) to stimulate the respiratory burst of wall-adherent and/or resident leukocytes had only slight effect on the CL response to aortic rings from control animals but extensively stimulated photon emission of aortic rings from cholesterol-fed rabbits. These findings are in agreement with the concept that the arterial wall in hypercholesterolemia and/or atherosclerosis is under increased "oxidative stress."
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PMID:Vascular release of superoxide radicals is enhanced in hypercholesterolemic rabbits. 789 85

Low-density lipoproteins (LDL) oxidized by oxygen radicals are a potent atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor, and could induce foam cell transformation. Post-translational nonenzymatic glycosylation of low density lipoprotein (LDL) occurs in vivo in diabetic patients. Glycosylated LDL (glcLDL) is degraded by macrophages in part by the classic LDL-receptor and in part by the scavenger receptor. This latter mechanism may contribute to the formation of foam cells and acceleration of atherosclerosis in diabetes mellitus. Oxygen free radicals (ORs) could induce LDL peroxidation and subsequent formation of foam cells. Glycosylation may alter protein conformation. A free radical is any chemical species that has an unpaired electron. This property renders it highly chemically reactive. When a radical reacts with a non radical another free radical is generated. This characteristic enables radicals to trigger chain reactions. Oxygen radicals are: superoxide anion (.O2-), hydroxyl radical (.OH) and hydrogen peroxide (H2O2). Thus, the aim of this study was to investigate whether glcLDL are susceptible to peroxidative modification by ORs. GlcLDL was prepared incubating LDL with 40 mM glucose in sterile phosphate-buffer-EDTA 1 mM for 10 days at 37 degrees C. Control LDL (cLDL) was similarly incubated with buffer but without glucose. After this preparation both forms of LDL were oxidized by CuSO4 (15 microM for 20 hours at 37 degrees C) or by xanthine/xanthine oxidase (X:2 mM/XO: 100 mU for 20 hours at 37 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The peroxidation of human glycosylated low-density lipoproteins is mediated by the superoxide radical: the protective effects of superoxide dismutase]. 808 16

Oxidative modification of low density lipoprotein (LDL) has been suggested as a causal step in atherosclerosis, and both redox-active transition metal ions and superoxide (O2.-) have been implicated in this process. In order to determine the mechanisms of metal ion-dependent oxidation of LDL in the presence of O2.-, LDL was exposed to hypoxanthine (HX) and purified xanthine oxidase (XO) without and with added CuCl2 or Fe(3+)-citrate. Production of O2.- and hydrogen peroxide (H2O2) at pH 7.4 by the HX/XO system in the absence of metal ions was not sufficient to oxidize LDL. Preincubation of LDL with Cu2+ or Fe(3+)-citrate with subsequent removal of metal ions not tightly bound to the lipoprotein did not enable the HX/XO system to oxidize LDL. However, incubation of LDL with HX/XO and Cu2+ resulted in extensive modification of LDL. Exposure of LDL to Cu2+ alone also led to extensive modification, although the LDL was initially free of detectable amounts of lipid hydroperoxides (LOOH), i.e., < 0.005 molecules of LOOH per LDL particle. Although HX/XO and Cu2+ did not produce detectable amounts of O2.- or aqueous hydroxyl radicals (HO.), oxidation of LDL under these conditions was partially inhibited by superoxide dismutase, and completely inhibited by the HO. scavenger thiourea. In contrast to Cu(2+)-mediated oxidation of LDL, oxidation mediated by Fe(3+)-citrate was strictly dependent upon O2.-, as it was abolished by omission of the HX/XO system or by addition of superoxide dismutase to this system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein. 824 25

Free radical-induced injury to the arterial wall has been implicated in the pathogenesis and progression of atherosclerosis. To model the in vitro effects of free radicals on endothelial cell function, protein and lipid synthesis were measured after exposing cells to a superoxide generating system of xanthine (X = 100 microM) and xanthine oxidase (XO = 0.2 units). Total protein synthesis, measured by [35S]methionine uptake, decreased by 87.65 +/- 2.04% over 4 hr compared to controls (P < 0.05). Examination of lipid synthesis by high-performance liquid chromatography in cells prelabeled with either [3H]oleic acid or [3H]sodium acetate revealed alterations in all lipid classes. Phospholipid and neutral glyceride synthesis significantly decreased in a time- and dose-dependent fashion compared to controls (two-way ANOVA). In contrast, cholesterol synthesis and lipid peroxidation increased in a time- and dose-dependent fashion. When X = 200 microM and XO = 0.3 units, there was a statistically significant increase in cholesterol synthesis and lipid peroxidation within 24 hr (Tukey's HSD). We conclude that there is evidence of endothelial cell injury as measured by decreases in protein, glyceride, and phospholipid synthesis. The concurrent increases in lipid peroxidation and cholesterol synthesis may explain the relationship between free radical injury and the pathogenesis of atherosclerosis.
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PMID:Free radical-induced alterations in endothelial cell function. 827 66

In response to homocysteine induced toxicity in human umbilical vein endothelial cells, minimal changes in the concentration of cellular protein thiols but substantial changes in the concentration of intracellular soluble thiols were observed. The latter correlated closely with changes in cellular glutathione levels. No correlation existed between cellular glutathione levels and cell viability, whereas a close correlation between NAD+ levels and cell viability was demonstrated. Large decreases in cellular NAD+ occurred in response to homocysteine induced toxicity which were accompanied by the production of single stranded DNA. 3-Aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase preserved cell viability and cellular NAD+ levels. Evidence that DNA synthesis was also compromised was revealed by the decreased capacity of homocysteine treated cells to incorporate deoxyuridine. Radical scavengers were also effective in preventing homocysteine induced toxicity. It is likely that the major threat to cells derives from radicals generated intracellularly. Eicosanoid metabolism and the xanthine oxidase system have been identified as two potential sources of radicals.
Atherosclerosis 1996 May
PMID:Homocysteine mediated endothelial cell toxicity and its amelioration. 876 80

Patients with homozygous familial hypercholesterolemia (FH), as a result of the increased levels and prolonged residence time of low density lipoprotein (LDL) in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall, causing premature atherosclerosis. This phenomenon may enhance per se the physiological degradation of both protein and lipid component of LDL, which be more susceptible to oxidative damage induced by oxygen radicals. It is well known that LDL may undergo oxidative modification before being taken up by macrophages which are then transformed into foam cells. It has been suggested that platelet-activating factor (PAF) may play an important role in atherogenesis and PAF catabolism is known to be mediated by serum acetylhydrolase, an enzyme that is normally associated with LDL. Thus, the present study was designed to investigate the structural properties of LDL, including acetylhydrolase activity, in homozygous FH as compared to normolipidemic subjects before and after xanthine/xanthine oxidase-mediated oxidation. We studied 8 homozygous FH patients matched with 8 normolipidemic volunteers. Lipids of LDL fraction were extracted and verified by thin layer chromatography (TLC) analysis. Fatty acids were methylated and injected into a gas chromatograph/mass spectrometer. Vitamin E in LDL was determined by high performance liquid chromatography (HPLC). As an index of susceptibility of LDL to oxidative modifications, the formation of lipid-conjugated dienes was continuously monitored at 234 nm. Lipid peroxidation was also evaluated from the amount of both lipid peroxides (LPO) and malonyldialdehyde (MDA) content. Apolipoprotein (apo) B-100 on LDL was carried on polyacrylamide and agarose gel electrophoresis. In the homozygous FH patients, the relative content of cholesteryl ester was slightly increased. Interestingly, the relative amount of arachidonic acid (20:4) was constantly increased in each lipid fraction in homozygous FH patients. The amount of vitamin E was not significantly different in the patient group from that in the control group. However, LDL from patients carried lower levels of vitamin E (nmol/mg LDL) than controls (2.7 +/- 0.4 vs. 2.9 +/- 0.3 P = NS). The results shows that lag time (min) was decreased (82 +/- 19 vs. 111 +/- 21; P < 0.05) and the maximal rate of diene production and total diene production was increased in homozygous FH patients. Mean levels of MDA were similar in both groups before oxidation, but levels after initiation of oxidation were significantly higher in the patient group. In contrast, mean levels of LPO were already higher in patients before oxidation (58 vs. 27 nmol/mg of protein; P < 0.05), and after initiation of oxidation were also significantly higher at each time points. When oxidized LDL was run on a polyacrylamide gel, an extensive apo B-100 fragmentation replaced by lower molecular mass fragments ranging from 45,000 to 205,000 m.wt., was observed only in LDL from homozygotes. Relative LDL agarose gel mobility shows that LDL from patients migrated higher than LDL of controls. Finally acetylhydrolase activity associated with LDL in patients was significantly reduced as compared to controls. Thus, in homozygous FH patients, LDL appeared more susceptible to oxidation in vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon might be due to prolonged residence time of LDL in these patients, as suggested from high basal LPO levels and lower vitamin E levels carried by LDL. This hypothesis may explain together with the high content of arachidonic acid, the enhanced susceptibility of LDL from homozygous FH patients to oxidative damage.
Atherosclerosis 1995 Dec
PMID:Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia. 877 Mar 20

Tissue destruction in atherosclerosis is partly due to uncontrolled protease and oxygen radical release. In this study we investigated the release of elastase and myeloperoxidase, as well as the production of reactive oxygen species by polymorphonuclear leukocytes (PMNLs) obtained from patients with obliterative atherosclerotic of the lower legs. In addition we measured the plasma concentration of xanthine oxidase. PMNLs of atherosclerotic patients have a greater ability to increase elastase and myeloperoxidase release after their stimulation with formyl-methionin-leucyl-phenylalanin (fMLP) and calcium ionophore, A23187, independently of their age, than PMNLs of healthy middle-aged subjects. Similarly to healthy elderly subjects there was an increased superoxide anion (O2-) production under basal condition in both atherosclerotic patient age-groups. The activation of PMNLs with fMLP and A23187 enhanced O2- formation both in healthy subjects and in patients with atherosclerotic disease of the lower legs, however the increase was significantly less in the latter group. No biochemical parameters showed significant correlation with patient's risk factors, however myeloperoxidase production was significantly higher in less severe stage of the disease (P < 0.05). We found that patients with atherosclerotic disease of the lower legs have higher plasma xanthine oxidase level than control subjects. This study indicates an other piece of evidence suggesting the activation and involvement of neutrophils in the pathogenesis of atherosclerosis of the lower legs. The similar tendencies in the reactivity of neutrophils during aging and in atherosclerosis suggest that atherosclerosis may be an early aging process.
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PMID:Neutrophils obtained from obliterative atherosclerotic patients exhibit enhanced resting respiratory burst and increased degranulation in response to various stimuli. 878 40

The goal of the present study was to determine whether oxygen-derived free radicals contribute to baroreceptor dysfunction in atherosclerosis. Baroreceptor activity was measured from the carotid sinus nerve during pressure ramps in isolated carotid sinuses of anesthetized rabbits. Rabbits fed a 0.5% to 1.0% cholesterol diet for 7.9 +/- 0.4 months (mean +/- SE; range, 5.5 to 10) developed atherosclerotic lesions in the carotid sinuses. Maximum baroreceptor activity measured at 140 mm Hg and the slope of the pressure-activity curve were reduced in atherosclerotic (n = 15) compared with normal (n = 13) rabbits (425 +/- 34 versus 721 +/- 30 spikes per second and 6.2 +/- 0.6 versus 10.8 +/- 0.8 spikes per second per mm Hg, respectively, P < .05). The level of activity was inversely related to plasma cholesterol concentration (r = .86, P < .001) and total cholesterol load (plasma concentration x duration of diet, r = .92). Mean arterial pressure was normal in both groups. Exposure of the carotid sinus to the free-radical scavengers superoxide dismutase (SOD) and catalase significantly increased maximum baroreceptor activity by 25 +/- 4% in atherosclerotic rabbits (n = 6) but caused only small and irreversible changes in activity in normal rabbits (n = 8). Catalase alone but not SOD also increased baroreceptor activity in atherosclerotic rabbits (n = 7). Exposure of the carotid sinus of normal rabbits to exogenous free radicals generated from the reaction between xanthine and xanthine oxidase inhibited baroreceptor activity in a dose-dependent and reversible manner (n = 8, P < .05). The inhibition of activity was attenuated by SOD and catalase but was not attenuated by the inhibitor of hydroxyl radical formation, deferoxamine. Neither restoration of baroreceptor activity in atherosclerotic rabbits by catalase nor inhibition of activity by xanthine/xanthine oxidase could be explained by changes in the carotid pressure-diameter relation or prostacyclin formation. These results indicate that oxidant stress inhibits baroreceptor activity and that endogenous oxyradicals produced in atherosclerotic carotid sinuses contribute to baroreceptor dysfunction.
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PMID:Oxygen-derived free radicals contribute to baroreceptor dysfunction in atherosclerotic rabbits. 883 4

We investigated the injurious effects of reactive oxygen metabolites on the intestinal epithelium and the possible protective role played by two olive oil phenolic compounds, (3,4-dihydroxyphenyl)ethanol and (p-hydroxyphenyl)ethanol, using the Caco-2 human cell line. We induced oxidative stress in the apical compartment, either by the addition of 10 mmol/L H2O2 or by the action of 10 U/L xanthine oxidase in the presence of xanthine (250 micromol/L); after the incubation, we evaluated the cellular and molecular alterations. Both treatments produced significant decreases in Caco-2 viability as assessed by the neutral red assay. Furthermore, we observed a significant increase in malondialdehyde intracellular concentration and paracellular inulin transport, indicating the occurrence of lipid peroxidation and monolayer permeability changes, respectively. The H2O2-induced alterations were completely prevented by preincubating Caco-2 cells with (3,4-dihydroxyphenyl)ethanol (250 micromol/L); when the oxidative stress was induced by xanthine oxidase, complete protection was obtained at a concentration of polyphenol as small as 100 micromol/L. In contrast, (p-hydroxyphenyl)ethanol was ineffective up to a concentration of 500 micromol/L. Our data demonstrate that (3,4-dihydroxyphenyl)ethanol can act as a biological antioxidant in a cell culture experimental model and that the ortho-dihydroxy moiety of the molecule is essential for antioxidant activity. This study suggests that dietary intake of olive oil polyphenols may lower the risk of reactive oxygen metabolite-mediated diseases such as some gastrointestinal diseases and atherosclerosis.
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PMID:The protective effect of the olive oil polyphenol (3,4-dihydroxyphenyl)-ethanol counteracts reactive oxygen metabolite-induced cytotoxicity in Caco-2 cells. 903 29

Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.
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PMID:Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells. 918 53


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