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)

A series of new 6-(alkylthio)ascorbic acids was synthesized, and their inhibitory effects on lipid peroxidation and the oxidative burst of human neutrophils were tested. Of 12 structurally different lipophilic ascorbic acid derivatives 6-S-n-hexadecyl-2-O-methyl-6-deoxy-6-thio-L-ascorbic acid (7b; B-003) inhibited the Fe2+/ADP-induced lipid peroxidation of rat liver microsomes with an IC50 value of 2 microM. In human neutrophils, 7b most potently inhibited the fMLP-induced oxidative burst in a cell density-dependent manner with an IC50 value of 0.6 microM at 5 x 10(5) cells/mL. Shorter alkyl chain lengths decreased the inhibitory potency for both lipid peroxidation and oxidative burst, but in general no correlation was found between the two parameters. Likewise, 6-S-n-hexadecyl-3-O-methyl-6-thio-L-ascorbic acid (7c; B-015), the regioisomer of 7b, was a potent antioxidant but did not affect the oxidative burst. Since superoxide anions generated by xanthine/xanthine oxidase were not quenched by 7b, it became evident that its target was somewhere between receptor stimulation and NADPH-oxidase activation. By measuring the cellular concentrations of 7b and 7c, an accumulation of the first was found explaining its potency and the dependence on cell density. Expecting a pKa value of 3.3 for 7b and 7.7 for 7c a protonophore action of 7b was likely and could be verified by the drop in intracellular pH (pHi) which did not occur with 7c. Ionophores such as nigericin, CCCP, or propionic acid also lowered the pHi but did not inhibit the oxidative burst, indicating that the pHi drop was not the cause for this inhibition. 7b also strongly inhibited the fMLP-induced secretion of azurophilic (IC50 = 7 microM) and specific (IC50 = 2.5 microM) granules.
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PMID:Antioxidant and neutrophil-inhibiting properties of new 2-O-methyl-6-(alkylthio)ascorbic acid derivatives. 825 24

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

Xanthine oxidase and iron-dependent lipid peroxidation has been studied extensively in many model systems, yet several details of this process remain unclear. Because redox reactions of iron are important parameters of iron-catalyzed lipid peroxidation, we have examined the roles of superoxide and hydrogen peroxide, produced by xanthine oxidase, to oxidize and reduce iron and thereby affect iron-catalyzed lipid peroxidation. Thus, we compared lipid peroxidation catalyzed by xanthine oxidase and ADP:Fe(III) to that catalyzed by xanthine oxidase and ADP:Fe(II). An examination of the action of superoxide on iron oxidation and reduction revealed that superoxide is a better oxidant of ADP:Fe(II) than a reductant of ADP:Fe(III). A superoxide generating system (composed of xanthine oxidase and catalase) and ADP:Fe(II) also resulted in a greater amount of lipid peroxidation than superoxide and ADP:Fe(III). Hydrogen peroxide, as expected, only served as an Fe(II) oxidant. A comparison of the oxidant activities of either superoxide or hydrogen peroxide on ADP:Fe(II) and the corresponding effects on lipid peroxidation revealed that both oxidants were roughly equivalent. We conclude that superoxide and hydrogen peroxide, produced from xanthine oxidase, support iron-catalyzed lipid peroxidation through their participation in redox reactions of iron, that is, they facilitate Fe(II) oxidation or Fe(III) reduction necessary for lipid peroxidation. The relevance of the reactions of O2-. and H2O2 on physiological chelates of iron are discussed.
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PMID:Xanthine oxidase- and iron-dependent lipid peroxidation. 838 2

Exogenous adenosine triphosphate (ATP) added to brush-border membrane vesicles was rapidly degraded mainly to inosine according to the high ecto-nucleotidase activities in these vesicles. In the absence of phosphate, inosine was slowly transformed into hypoxanthine, and xanthine oxidase and dehydrogenase activities were not detected. The presence of ecto-adenosine deaminase and ecto-adenosine monophosphate (AMP) nucleotidase was shown. The ecto-adenosine deaminase was inhibited by deoxycoformycin and was also detected in rat renal brush-border membrane vesicles. Using orthovanadate, levamisole, and alpha, beta-methylene adenosine diphosphate as possible inhibitors, alkaline phosphatase was shown to be the main agent responsible for ecto-AMP nucleotidase activity. In pig renal basolateral membrane vesicles and in whole cell extracts from pig renal cortex, ecto-AMP nucleotidase was the limiting factor in ATP degradation. Comparing the ATP catabolism in the whole cell cortical extract with the catabolism in the same sample precleared of membranes, it was shown that ectonucleotidase activity is mainly bound to the membranous components. It is also shown that the whole cell extract of pig renal cortex has hypoxanthine phosphoribosyl transferase activity, and it seems probable that the rapid and specific formation of luminal inosine and its transport into the cell in competition with adenosine may start the purine salvage pathway through the synthesis of IMP from hypoxanthine.
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PMID:Adenine nucleotides and adenosine metabolism in pig kidney proximal tubule membranes. 840 44

Reoxygenation of rat-liver mitochondria after anoxic incubation induced release of matrix proteins. As assessed by release of a matrix enzyme, it was proportional to the rate of H2O2 production. The release was not observed with low concentrations of extramitochondrial free Ca2+, indicating a Ca(2+)-dependent pathway. Phospholipase A2 was not involved in the reoxygenation injury, because non-esterified fatty acids did not increase on reoxygenation even when re-acylation was inhibited and because inhibitors of phospholipase A2 had little effect on enzyme release. Cyclosporin A, ATP, ADP and inhibitors of pyridine nucleotide oxidation had a protective effect, strongly suggesting involvement of so-called Ca(2+)-dependent permeability transition. Ca2+ was also released from reoxygenated mitochondria and inhibition of reuptake of released Ca2+ attenuated the enzyme release. Similar releases of aspartate aminotransferase and Ca2+ were observed with mitochondria in an oxygen radical-generating system, hypoxanthine and xanthine oxidase. In this system, lecithin-cardiolipin liposomes also released entrapped Ca2+ without disruption of the membrane. From these results, we conclude that during reoxygenation, Ca2+ release and subsequent reuptake induced permeability transition of mitochondria, resulting in reoxygenation injury.
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PMID:Ca(2+)-induced, phospholipase-independent injury during reoxygenation of anoxic mitochondria. 841 80

This study was designed to investigate the influence of intracellular ionized calcium ([Ca2+]i) on the induction of c-fos, c-jun, c-myc, and hsp70 genes after oxidant stress induced by xanthine/xanthine oxidase (X/XOD) treatment or after heat shock using primary cultures of rat proximal tubule epithelium (PTE). X/XOD (500 microM/25 mU/mL) induced all of these genes; ionomycin also resulted in similar kinetics of induction of all genes. The expression of both c-fos following X/XOD treatment and hsp70 following heat shock was markedly decreased through chelation of [Ca2+]i by Quin 2/AM. The c-fos expression following X/XOD treatment was partly reduced by a protein kinase C inhibitor, staurosporine (ST), and markedly inhibited by another protein kinase inhibitor, 2-aminopurine (2AP), while both ST and 2AP markedly reduced hsp70 expression. The ADP-ribosylation transferase inhibitor 3-aminobenzamide had no effect on either c-fos or hsp70 expression. These results suggest that cell injuries leading to increased [Ca2+]i in PTE result in induction of c-fos, c-jun, c-myc, and hsp70; and that the activation of c-fos and hsp70 genes may be regulated by [Ca2+]i and [Ca2+]i-dependent protein kinases.
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PMID:Induction of immediate early and stress genes in rat proximal tubule epithelium following injury: the significance of cytosolic ionized calcium. 846 83

Reactive oxygen species (ROS) have been reported to alter cardiac myofibrillar function as well as myofibrillar enzymes such as myosin ATPase and creatine kinase (CK). To understand their precise mode and site of action in myofibrils, the effects of the xanthine/xanthine oxidase (X/XO) system or of hydrogen peroxide (H2O2) have been studied in the presence and in the absence of phosphocreatine (PCr) in Triton X-100-treated cardiac fibers. We found that xanthine oxidase (XO), with or without xanthine, induced a decrease in maximal Ca(2+)-activated tension. We attributed this effect to the high contaminating proteolytic activity in commercial XO preparations, since it could be prevented a protease inhibitor, phenylmethylsulfonyl fluoride (PMSF), and it could be mimicked by trypsin. In further experiments, XO was pre-treated with 1 mmo1/L PMSF. Superoxide anion production by the X/XO system, characterized by electron paramagnetic resonance spin-trapping technique, was not altered by PMSF. A slight increase in maximal force was then observed either with X/XO (100 mumol/L per 30 mIU/mL) or H2O2. pMgATP-rigor tension relationships have been established in the presence and in the absence of PCr to separate the effects of ROS on myosin ATPase and myofibrillar-bound CK. In the absence of PCr, pMgATP50, the pMgATP necessary to induce half-maximal rigor tension, was reduced from 5.03 +/- 0.17 (n = 21) to 4.22 +/- 0.22 (n = 4) after 25 minutes of incubation in the presence one of 30 mIU/mL. XO and 100 mumol/L xanthine or to 4.04 +/- 0.1 (n = 11) after incubation in the presence of 2.5 mmol/L H2O2. The ROS effects were partially prevented or antagonized by 1 mmol/L dithiothreitol. No effect was observed on pMgATP50 when PCr was absent. pCa-tension relationships have been evaluated to assess the effects of ROS on active tension development. Incubations with H2O2 induced on increase in Ca2+ sensitivity and resting tension when MgATP was provided through myofibrillar CK (PCr and MgADP as substrates) but not when MgATP was added directly. These results suggest that myofibrillar CK was inhibited by ROS. Active stiffness and the time constant of tension changes after quick stretches applied to the fibers were dose-dependently increased by H2O2 only in the presence of PCr. In addition, myofibrillar CK but not myosin ATPase enzymatic activity was depressed after incubation with either ROS. These results suggest that ROS mainly alters CK in myofibrils, probably by the oxidation of its essential sulfhydryl groups. Such CK inactivation results in a decrease in the intramyofibrillar ATP-to-ADP ratio. The effects of ROS on cytosolic and bound CKs may take part in the overall process of myocardial stunning after cardiac ischemia and reperfusion.
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PMID:Creatine kinase is the main target of reactive oxygen species in cardiac myofibrils. 863 32

The formation of poly(ADP-ribose) in primary cultures of rabbit synovial fibroblasts after treatment with active oxygen released by xanthine/xanthine oxidase is inhibited by addition of 1 and 10 microM 4-hydroxy-2,3-trans-nonenal (HNE). The endogenous formation of HNE by the xanthine/xanthine oxidase system is not responsible for the inhibitory effect of the aldehyde, owing to the low accumulation rate of the lipid peroxidation product in the system used. HNE is able to inhibit the isolated nuclear enzyme ADP-ribosyltransferase, as shown by an in vitro assay with an Ki of 4 mumol/litre. Therefore the molecular basis of HNE-mediated effects on cell proliferation, differentiation and transformation might be due to the inhibitory effect of poly(ADP-ribos)ylation.
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PMID:Inhibition of poly(ADP-ribose) formation by 4-hydroxynonenal in primary cultures of rabbit synovial fibroblasts. 864 46

Iron catalyzed free radical formation and lipid peroxidation are accepted mechanisms of heme protein-induced acute renal failure. However, the source(s) of those free radicals which trigger lipid peroxidation in proximal tubular cells remains unknown. This study tested the potential involvement of mitochondrial electron transport, xanthine oxidase activity, and arachidonic acid metabolism in the heme-induced peroxidative state. The impact of cytosolic Ca2+ loading also was assessed. Rhabdomyolysis was induced in mice by glycerol injection, and two hours later heme-laden proximal tubular segments (PTS) were isolated for study. PTS from normal mice served as controls. During 30 to 60 minute incubations, heme loaded PTS developed progressive cytotoxicity (LDH release) and iron-dependent lipid peroxidation (malondialdehyde, MDA, generation; inhibited by deferoxamine). Site 2 (antimycin A) or site 3 (cyanide, hypoxia) mitochondrial respiratory chain inhibition completely blocked lipid peroxidation, whereas site 1 inhibition (rotenone) doubled its extent (presumably by shunting NADH through NADH dehydrogenase, a free radical generating system). Conversely, these agents did not substantially alter MDA in normal PTS. Normal and heme loaded PTS developed comparable degrees of LDH release during respiratory blockade irrespective of increased or decreased MDA production (indicating that lipid peroxidation was not a critical determinant of cell death). Neither increasing free arachidonic acid (PLA2 treatment) nor adding cyclooxygenase/lipoxygenase/cytochrome p450 inhibitors conferred a consistent protective effect. Altering free Ca2+ status (chelators; ionophore addition) and xanthine oxidase inhibition had no discernible impacts. Despite mitochondrial free radical production, mitochondrial function, as assessed by the ATP/ADP ratio, seemingly remained intact. In conclusion, (1) the terminal mitochondrial respiratory chain is the dominant source of free radicals which trigger PTS lipid peroxidation; (2) iron is a required secondary factor; (3) although mitochondria fuel lipid peroxidation, they do not appear to be critical targets of the heme-induced oxidant attack.
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PMID:Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria. 864 15

A biphenyl compound, 3,4,3',4'-tetrahydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl (1), and a flavonoid, eriodicytol (2), were isolated as antioxidative components from the leaves of Thymus vulgaris by bioassay-directed fractionation. These compounds inhibited superoxide anion production in the xanthine/xanthine oxidase system. Mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH were also inhibited by these compounds. Compound 1 is an extremely potent antioxidant; complete inhibition was observed at 1 microM against both microsomal and mitochondrial peroxidation. Furthermore, compound 1 protected red cells against oxidative hemolysis. These phenolic compounds were shown to be effective to protect biological systems against various oxidative stresses.
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PMID:Antiperoxidative components in Thymus vulgaris. 869 32


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