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)

Nitration of proteins by peroxynitrite may alter protein function. We hypothesized that reactive nitrogen species modulate fibronectin-induced fibroblast migration. To test this hypothesis, we evaluated fibroblast migration induced by fibronectin incubated with and without peroxynitrite. Peroxynitrite attenuated fibronectin-induced fibroblast migration in a dose-dependent manner but did not attenuate complement-activated serum-induced fibroblast migration. The reducing agents, deferoxamine and dithiothreitol (DTT), and L-tyrosine reversed the inhibition by peroxynitrite. PAPA-NONOate, a nitric oxide (NO) donor, and superoxide generated by the action of xanthine oxidase on lumazine or xanthine, also showed an inhibitory effect on fibroblast migration. The peroxynitrite generator, 3-morpholinosydnonimine (SIN-1), caused a concentration-dependent inhibition of fibroblast migration. Peroxynitrite reduced fibronectin binding to fibroblasts and resulted in nitrotyrosine formation. These findings are consistent with nitration of tyrosine by peroxynitrite with subsequent inhibition of fibronectin binding to fibroblasts and suggest that peroxynitrite may play a role in regulation of fibroblast migration.
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PMID:Reactive oxygen and nitrogen metabolites modulate fibronectin-induced fibroblast migration in vitro. 1113 92

Hydroxylation of l-phenylalanine (Phe) by hydroxyl radical (*OH) yields 4-, 3-, and 2-hydroxyl-Phe (para-, meta-, and ortho-tyrosine, respectively). Phe derivative measurements have been employed to detect *OH formation in cells and tissues, however, the specificity of this assay is limited since Phe derivatives also arise from intracellular Phe hydroxylase. d-Phe, the d-type enantiomer, is not hydroxylated by Phe hydroxylase. We evaluate whether d-Phe reacts with *OH as well as l-Phe, providing a more reliable probe for *OH generation in biological systems. With *OH generated by a Fenton reaction or xanthine oxidase, d- and l-Phe equally gave rise to p, m, o-tyr and this could be prevented by *OH scavengers. Resting human neutrophils (PMNs) markedly converted l-Phe to p-tyr, through non-oxidant-mediated reactions, whereas d-Phe was unaffected. In contrast, when PMNs were stimulated in the presence of redox cycling iron the *OH formed resulted in more significant rise of p-tyr from d-Phe (9.4-fold) than l-Phe (3.6-fold) due to the significant background formation of p-tyr from l-Phe. Together, these data indicated that d- and l-Phe were equally hydroxylated by *OH. Using d-Phe instead of l-Phe can eliminate the formation of Phe derivatives from Phe hydroxylase and achieve more specific, sensitive measurement of *OH in biological systems.
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PMID:Detection of hydroxyl radicals by D-phenylalanine hydroxylation: a specific assay for hydroxyl radical generation in biological systems. 1118 Sep 47

Xanthine oxidase (XO) has been investigated for its decreased activity in several cancerous tissues and constitutive generation of reactive oxygen species (ROS) in vivo seems to contribute significantly to its inactivation. Singlet oxygen (1O2) production has been suggested to be relevant when considering folic acid metabolism by cancer cells. Thus, the susceptibility of XO to inactivation by 1O2 generated either by the bioenergized systems folic acid/peroxidase/GSH/Mn2+/O2 and malonaldehyde/peroxidase/Mn2+/O2 or by methylene blue (MB) or eosin-sensitized photooxygenation was studied. Our results showed that other ROS were also responsible for XO inactivation when MB was used. In contrast, eosin produced almost exclusively 1O2. Kinetic studies of XO oxidation in the malonaldehyde/peroxidase system showed that histidine (His) is a competitive inhibitor with respect to XO. A similar result was observed in the eosin-photosensitized process, suggesting the involvement of 1O2 in both processes. In addition, an efficient quenching of XO oxidation by guanosine in the folic acid/peroxidase system was observed. Amino acid analysis revealed that cysteine (Cys) is more affected than other XO amino acids also prone to oxidation such as tyrosine (Tyr), methionine (Met) and His. These results indicate that 1O2 may cause oxidative damage to the Cys residues of XO, with loss of enzyme activity. Alteration of the flavin prosthetic site is hypothesized.
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PMID:Sensitized photooxygenation and peroxidase-catalyzed inactivation of xanthine oxidase--evidence of cysteine damage by singlet oxygen. 1138 36

Incubation of Jurkat cells in the presence of H2O2 either directly added to the culture medium or generated with glucose oxidase, menadione or the couple xanthine/xanthine oxidase induced a marked decrease of phosphatidylserine synthesis in the absence of changes in the synthesis of phosphatidylcholine and phosphatidylethanolamine. Concentration dependent response curves indicated that H2O2 induced inhibition of phosphatidylserine synthesis with an IC(50)=5 microM while both induction of tyrosine phosphorylation of proteins and Ca(2+) signals were obtained with an EC(50)=300 microM. The tyrosine kinase and Ca(2+) independent mechanism was confirmed by comparing the H2O2-induced and the CD3-induced inhibition of phosphatidylserine synthesis using several Jurkat clones differing in the expression of cell surface receptors such as CD3/TCR and CD45 and protein tyrosine kinase such as p72syk, ZAP-70 and p56lck. While CD3-induced inhibition of phosphatidylserine synthesis necessitates protein tyrosine phosphorylation and Ca(2+) signals, H2O2 provoked its effect in all the clones studied independently of the presence or absence of the proteins previously shown to be key elements in T cell signal transduction. Conversely, the antioxidant molecule, butylated hydroxanisole, generates an increased PtdSer synthesis, suggesting that the synthesis of this phospholipid is regulated by the redox status of the cells.
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PMID:Inhibition of phosphatidylserine synthesis in Jurkat T cells by hydrogen peroxide. 1142 Jan 23

Semenogelin (Sg), the major protein of the human semen coagulum, is present at high concentrations in seminal vesicle secretions. It is degraded by the prostate-specific antigen (PSA) to generate peptides of various biological activities that were found on and inside spermatozoa. Our aim was to determine the effect of Sg on capacitation, which is the series of transformations that spermatozoa must undergo to become fertile. At concentrations of 0.1 to 1.0 mg/mL (600- to 20-fold lower than those of semen), Sg did not affect sperm motility (%) but completely prevented capacitation induced by fetal cord serum ultrafiltrate; a partial inhibition of capacitation was noted with 0.03 mg Sg/mL. There was also a dose-dependent decrease in the tyrosine phosphorylation of fibrous sheath proteins and in the O2-.-related chemiluminescence. Ribonuclease (RNase), which has as high an isoelectric point (pI = 9.7) as Sg (pI = 9.5), also prevented sperm capacitation and O2-.-related chemiluminescence but to a lower extent, suggesting that one mechanism of Sg action on spermatozoa could be related to its positive charge at physiological pH. Sg at 1, but not 0.3 or 0.1 mg/mL, scavenged the O2-. generated by the mix of xanthine + xanthine oxidase and modified the kinetics of the reaction; RNase did not have such effects. Therefore, Sg is a potential scavenger for O2-. but probably also affects the sperm oxidase. Spermatozoa rapidly processed Sg; a high proportion of Sg was degraded after 15 minutes of incubation. The resulting polypeptide patterns were reminiscent of those obtained with PSA as a proteolytic enzyme. These data suggest that Sg, its degradation products, or both may be natural regulators of sperm capacitation and could prevent this process from occurring prematurely. One mechanism by which Sg acts could involve an interference with the O2-. that is normally generated during this process.
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PMID:Semenogelin, the main protein of semen coagulum, inhibits human sperm capacitation by interfering with the superoxide anion generated during this process. 1145 65

Increasing evidence regarding free-radical generating agents and the inflammatory process suggests that accumulation of reactive oxygen species (ROS) can involve hepatotoxicity. Previously, we found that protocatechuic acid (PCA), a polyphenolic compound from Hibiscus sabdariffa L. possessing free radical-scavenging capacity, protected against oxidative damage induced by tert-butylhydroperoxide (t-BHP) in rat primary hepatocytes. In this study, first PCA was evaluated by its capacity of inhibiting xanthine oxidase (XO) and lipoxygenase (LO) activity in vitro, then it was used to induce hepatotoxicity to assess the antioxidant and anti-inflammatory bioactivity of PCA in vivo. Our investigation showed that pretreatment with PCA (50-100 mg/kg) by gavage for 5 days before a single dose of t-BHP (ip; 0.2 mmol/kg ) significantly lowered serum levels of the hepatic enzyme markers lactate dehydrogenase (LDH) and alanine (ALT) and aspartate (AST) aminotransferase, and reduced oxidative stress of the liver by evaluating malondialdehyde (MDA) and glutathione (GSH). Histopathological evaluation of the rat livers revealed that PCA reduced the incidence of liver lesions, including hepatocyte swelling, leukocyte infiltration, and necrosis induced by t-BHP. In addition, PCA inhibited t-BHP-induced tyrosine phosphorylation, an implication of the activation of a stress signal pathway, in the liver. These results indicate that PCA protects against t-BHP-induced hepatotoxicity by its antioxidant and anti-inflammatory characteristics accompanied by blocking of stress signal transduction.
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PMID:In vivo protective effect of protocatechuic acid on tert-butyl hydroperoxide-induced rat hepatotoxicity. 1195 69

Growth inhibitory factor (GIF), a brain-specific member of the metallothionein family (MT-III), has been characterized as a inhibitory substance for neurotrophic factors in Alzheimer's disease brains. However, the function of GIF, other than the inhibition of neurotrophic factors, remains unknown. We demonstrate here that exogenous GIF prevents neurite extension of cortical neurons in the early period of differentiation and the death of differentiated neurons caused by high oxygen exposure. Down-regulation of GIF in cortical neurons with antisense S-oligonucleotides promoted neuronal death under high oxygen conditions. ESR spin-trapping studies demonstrated that GIF at 2-6 microm scavenged hydroxyl radicals generated by a Fenton-type reaction or the photolysis of hydrogen peroxide much more effectively than the same concentration of metallothionein I+II. GIF did not scavenge either superoxide produced by the xanthine/xanthine oxidase reaction or NO generated from 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene. Moreover, GIF at 40-80 microm inhibited tyrosine nitration by peroxynitrite as efficiently as metallothionein I+II at the same concentration. These results indicate that GIF prevents neurite extension of neurons in the early period of differentiation and supports the survival of differentiated neurons by scavenging hydroxyl radicals.
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PMID:Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging. 1205 24

The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO(-)) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. Cogeneration of nitric oxide (NO) and superoxide (O(2)(-)), from spermine/NO (2.7 microM/min) and xanthine oxidase (1-28 microM O(2)(-)/min), respectively, resulted in protein nitration only when these species were produced at approximately equivalent rates. Addition of ferriprotoporphyrin IX (hemin) to this system increased nitration over a broad range of O(2)(-) concentrations with respect to NO. Nitration in the presence of superoxide dismutase but not catalase suggested that ONOO(-) might not be obligatory to this process. Hemin-mediated NT formation required only the presence of NO(2)(-) and H(2)O(2), which are stable end-products of NO and O(2)(-) degradation. Ferrous, ferric, and cupric ions were also effective catalysts, indicating that nitration is mediated by species capable of Fenton-type chemistry. Although ONOO(-) can nitrate proteins, there are severe spatial and temporal constraints on this reaction. In contrast, accumulation of metals and NO(2)(-) subsequent to NO synthase activity can result in far less discriminate nitration in the presence of an H(2)O(2) source. Metal catalyzed nitration may account for the observed specificity of protein nitration seen under pathological conditions, suggesting a major role for translocated metals and the labilization of heme in NT formation.
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PMID:Protein nitration is mediated by heme and free metals through Fenton-type chemistry: an alternative to the NO/O2- reaction. 1222 78

We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.
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PMID:Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). 1241 65

The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.
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PMID:Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. 1243 85


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