Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of induced nitric oxide synthase (NOS) in isolated rat hepatocytes is poorly understood. The specific protein tyrosine kinase inhibitor genistein was used to determine if NOS induction is dependent on protein tyrosine kinase activation. Genistein inhibited tumor necrosis factor-alpha (TNF-alpha)-stimulated induction of NOS activity and NOS protein in a dose-dependent manner. Genistein also impaired TNF-alpha-induced NOS mRNA accumulation, suggesting protein tyrosine kinase regulation of NOS induction occurred at the level of transcription-translation. Like TNF-alpha, genistein inhibited induction of NOS protein by a second proinflammatory cytokine, interleukin-1beta, suggesting similar activation mechanisms by proinflammatory cytokines. NOS induction by other stimuli, including phorbol 12-myristate 13-acetate and the superoxide-generating system xanthine/xanthine oxidase, was also inhibited by genistein. Finally, cytokine-stimulated protein tyrosine kinase activity in hepatocytes was demonstrated by increased tyrosine phosphorylation of five high molecular mass protein bands. Genistein inhibited this cytokine-induced phosphotyrosine increase. The commonality of genistein inhibition suggests that protein tyrosine kinase activity is critical for NOS induction by a variety of stimuli.
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PMID:Protein tyrosine kinase activity regulates nitric oxide synthase induction in rat hepatocytes. 912 43

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

Previously, superoxide (O2 -) has been observed to impair pial artery dilation (PAD) to activators of the ATP-sensitive (KATP) and calcium-sensitive (KCa) K+ channels. This study tested the hypothesis that activation of protein tyrosine kinase (PTK) and the ERK isoform of MAPK by O2 - contribute to impairment of KATP and KCa channel PAD. Exposure of the cerebral cortex to a xanthine oxidase O2 --generating system (OX) blunted PAD to cromakalim, a KATP agonist, but preadministration of genistein, a PTK antagonist, or U-0126, an ERK MAPK inhibitor, almost completely prevented such impairment (11 +/- 1 and 22 +/- 1 vs. 3 +/- 1 and 7 +/- 1 vs. 10 +/- 1 and 16 +/- 2% for cromakalim with 10-8 and 10-6 M PAD during control, OX, and OX + genistein conditions). In contrast, neither genistein nor U-0126 robustly protected PAD to NS-1619, a KCa agonist, after OX exposure (11 +/- 1 and 18 +/- 2 vs. 1 +/- 1 and 2 +/- 1 vs. 4 +/- 1 and 6 +/- 1% for 10-8 and 10-6 M NS-1619 during control, OX, and OX + genistein conditions). These data show that PTK and ERK MAPK activation contribute to O2 --induced KATP and KCa channel PAD impairment and suggest a differential greater role for PTK and ERK MAPK in KATP vs. KCa channel PAD impairment.
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PMID:Differential role of PTK and ERK MAPK in superoxide impairment of K(ATP) and K(Ca) channel cerebrovasodilation. 1279 95

Previous studies in piglets have shown that the generation of oxygen free radicals (O(-)(2)) following traumatic brain injury and hypoxia/ischemia contribute to the reversal of N-methyl-D-aspartate (NMDA)-induced pial artery dilation to vasoconstriction. This study determined the contribution of protein tyrosine kinase (PTK) and mitogen-activated protein (MAPK) activation to impairment of NMDA cerebrovasodilation by O(-)(2) in piglets equipped with a closed window. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system (OX) reversed NMDA (10(-8), 10(-6) M) dilation to vasoconstriction but such impairment was partially prevented by the PTK inhibitor, genistein, the MAPK (ERK isoform) inhibitor, U0126, and the MAPK (p38 isoform) inhibitor, SB203580 (9+/-1 and 15+/-1 vs. -1+/-1 and -1+/-1 vs. 5+/-1 and 9+/-1% for sham control, OX and OX in the presence of genistein, respectively). However, the p38 MAPK inhibitor, SB203580, prevented NMDA dilator impairment significantly less than the ERK MAPK inhibitor, U0126. Similar results were obtained for glutamate. These data show that PTK and MAPK activation by the presence of O(-)(2) contributes to the impairment of NMDA dilation. Furthermore, these data indicate a differential role for ERK and p38 MAPK activation in impairment of NMDA dilation by O(-)(2) in the brain.
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PMID:Differential role of PTK, ERK and p38 MAPK in superoxide impairment of NMDA cerebrovasodilation. 1285 May 76

Reactive oxygen species (ROS) contribute to the pathogenesis of cardiovascular diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and diabetes mellitus. Oxidative stress is resulted from excessive generation of ROS that outstrips the antioxidant system. Various agonists, pathological conditions and therapeutic interventions lead to modulated expression and function of oxidant and antioxidant enzymes, including NAD(P)H oxidase, endothelial nitric oxide synthase, xanthine oxidase, myeloperoxidase, superoxide dismutases, catalase and glutathione peroxidase. ROS formed in vascular wall target a wide range of signaling molecules and cellular pathways in both endothelium and vascular smooth muscle, such as transcription factors, protein tyrosine phosphatase, protein tyrosine kinase, mitogen-activated protein kinase, Ca(2+)-transporting system and protein modification. ROS also have distinct physiological and pathophysiological impacts on vascular cells. ROS contribute to vascular dysfunction and remodeling through oxidative damage by (1) reducing the bioavailability of NO, (2) impairing endothelium-dependent vasodilatation and endothelial cell growth, (3) causing apoptosis or anoikis, (4) stimulating endothelial cell migration, and (5) activating adhesion molecules and inflammatory reaction, leading to endothelial dysfunction, an initial episode progressing toward hypertension and atherosclerosis. Cellular events underlying these processes involve changes in vascular smooth muscle cell growth, apoptosis/anoikis, cell migration, inflammation, and vasoconstriction. The present communication focuses on the biology of ROS signaling in vascular cells, discusses how oxidative stress contributes to vascular damage, and the therapeutic strategies/biotic factors that can prevent or treat ROS-associated cardiovascular disorders.
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PMID:Reactive oxygen species in vascular wall. 1672 32

A molecular docking investigation has been carried out on cytotoxic prenylated flavonoids from Lonchocarpus haberi with cancer-relevant chemotherapeutic targets known to be inhibited by flavonoids. Two molecular docking programs, Molegro and ArgusDock, were used to compare the binding energies of Lonchocarpus flavonoids with other flavonoids, inhibitors, or known ligands, to aromatase (CYP 19), fatty acid synthase (FAS), xanthine oxidase (XO), cyclooxygenases (COX-1 and COX-2), lipoxygenase (LOX-3), ornithine decarboxylase (ODC), protein tyrosine kinase (PTK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), topoisomerase II (ATP binding site), ATP binding cassette (ABC) transporter, and phospholipase A(2) (PLA). The Lonchocarpus flavonoids examined in this study exhibited docking energies comparable to or stronger than other flavonoids that had been previously shown to be effective inhibitors of these enzymes. Furthermore, prenylated flavonoids, such as the Lonchocarpus flavonoids and xanthohumol, generally showed greater binding energies than the non-prenylated flavonoids. We conclude, therefore, that the Lonchocarpus flavonoids possibly owe their cytotoxic activity by inhibition of one or more of these enzymes.
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PMID:Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis. 1960 3