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

The reaction kinetics of radioadaptive response of low doses of X-rays have been studied in quiescent cultured mouse cells. Mouse m5S cells pre-exposed in G1 to low doses of X-rays became insensitive to the induction of chromosome aberrations, mutation toward 6-thioguanine resistance, and cell killing. Adapted cells were, however, more susceptible to morphological transformation by subsequent high challenging doses of X-rays. The cytogenetic adaptation, which lasted about 20 h pertained to a narrow dose range. X-ray doses below and above 0.1 Gy appeared to be recognized as different signals; higher doses of X-rays were incapable of inducing adaptation and rapidly extinguished the adapted condition. Treatment with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and hydrogen peroxide, but not the xanthine/xanthine oxidase superoxide-generating system, mimicked X-rays in inducing adaptation when applied at low doses. Over-exposure to TPA or inhibitors of protein kinase C (PKC) abrogated the adaptive response to X-rays, providing evidence for the involvement of a PKC-mediated signalling pathway. The lack of radioadaptive response in a tumorigenic variant, clone 6110, and its restoration in the morphological revertant obtained by introducing human chromosome 11 further suggested that interference of signalling pathways may alter radioadaptive responses in malignant cells.
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PMID:On the reaction kinetics of the radioadaptive response in cultured mouse cells. 756 88

The effects of ketotifen fumarate (KF) and clemastine fumarate (CF) on neutrophil chemiluminescent (CL) responses to zymosan particles coated with either IgG (IgGZ), C3 (C3Z), or both (IC3Z), were examined in vitro. These opsonized zymosans caused not only detectable neutrophil superoxide anion generation evaluated by an MCLA-dependent CL (MDCL) assay, with the order of light emission being IC3Z > IgGZ > C3Z, but also a transient rise of neutrophil [Ca2+]i measured by an aequorin-dependent CL (ADCL) assay. Both KF and CF could suppress all opsonized zymosan-induced neutrophil MDCL in a dose-dependent fashion, but not all ADCL. Similar inhibitory effects of KF and CF were observed on the phorbol myristate acetate-induced MDCL. However, there was no interference by these two drugs with the measurement of MDCL in the hypoxanthine/xanthine oxidase superoxide anion generation system. These results indicate that the inhibitory effects of both KF and CF on Fc gamma R- and/or CR-mediated neutrophil oxidative potential is attributable to effects on an enzymatic reaction after protein kinase C activation in the oxidative signal transduction pathway.
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PMID:Inhibition of Fc gamma R- and CR-mediated human neutrophil chemiluminescent responses by anti-allergic and anti-histaminergic drugs. 756 65

To gain insight into the gene regulation and signal transduction effects of active oxygen in tumour promotion and progression, we studied the effect of active oxygen generated extracellularly by xanthine/xanthine oxidase (X/XO) in promotion-insensitive (P-), promotion-sensitive (P+) and transformed (Tx) mouse epidermal JB6 cells. Active oxygen inhibited growth, particularly of P- cells and increased poly ADPR transferase activity and PKC activity more significantly in P- cells. No phenotypic differences in the distribution pattern of PKC isotypes alpha, beta and gamma were seen in JB6 cells. PKC alpha was expressed abundantly, whereas beta and gamma were not detected. Basal levels of the antioxidant enzymes catalase and CuZn. Superoxide dismutase were higher in P+ and Tx cells. X/XO resulted in an initial decrease in the activity of these enzymes, followed by recovery or transient induction in Tx and P+ cells. X/XO induced c-myc and c-fos expression in JB6 cells, with c-fos induction being more pronounced in P- cells, whereas a biphasic increase in c-jun was seen in P+ cells. These early genes may play a role in proliferation whereas post-translational poly ADP-ribosylation and, perhaps, phosphorylation suggest a genetic-epigenetic mechanism in oxidant tumour promotion and progression.
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PMID:The effect of active oxygen generated by xanthine/xanthine oxidase on genes and signal transduction in mouse epidermal JB6 cells. 760 57

To examine the effects of oxidants on the airway epithelial barrier functions, human tracheal epithelial cells were cultured on porous filter membrane. Glucose oxidase (GO; 10 U/ml), hydrogen peroxide (H2O2; 4 x 10(-3) M), and xanthine (5 x 10(-4) M) plus xanthine oxidase (20 mU/ml) (X-XO) significantly increased electrical conductance across epithelial membrane (G), short-circuit current (Isc) measured with Ussing's chamber methods, and [3H]mannitol flux through the cultured epithelium. Increases in G and Isc induced by oxidants were significantly inhibited by catalase (1,000 U/ml) and the protein kinase C inhibitor staurosporine (10(-7) M), but superoxide dismutase (SOD; 100 U/ml) was without effect. GO, H2O2, and X-XO inhibited the epithelial cell growth, [3H]thymidine incorporation by the cells, and epithelial repair of artificially produced focal epithelial defects (1-2 mm diam) on plastic vessels. Catalase also inhibited effects induced by oxidants on cell growth and proliferation. These results suggest that oxidants reduce tracheal epithelial barrier functions by damaging tight junctions and inhibiting cell proliferation, and these effects of oxidants on epithelial cells may be mediated by H2O2 rather than superoxide anion and by activation of protein kinase C.
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PMID:Oxidants affect permeability and repair of the cultured human tracheal epithelium. 786 48

Vitamin K3 (menadione), a synthetic vitamin K congener, inhibits the growth of tumor cells. Here, we examined possible effects of vitamin K3 on phospholipase D (PLD) activity, an enzyme which produces growth regulatory substances. In NIH 3T3 fibroblasts, vitamin K3 (50-100 microM) alone had no effect on PLD-catalyzed formation of phosphatidylethanol, a marker of PLD activity, but it slightly (10-21%) inhibited the stimulatory effect of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Of the two major substrates of PLD, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn), vitamin K3 (10-100 microM) preferentially inhibited PtdEtn hydrolysis when stimulated by PMA or platelet-derived growth factor, the latter being a hormonal activator of PKC. Vitamin K3 had no inhibitory effect on sphingosine- or staurosporine-induced hydrolysis of PtdEtn or PtdCho. Inhibition of PMA-induced PtdEtn hydrolysis by vitamin K3 was effectively reduced by both cysteine (1 mM) and reduced glutathione (1 mM) and was mimicked by the superoxide-generating xanthine/xanthine oxidase system. The results show that vitamin K3 preferentially inhibits the effects of PKC activators on PLD-mediated hydrolysis of PtdEtn by a mechanism which may involve oxidation of thiols in a critically important regulatory component.
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PMID:Vitamin K3 preferentially inhibits stimulation of phospholipase D-mediated hydrolysis of phosphatidylethanolamine by protein kinase C activators in NIH 3T3 fibroblasts. 794 97

The biochemical effects of the non-12-0-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter thapsigargin (TG), which does not bind to the phorbol-ester receptor, or activate protein kinase C (PKC) or increase inositol polyphosphates, were characterized in mouse epidermis in vivo. The cold scraping method is required to detect the induction of ornithine decarboxylase (ODC) activity by TG, a response much smaller than that caused by TPA and with a different time course. TG pre-treatments do not alter or cause a refractory state against ODC induction by TPA. But TG stimulates hydroperoxide (HPx) production and RNA, protein, and DNA synthesis almost as much as TPA. Moreover, the sequential effects of TG and TPA on DNA synthesis are identical: early inhibition at 8 hr followed by maximal stimulation at 16-32 hr. TG-stimulated HPx production requires protein synthesis and xanthine oxidase, phospholipase A2, and lipoxygenase activities but not RNA and DNA synthesis, and cyclooxygenase and protease activities. The HPx response to TG is not mimicked by the PKC activator prostratin or inhibited by pre-treatments with prostratin or specific PKC inhibitors. However, the Ca(2+)-ATPase inhibitor cyclopiazonic acid and the Ca2+ ionophore and weak ODC inducer A23187 mimic remarkably the HPx responses to TG and TPA. Since TG and A23187 are known to be, respectively, weak and incomplete tumor promoters as compared with TPA, the present results suggest that the HPx responses common to Ca(2+)-mobilizing and TPA- or non-TPA-type agents are insufficient to achieve tumor promotion in the absence of major ODC induction.
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PMID:Ability of the non-phorbol ester-type tumor-promoter thapsigargin to mimic the stimulatory effects of 12-0-tetradecanoylphorbol-13-acetate on ornithine decarboxylase activity, hydroperoxide production, and macromolecule synthesis in mouse epidermis in vivo. 825 22

In in situ perfused rat lungs, it was demonstrated that the perfusing pressure and permeability of pulmonary capillaries were obviously increased after activated neutrophils (PMNs) were added to the perfusate. The effect of free radicals generated by the xanthine-xanthine oxidase system on isolated rabbit pulmonary arterial ring tension was also observed, and the contractile response was found to be dose dependent: The smaller the vessel diameter, the higher the contractile response. Superoxide dismutase and catalase were able to obviously attenuate the contractile response. The response was endothelium independent, and was influenced neither by indomethacin (cyclooxygenase inhibitor) nor by nordihydroguaiaretic acid (lipoxygenase inhibitor), while removal of Ca from the bath solution or addition of the protein kinase C (PKC) inhibitor "H7" or an antiinflammatory drug (764-3, the effective component of Radix Salvia miltiorrhizae) could significantly inhibit the contractile response. The results suggest that activated PMNs may play an important role in the pathogenesis of pulmonary hypertension.
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PMID:The role of activated neutrophils and free radical in the pathogenesis of pulmonary hypertension. 827 14

Active oxygen species are generated during pathophysiologic conditions such as inflammation and ionizing radiation exposure. We tested the hypothesis that an early cellular event in response to these species involves regulation of ion channels. We exposed cells to gamma-irradiation or treated them with hydrogen peroxide, xanthine/xanthine oxidase, or [3H]thymidine and then monitored channel activity by the technique of whole-cell voltage clamping. Recordings showed that both normal and tumor cells exhibit an increase in K+ currents after treatment with radiation, H2O2, and xanthine/xanthine oxidase but not with high specific activity [3H]thymidine, suggesting that the signal for K+ channel activation originates at the cell membrane. A single noncytotoxic dose of 10 cGy induced measurable levels of K+ currents, suggesting that the induction of currents regulates biochemical changes in response to stress. To test whether channel activity is sensitive to active oxygen species, we pretreated cells with N-acetyl-L-cysteine (NAC) to increase cellular pools of free radical scavengers before radiation. In NAC-pretreated cells, K+ channel activation by gamma-irradiation was abolished. It has previously been shown that protein kinase C (PKC) is activated by ionizing radiation and can regulate K+ channels in some cells. However, the effect of radiation on induction of K+ channel activity was independent of PKC, since cells chronically exposed to phorbol esters still produced K+ currents after radiation. These results suggest that an early cellular response to oxidative stress is the activation of K+ channels.
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PMID:Potassium-channel activation in response to low doses of gamma-irradiation involves reactive oxygen intermediates in nonexcitatory cells. 843 Jan 4

The biochemical basis for the cancer chemopreventive and anti-cancer activities of glucarate, retinoids (13-cis-retinoic acid, hydroxyphenyl retinamide) and their synergistic combination, has been evaluated. Neither alone nor in combination did these agents affect the level in the rat, of enzymes which are (a) known to correlate with reduced risk of carcinogenesis (detoxification enzyme, catalase, glutathione reductase) nor (b) enzymes which correlate with increased risk of carcinogenesis (beta-glucuronidase, xanthine oxidase, glucose-6-phosphate dehydrogenase). Retinoids, but neither glucarate nor its lactone inhibited free radical-induced lipid peroxidation. Both agents alone and synergistically in combination, raise cellular cAMP levels, repress protein kinase C and more generally inhibited DNA synthesis.
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PMID:Basis for the anti-tumor and chemopreventive activities of glucarate and the glucarate:retinoid combination. 851 53

The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters, okadaic acid (OA) and calyculin-A (CAL-A), which neither interact with the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HPx) production in mouse epidermis in vivo. The time course and dose dependency for the stimulation of HPx production by O and TPA are similar. HPx production is maximally stimulated 16 h after two applications of 2 nmol of OA at a 48-h interval. However CAL-A is a stimulator of HPx production about 4 times more potent than OA or TPA. Combinations of TPA and OA or CAL-A have subadditive effects on HPx production. The discrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide, Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistamines block or decrease OA-stimulated HPx production. Although most of these inhibitors may have more than one action, their effects suggest that protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activities, the lipoxygenase pathway of arachidonic acid metabolism, and vascular permeability may be involved in the inflammatory and HPx responses that occur after tumor promoter treatment. The increased HPx-producing activity of the epidermis, therefore, may be a common event resulting from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.
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PMID:Ability of okadaic acid and other protein phosphatase inhibitors to mimic the stimulatory effects of 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production in mouse epidermis in vivo. 855 15


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