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)

The generation of free oxygen radicals from the xanthine-xanthine oxidase system produced a decrease in the steady-state calcium load of canine cardiac sarcoplasmic reticulum (SR) vesicles and an increase in the SR passive calcium permeability. This effect of free oxygen radicals was completely inhibited by superoxide dismutase, a scavenger of superoxide anion radical (.O2-). Treatment of intact SR with a specific calmodulin antagonist, compound 48/80 or W-7, lead to the enhancement of the free oxygen radical-mediated reduction of steady-state calcium accumulation with little effect on passive calcium permeability and Ca,Mg-adenosine triphosphatase activity. The effects of free oxygen radicals and the calmodulin antagonists on steady-state calcium accumulation, but not on passive calcium permeability, were only observed in the presence of the endogenous calmodulin of SR vesicles. These results indicate that stimulation by .O2- and/or a closely related species of free oxygen radical of the passive calcium leak pathway is not calmodulin-dependent and is not a potent way of changing the steady-state calcium accumulation. Hence, we propose that calmodulin-dependent component of calcium fluxes in cardiac SR vesicles is modified directly by free oxygen radicals, and that free oxygen radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin, but not due to reduced catalytic activity of the pump.
 ...
PMID:Calmodulin and free oxygen radicals interaction with steady-state calcium accumulation and passive calcium permeability of cardiac sarcoplasmic reticulum. 252 16

Xanthine/xanthine oxidase and H2O2 stimulated sugar transport. Application of superoxide dismutase and catalase to the cells showed an inhibitory effect on these agent-stimulated sugar transports. Addition of amiloride and 4-acetamide-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), which abolish the cytoplasmic alkalinization, inhibited the stimulation of sugar transport by xanthine/xanthine oxidase in the presence of catalase. The calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and trifluoperazine inhibited H2O2-stimulated sugar transport. These results suggest that O2- stimulates sugar transport in an intracellular pH-dependent manner and that H2O2 stimulates sugar transport in a calcium-calmodulin-dependent manner. These mechanisms may be involved in sugar-transport stimulation in mouse fibroblast BALB/3T3 cells by the tumor-promoting phorbol ester phorbol-12,13-dibutyrate and insulin, since the stimulatory effects of these agents were inhibited by scavengers of oxygen radicals.
 ...
PMID:Mechanism of O2- (-) and H2O2-induced stimulation of sugar transport in mouse fibroblast BALB/3T3 cells. 284 89

The effect of scavengers of oxygen radicals on canine cardiac sarcoplasmic reticulum (SR) Ca2+ uptake velocity was investigated at pH 6.4, the intracellular pH of the ischemic myocardium. With the generation of oxygen radicals from a xanthine-xanthine oxidase reaction, there was a significant depression of SR Ca2+ uptake velocity. Xanthine alone or xanthine plus denatured xanthine oxidase had no effect on this system. Superoxide dismutase (SOD), a scavenger of .O2-, or denatured SOD had no effect on the depression of Ca2+ uptake velocity induced by the xanthine-xanthine oxidase reaction. However, catalase, which can impair hydroxyl radical (.OH) formation by destroying the precursor H2O2, significantly inhibited the effect of the xanthine-xanthine oxidase reaction. This effect of catalase was enhanced by SOD, but not by denatured SOD. Dimethyl sulfoxide (Me2SO), a known .OH scavenger, completely inhibited the effect of the xanthine-xanthine oxidase reaction. The observed effect of oxygen radicals and radical scavengers was not seen in the calmodulin-depleted SR vesicles. Addition of exogenous calmodulin, however, reproduced the effect of oxygen radicals and the scavengers. The effect of oxygen radicals was enhanced by the calmodulin antagonists (compounds 48/80 and W-7) at concentrations which showed no effect alone on Ca2+ uptake velocity. Taken together, these findings strongly suggest that .OH, but not .O2-, is involved in a mechanism that may cause SR dysfunction, and that the effect of oxygen radicals is calmodulin dependent.
 ...
PMID:Calmodulin participation in oxygen radical-induced cardiac sarcoplasmic reticulum calcium uptake reduction. 303 9

We have investigated the phosphorylation of the ribosomal S6 protein which may be on the pathway of mitogenic stimulation in response to oxidants. Mouse epidermal cells JB6 (clone 41) were exposed to active oxygen generated extracellularly by glucose/glucose oxidase (producing H2O2) or xanthine oxidase (producing H2O2 plus superoxide) or active oxygen produced intracellularly by the metabolism of menadione (producing mostly superoxide). All three sources of active oxygen induced rapidly a protein kinase activity which phosphorylated S6 in cellular extracts prepared in the presence of the phosphatase inhibitor beta-glycerophosphate. Maximal activity was reached within 15 min of exposure, and phosphorylation occurred specifically at serine residues. Strong activation of the protein kinase activity was also observed by diamide which selectively oxidizes SH functions. The following observations characterize the reaction: 1) Extracellular addition of catalase but not Cu,Zn-superoxide dismutase was inhibitory, implicating H2O2 rather than superoxide as the active species. 2) Exposure of JB6 cells to reagent H2O2 or H2O2 released by glucose/glucose oxidase resulted in a measurable increase in intracellular free Ca2+. 3) The intracellular Ca2+ complexer quin 2 suppressed the reaction. 4) The calmodulin antagonist trifluoperazine prevented the activation of the protein kinase. 5) Exposure of cells to Mn2+ and La3+, which stimulate calmodulin-dependent activities, potently increased the S6 kinase activity of the cell extracts. 6) Desalted extracts strictly required the addition of Mg2+ and their activity was inhibited by Mn2+. In contrast, the phosphorylation of a 95-kDa protein was strongly stimulated by Mn2+. 7) For several agonists, i.e. active oxygen, phorbol 12-myristate 13-acetate, and serum, tryptic peptide analysis yielded the same phosphopeptides, suggesting that a common S6 kinase is involved in these reactions. From these data we propose that oxidants induce an increase in intracellular free Ca2+ which activates a Ca2+/calmodulin-dependent protein kinase and, as a consequence, an S6 kinase.
 ...
PMID:Oxidants induce phosphorylation of ribosomal protein S6. 314 21

The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response and in postischemic tissue injury, although the sources and actions of the radical are quite different in these two pathological states. While neutrophils produce superoxide for the primary purpose of aiding in the killing of ingested microbes, a second useful function has evolved. The superoxide released from actively phagocytosing neutrophils serves to attract more neutrophils by reacting with, and activating, a latent chemotactic factor present in plasma. Superoxide dismutase, by preventing the activation of this superoxide-dependent chemotactic factor, exerts potent anti-inflammatory action. During ischemia, energy-starved tissues catabolize ATP to hypoxanthine. Calcium transients in these cells appear to activate a calmodulin regulated protease which attacks the enzyme xanthine dehydrogenase, converting it to a xanthine oxidase capable of superoxide generation. When the tissue is reperfused and reoxygenated, all the necessary components are present (xanthine oxidase, hypoxanthine, and oxygen) to produce a burst of superoxide which results in extensive tissue damage. Ischemic tissues are protected by superoxide dismutase or allupurinol, an inhibitor of xanthine oxidase.
 ...
PMID:The pathophysiology of superoxide: roles in inflammation and ischemia. 629 73

Several phenothiazines were found to provide significant protection against loss of tissue creatine phosphokinase caused by the calcium paradox. The concentration of phenothiazine required for protection lies within the range generally attributable to their calmodulin inhibition properties. Moreover, the order of effectiveness in protecting the calcium overloaded myocardium is consistent with their potency as calmodulin inhibitors (trifluoperazine greater than chloropromazine greater than promethazine). The most potent calmodulin inhibitor was shown to dramatically reduce the amount of creatine phosphokinase loss from calcium depleted hearts exposed to buffer containing calcium under anoxic conditions. On the other hand, the drug failed to alter the oxygen-dependent component of the calcium paradox. It also failed to prevent the proteolytic conversion of xanthine dehydrogenase to xanthine oxidase. The possibility that calmodulin activation promotes cellular damage by activating either directly or indirectly specific membrane cellular phospholipases is discussed. Also discussed is the hypothesis that oxygen-dependent damage may be linked to the generation of superoxide anion by the enzyme xanthine oxidase.
 ...
PMID:Possible role for calmodulin in calcium paradox-induced heart failure. 658 73

Hypoxia and reoxygenation (H/R) generate oxygen free radicals that result in renal cell injury. We tested the roles of calcium and calmodulin in mediating xanthine oxidase-derived oxygen free radical production during H/R. Lowering extracellular Ca2+ attenuated lethal cell injury. H/R increased superoxide radical production over basal levels, whereas removing extracellular Ca2+ before hypoxia decreased superoxide radical production to basal levels. Pretreatment with either 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride or thapsigargin, to inhibit release or deplete stores of intracellular Ca2+, did not affect injury following H/R. Ionomycin increased lactate dehydrogenase release during H/R but did not increase superoxide radical to levels greater than that observed for H/R alone. The calmodulin inhibitors trifluoperazine, calmidazolium, or N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide decreased cell injury to varying degrees. Trifluoperazine also decreased superoxide radical production during H/R and was shown to inhibit the conversion of xanthine dehydrogenase to xanthine oxidase. Cell injury and superoxide radical production correlated with cytosolic free Ca2+ during H/R as determined with the Ca(2+)-sensitive fluoroprobe indo 1. Cytosolic free Ca2+ increased slightly during hypoxia and showed a dramatic increase as soon as cells were reoxygenated. Cells incubated in a Ca(2+)-free medium actually showed a small decrease in intracellular Ca2+ despite H/R. In summary, Ca2+ derived from extracellular sources promoted superoxide radical production and renal cell injury by a calmodulin-dependent conversion of xanthine dehydrogenase to xanthine oxidase, a major source of oxygen free radicals during H/R.
 ...
PMID:Calcium and free radicals in hypoxia/reoxygenation injury of renal epithelial cells. 830 79

The conversion from xanthine dehydrogenase (XD) to xanthine oxidase (XO) and the effect of trifluoperazine (TFP), a calmodulin inhibitor, on the conversion were examined during the normothermic ischemia of the rat small intestine. Rat jejunums were stored in lactated Ringer's solution (LR) at 37 degrees C for various hours after intravascular flushing with LR. The extents of the conversion from XD to XO (%XO) constituted 21.1% +/- 3.0%, 36.2% +/- 7.0%, 63.2% +/- 8.1%, and 88.2% +/- 8.6% after 0, 2, 4, and 6 hours of the preservation, respectively (control group). The preservation without the intravascular flushing showed significant increase in the %XO (99.5% +/- 6.0%) only after 6 hours compared with those in the control group (P < .05). When the intestines were stored in LR containing 50 mg/L of TFP at 37 degrees C, or stored in LR at 37 degrees C after the intraperitoneal pretreatment with 10 mg/kg of TFP 1 hour before laparotomy showed significant decrease in the extents of the conversion after 4 hours (P < .005) and 6 hours (P < .025) of the preservation, compared with those in the control group. When the dose of TFP for the pretreatment was increased to 50 mg/kg, the suppressive effect on the conversion was found even after 2 hours (P < .025) as well as after 4 hours (P < .005) and 6 hours (P < .025) of the preservation. These results suggest that TFP could be effective on reducing the XO-mediated postischemic reperfusion injury by means of inhibiting the conversion during ischemia of the rat small intestine.
 ...
PMID:Conversion of xanthine dehydrogenase to xanthine oxidase during ischemia of the rat small intestine and the effect of trifluoperazine on the conversion. 848 75

In the present study we demonstrated that synaptosomes isolated from rabbit brain cortex contain NO synthase and xanthine oxidase that can be activated by ultraviolet B radiation and Ca2+ accumulation to produce nitric oxide and superoxide which react together to form peroxynitrite. Irradiation of synaptosomes with ultraviolet B (up to 100 mJ/cm2), or increase the intrasynaptosomal calcium concentration using various doses (up to 100 mu M) of the calcium ionophore A 23187, a gradual increase in both nitric oxide and peroxynitrite release that was inhibited by N-monomethyl-L-arginine (100 mu M) was observed. The rate of nitric oxide release and cyclic GMP production by NO synthase and soluble guanylate cyclase, both located in the soluble fraction of synaptosomes (synaptosol), were increased approximately eight fold after treatment of synaptosomes with Ultraviolet B radiation (100 mJ/cm2). In reconstitution experiments, when purified NO synthase isolated from synaptosol was added to xanthine oxidase, in the presence of the appropriate cofactors and substrates, a ten fold increase in peroxynitrite production at various doses (up to 20 mJ/cm2) of UVB radiation was observed. Ultraviolet B irradiated synaptosomes promptly increased malondialdehyde production with subsequent decrease of synaptosomal plasma membrane fluidity estimated by fluorescence anisotropy of 1-4-(trimethyl-amino-phenyl)-6-phenyl-hexa-1 ,3,5-triene. Desferrioxamine (100 mu M) tested in Ultraviolet B-irradiated synaptosomes showed a decrease (approximately 80%) in malondialdehyde production with subsequent restoration of the membrane fluidity to that of non-irradiated (control) synaptosomes. Ca(2+)-stimulated ATPase activity was decreased after Ultraviolet B (100 mJ/cm2) radiation of synaptosomes indicating that the subsequent increase of intrasynaptosomal calcium promoted peroxynitrite production by a calmodulin-dependent increase of NO synthase and xanthine oxidase activities. Furthermore, it was shown that UVB-irradiated synaptosomes were subjected to higher oxidative stress by exogenous peroxynitrite (100 mu M) compared to non-irradiated (control) synaptosomes. In summary, the present results indicate that activation of NO synthase and xanthine oxidase of brain cells lead to the formation of peroxynitrite providing important clues in the role of peroxynitrite as a causative factor in neurotoxicity.
 ...
PMID:NO synthase and xanthine oxidase activities of rabbit brain synaptosomes: peroxynitrite formation as a causative factor of neurotoxicity. 883 24

Not all possible mediators of lung I/R injury that have been studied, such as cyclooxygenase and lipoxygenase products, have been presented in this review, but it is very clear that oxygen free radicals are the primary mediators of the damage, regardless of their origin. Oxygen radicals are generated by neutrophils, which are sequestered and activated in the ischemic-reperfused pulmonary tissue, and by xanthine oxidase, which is upregulated by ischemia and/or activated neutrophils. The contributions to lung injury by different species of oxygen radicals may very depending upon the lung model used to study I/R. Also, nitric oxide may be injurious or protective in lung I/R injury, depending upon some critical alveolar PO2 level present either during ischemia or at reperfusion. I/R-induced lung microvascular injury ultimately depends upon some balance between lung metabolic stress, the extent of the I/R-induced inflammatory response, endogenous antioxidant levels, and the timing, magnitude, and duration of oxygen free radical generation during both periods of ischemia and reperfusion. The final common pathway causing microvascular permeability to increase after lung I/R is the activation of the endothelial cell's contractile machinery. Particularly, endothelial contraction may occur in a MLCK-dependent fashion. Endothelial contraction may also be related to an intracellular Ca++ increase and subsequent calmodulin activation. The initiating event causing increased intracellular Ca++ is not known, but may be due to endothelial cell/leukocyte interactions, oxygen radical-mediated Ca++ transients, mobilization of intracellular Ca++ pools by various second messengers, or stimulation of Ca++ influx secondarily to changes in the activity of membrane ion pumps such as the Na+/H+ antiport. Increasing cAMP levels in the postischemic lung can prevent and actually reverse I/R-induced microvascular injury, by affecting MLCK, the endothelial cell cytoskeleton, and/or the function of sequestered leukocytes. Also, cAMP elevation aids the resolution of pulmonary edema by facilitating capillary fluid reabsorption. Whatever the mechanism, elevation of cAMP in the setting of lung I/R injury represents a potentially useful therapy for improving early lung function following lung transplantation. Finally, additional studies are necessary to elucidate the complete mechanisms responsible for producing microvascular injury during lung I/R. Specifically, a better understanding of the relationships between the many factors required to produce lung damage is needed. Many interventions into the lung I/R process provide protection against microvascular injury, suggesting that regulation of the endothelial barrier permeability to fluid, protein, and leukocytes is accomplished by several redundant systems. This situation may be similar to mechanisms reported to regulate the immune response mediated by T cells (62a), where T cell activation depends upon multiple signal inputs for the full immune response to occur. Thus, multiple signals in a correct sequence delivered to the endothelium may be necessary to produce the microvascular injury associated with lung ischemia and reperfusion.
 ...
PMID:Endothelial damage caused by ischemia and reperfusion and different ventilatory strategies in the lung. 890 6


1 2 Next >>