UNIPROT:P47989 - FACTA Search

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Query: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of immunomodulating agents of different origin have been shown to reduce liver injury of various etiologies. Immunostimulants like levamisole, BCG, a protein polysaccharide from myceria Coriolus vesicolor PS-K, a streptoccocal preparation OK-432 and immunomodulators like N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and its analogs. Selective T-cell suppressors like the polypeptide cyclosporine A (CsA) and the macrolide FK 506 (tacrolimus) have also been claimed to possess hepatoprotrophic or hepatoprotective properties at low doses. The aim of this review article is to highlight the interplay between the administration of immunomodulating agents and the amelioration of hepatic injuries. Hepatic effects of exogenous immunomodulators are discussed with special focus on the most widely used immunosuppressive agents, CsA and tacrolimus. An important question exists as to whether these potential hepatoprotective effects are related mechanistically to the immune system or are working at different levels. Due to the differences in effects and modes of actions of various immunoactive substances presented herein, a common mechanism for their cytoprotective effects cannot be formulated at this stage. Levamisole and cyanidanol may protect cells against necrosis by acting as free radical scavengers. MDP and its analogs reduce carbon tetrachloride-elevated (CCl4) lipid peroxides and their protective effects are primarily on hepatic cytoplasmic membranes where lipid peroxidation and calcium homeostasis interact. MDP reduced CCl4-elevated calcium in both intact hepatocytes and in the post microsomal supernatant suggest that the influx of extracellular calcium across plasma membrane is affected. Elevations of intracellular calcium above a threshold are involved in: the stimulation of Ca2+-sensitive enzymes such as phospholipase A2, endonucleases and proteases, the conversion of xanthine dehydrogenase to xanthine oxidase and the formation of free radicals, all of which disturb biomembranes. MDP and its analogs, in a specific dose range, may act to maintain intracellular calcium within physiological ranges. Highly complex cellular signalling systems, including calcium, are involved in the explanation of the mechanism of the immunosuppressive effect of CsA and tacrolimus. The hepatoprotective effects of these selective immunosuppressive agents, however, are independent of the inhibition of T-cell activation. The cyclophilin and tacrolimus binding proteins of the mitochondria are the receptors for these compounds and play a key role in the regulation of mitochondrial permeability transition pores. CsA or tacrolimus inhibition of mitochondrial permeability transition pores does not require interaction with calcineurin, indicating a dissociation between immunosuppression and mitochondrial protection. The involvement of intracellular or intramitochondrial proteins in the modulation of mitochondrial permeability transition pores with the creation of a partially impermeable state for Ca2+ movement in drug-treated mitochondria and the dissociation of this effect from immunomodulatory actions potentially offers new and promising approaches for the development of new pharmacologicals targeted at therapeutic intervention. Clinical trials of these drugs as hepatoprotective agents are limited. Use of CsA in patients with primary biliary cirrhosis and autoimmune chronic hepatitis and in cirrhotic animal models produced by chronic administration of CCl4 have yielded encouraging results. It seems that this class of compounds may be of substantial benefit in liver protection against many pathological conditions where disturbance in mitochondrial function and in Ca2+ homeostasis appear to be prerequisites for cell injury.
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PMID:Immunopharmacologic agents in the amelioration of hepatic injuries. 973 Feb 49

The susceptibility of the developing brain to hypoxia should depend on the lipid composition of the brain cell membrane; the rate of lipid peroxidation; the presence of antioxidant defenses; and the development and modulation of the excitatory neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca++ and intranuclear Ca++-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. In the fetal guinea pig and newborn piglet models, studies have demonstrated that brain tissue hypoxia results in brain cell membrane damage as evidenced by increased membrane lipid peroxidation and decreased Na+,K+-ATPase activity. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin-adducts, studies from our laboratory have demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. We have also shown that brain tissue hypoxia modifies the N-methyl-D-aspartate receptor-ion channel, recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca++ in synaptosomes of hypoxic as compared to normoxic fetuses was demonstrated. The increase in intracellular Ca++ may activate several enzymatic pathways such as phospholipase A2 and metabolism of arachidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases and activation of nitric oxide synthase. Using specific inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol) and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane lipid peroxidation and cell membrane dysfunction in the hypoxic brain. We suggest that, during hypoxia, the increased intracellular Ca++ may lead to an increased intranuclear Ca++ concentration and alter nuclear events including transcription of specific genes responsible for programmed cell death. In view of the developmental studies presented, the susceptibility of the fetal brain to hypoxia appears to increase with brain development as gestation approaches term.
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PMID:Cellular mechanisms of hypoxic injury in the developing brain. 1022 30

During inflammation and other pathological states, the lipid mediator platelet-activating factor (PAF) and reactive oxygen species (ROS) are both generated. We have been investigating the effect of exogenous PAF on ROS formation in the human keratinocyte cell line (HaCaT). ROS production, measured using luminol-enhanced chemiluminescence (CL), proved to be rapid, transient, PAF receptor-mediated, and totally dependent on an increase in intracellular Ca2+ ([Ca2+]i) and on the presence of extracellular Ca2+. Repeated administration of PAF resulted in refractoriness to the agonist in terms of both capacities to increase [Ca2+]i and generate ROS. The cells, however, continued to respond fully to other stimulants (bradykinin, epidermal growth factor, thapsigargin). The PAF-induced increases in [Ca2+]i (monitored using the fluorescent probe Fluo-3) were also rapid and transient and paralleled those of ROS generation. Relatively specific inhibitors of potential ROS-producing systems were administered in an attempt to characterize the ROS producing system(s). Inhibitors of xanthine oxidase, phospholipase A2, lipoxygenase, cyclooxygenase and NO synthase did not interfere with PAF evoked ROS. The flavoprotein inhibitor diphenyleneiodonium and the mitochondrial cytochrome oxidase inhibitor KCN, prevented generation of ROS, making NAD(P)H a candidate for the electron source of the ROS and the mitochondria a potential major site of formation.
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PMID:Calcium-dependent PAF-stimulated generation of reactive oxygen species in a human keratinocyte cell line. 1036 77

Although endothelium-derived hyperpolarizing factor (EDHF) is thought to be a cytochrome P-450 product (arachidonic acid metabolite) in some tissues, in porcine coronary arteries (PCAs) its nature remains unclear. Because phospholipase A2 and C are involved in the synthesis and/or release of EDHF in the PCA, the arachidonic acid (AA) pathway may be involved. In the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) and the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M), both bradykinin (BK; 10(-9)-10(-6) M) and AA (10(-7)-10(-4) M) induced dose-dependent relaxation of PGF2alpha-contracted PCA rings, which was blocked by a high extracellular concentration of KCl (30 mM) or pretreatment with ouabain, a Na+/K+-adenosine triphosphatase (ATPase) inhibitor (5 x 10(-7) M). Eicosatetraynoic acid (ETYA; 20 microM), which inhibits all AA pathways, slightly affected the response to BK and AA; however, lipoxygenase or cytochrome P-450 inhibitors had no effect, suggesting that relaxation is independent of these enzymatic pathways. Because endothelial cells can generate reactive oxygen species (ROS) via metabolism of AA and independent of cyclooxygenase activity, we also studied (a) whether ROS can relax the PCA, as well as the mechanism(s) involved, and (b) the role of ROS in BK- and AA-induced relaxation. Xanthine (X; 100 microM) plus xanthine oxidase (XO; 0.02 U/ml) induced time-dependent relaxation of PGF2alpha-contracted PCA rings in the presence of indomethacin and L-NAME. Dilatation was not affected by superoxide dismutase (SOD; 500 U/ml) but was abolished by catalase (300 U/ml), suggesting that hydrogen peroxide (H2O2) is involved. When rings were contracted by depolarizing them with 30 mM KCl, X/XO failed to elicit relaxation. Ouabain abolished the response to X/XO, suggesting that X/XO may induce relaxation by hyperpolarizing vascular smooth muscle cells via stimulation of the Na+/K+-ATPase pump. We therefore questioned whether ROS might be involved in BK- and AA-induced relaxation. Because catalase combined with SOD had little or no effect, we concluded that in the PCA, the relaxation induced by BK via EDHF involves some mechanism independent of NO, AA metabolism, or ROS.
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PMID:Reactive oxygen species: role in the relaxation induced by bradykinin or arachidonic acid via EDHF in isolated porcine coronary arteries. 1051 Nov 33

Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long-term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca(2+)-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia-induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion-channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia-induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
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PMID:Mechanisms of perinatal cerebral injury in fetus and newborn. 1081 2

The barrier functions in epithelial and endothelial cells seem to be very important for maintaining normal biological homeostasis. However, it is unclear whether or how bile acids affect the epithelial barrier. We examined the bile acid-induced disruption of the epithelial barrier. We measured the transepithelial electrical resistance (TEER) of Caco-2 cells as a marker of disruption of the epithelial barrier. Reactive oxygen species (ROS) generation was also measured. Cholic acid (CA) decreased the TEER and increased intracellular ROS generation. PLA2 (phospholipase A2), COX (cyclooxygenase), PKC (protein kinase), ERK 1/2 (extracellular signal-regulated kinase 1/2), PI 3 K (phosphatidylinositol 3-kinase), p38 MAPK (p38 mitogen-activated protein kinase), MLCK (myosin light-chain kinase), NADH dehydrogenase, and XO (xanthine oxidase) inhibitors or ROS scavengers prevented the CA-induced TEER decrease. PLA2, COX, PKC, NADH dehydrogenase, and XO inhibitors prevented the CA-induced ROS generation but not ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors. If the cells were treated with ROS generators such as superoxide dismutase, the TEER decreased. ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors prevent these ROS generators from inducing the TEER decrease. These results suggest that ROS play an important role. In addition, PLA2, COX, PKC, NADH dehydrogenase, and XO are located upstream of the ROS generation, but ERK 1/2, PI 3 K, p38 MAPK, and MLCK are downstream during the signaling of CA-induced TEER alterations.
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PMID:Bile acid modulates transepithelial permeability via the generation of reactive oxygen species in the Caco-2 cell line. 1610 7

Ischemic stroke is caused by obstruction of blood flow to the brain, resulting in energy failure that initiates a complex series of metabolic events, ultimately causing neuronal death. One such critical metabolic event is the activation of phospholipase A2 (PLA2), resulting in hydrolysis of membrane phospholipids and release of free fatty acids including arachidonic acid, a metabolic precursor for important cell-signaling eicosanoids. PLA2 enzymes have been classified as calcium-dependent cytosolic (cPLA2) and secretory (sPLA2) and calcium-independent (iPLA2) forms. Cardiolipin hydrolysis by mitochondrial sPLA2 disrupts the mitochondrial respiratory chain and increases production of reactive oxygen species (ROS). Oxidative metabolism of arachidonic acid also generates ROS. These two processes contribute to formation of lipid peroxides, which degrade to reactive aldehyde products (malondialdehyde, 4-hydroxynonenal, and acrolein) that covalently bind to proteins/nucleic acids, altering their function and causing cellular damage. Activation of PLA2 in cerebral ischemia has been shown while other studies have separately demonstrated increased lipid peroxidation. To the best of our knowledge no study has directly shown the role of PLA2 in lipid peroxidation in cerebral ischemia. To date, there are very limited data on PLA2 protein by Western blotting after cerebral ischemia, though some immunohistochemical studies (for cPLA2 and sPLA2) have been reported. Dissecting the contribution of PLA2 to lipid peroxidation in cerebral ischemia is challenging due to multiple forms of PLA2, cardiolipin hydrolysis, diverse sources of ROS arising from arachidonic acid metabolism, catecholamine autoxidation, xanthine oxidase activity, mitochondrial dysfunction, activated neutrophils coupled with NADPH oxidase activity, and lack of specific inhibitors. Although increased activity and expression of various PLA2 isoforms have been demonstrated in stroke, more studies are needed to clarify the cellular origin and localization of these isoforms in the brain, their responses in cerebral ischemic injury, and their role in oxidative stress.
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PMID:Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. 1644 52

The disturbance of endothelium-dependent and endothelium-independent vascular reactions of relaxation was registered in the preparations of aorta of radiosensitive BALB/c mice, exposed to chronic external gamma-irradiation (cumulative dose of 0.43 Sv). Low doses of radiation induced an intensive hydrolysis of membrane phospholipids by phospholipase A2, displayed by an increase in the level of eukosanoisds--LTC4 and TxB2, formed under effects of lipid oxidases (lipoxygenase and cyclooxygenase) at the same time with O2 generation. High doses of O2- can also be formed under the effect of low doses of radiation along xanthine oxidase pathway simultaneously with uric acid. In these conditions *OH-radical is formed not only at the expense of water radiolysis, which is observed under the effect of high doses, as well as along the two--NO-dependent and NO-independent--pathways. Significant increase in the content of lipid peroxidation products--dienic conjugates and valonic dialdehyde--in the organs of cardiovascular system is a confirmation of active generation of *OH and *NO2 under the effect of low doses of radiation. The latter induce significant changes in the pools of NO stable metabolites, which can cause disturbance of NO-dependent physiological functions of both heart and aorta. Significant decrease in the levels of nitrite and nitrozothiols in these conditions may result in an oxidative stress. In increased simultaneous generation of *O2- and NO they may bind and thus form a toxic substance peroxynitrite. This notion can be confirmed by the low doses of nitrite, which are formed spontaneously in the presence of molecular oxygen against the background of increased or control levels of nitrate, which is formed mainly at the degradation of peroxynitrite, i.e. at high levels of superoxide anion.
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PMID:[Vascular reactivity and metabolism of the reactive oxygen species and nitrogen in effects of low doses of radiation]. 1979 69

Rodents exposed to intermittent hypoxia (IH), a model of obstructive sleep apnea (OSA), manifest impaired learning and memory and somnolence. Increased levels of reactive oxygen species (ROS), oxidative tissue damage, and apoptotic neuronal cell death are associated with the presence of IH-induced CNS dysfunction. Furthermore, treatment with antioxidants or overexpression of antioxidant enzymes is neuroprotective during IH. These findings mimic clinical cases of OSA and suggest that ROS may play a key causal role in OSA-induced neuropathology. Controlled production of ROS occurs in multiple subcellular compartments of normal cells and de-regulation of such processes may result in excessive ROS production. The mitochondrial electron transport chain, especially complexes I and III, and the NADPH oxidase in the cellular membrane are the two main sources of ROS in brain cells, although other systems, including xanthine oxidase, phospholipase A2, lipoxygenase, cyclooxygenase, and cytochrome P450, may all play a role. The initial evidence for NADPH oxidase and mitochondrial involvement in IH-induced ROS production and neuronal injury unquestionably warrants future research efforts.
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PMID:Reactive oxygen species and the brain in sleep apnea. 2083 73

The production of reactive oxygen and nitrogen species (RONS) by skeletal muscle is important as it (i) underlies oxidative damage in many degenerative muscle pathologies and (ii) plays multiple regulatory roles by fulfilling important cellular functions. Superoxide and nitric oxide (NO) are the primary radical species produced by skeletal muscle and studies in the early 1980s demonstrated that their generation is augmented during contractile activity. Over the past 30 years considerable research has been undertaken to identify the major sites that contribute to the increased rate of RONS generation in response to contractions. It is widely accepted that NO is regulated by the nitric oxide synthases, however the sites that modulate changes in superoxide during exercise remain unclear. Despite the initial indications that the mitochondrial electron transport chain was the predominant source of superoxide during activity, with the development of analytical methods a number of alternative potential sites have been identified including the NAD(P)H oxidases, xanthine oxidase, cyclooxygenases, and lipoxygenases linked to the activity of the phospholipase A2 enzymes. In the present review we outline the subcellular sites that modulate intracellular changes in superoxide in skeletal muscle and based on the available experimental evidence in the literature we conclude that the NAD(P)H oxidases are likely to be the major superoxide generating sources in contracting skeletal muscle.
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PMID:Redefining the major contributors to superoxide production in contracting skeletal muscle. The role of NAD(P)H oxidases. 2391 64

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