Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capacity of the cell to detoxify these potentially injurious oxidants using endogenous antioxidant defense systems. Conditions associated with oxidative stress include ischemia/reperfusion, hypercholesterolemia, diabetes, and hypertension. The adhesion of circulating blood cells (leukocytes, platelets) to vascular endothelium is a key element of the pro-inflammatory and prothrombogenic phenotype assumed by the vasculature in these and other disease states that are associated with an oxidative stress. There is a growing body of evidence that links the blood cell endothelial cell interactions in these conditions to the enhanced production of ROS. Potential enzymatic sources of ROS within the microcirculation include xanthine oxidase, NAD(P)H oxidase, and nitric oxide synthase. ROS can promote a pro-inflammatory/prothrombogenic phenotype within the microvasculature by a variety of mechanisms, including the inactivation of nitric oxide, the activation of redox-sensitive transcription factors (e.g., nuclear factor-kappaB) that govern the expression of endothelial cell adhesion molecules (e.g., P-selectin), and the activation of enzymes (e.g., phospholipase A(2)) that produce leukocyte-stimulating inflammatory mediators (e.g., platelet-activating factor). The extensively documented ability of different oxidant-ablating interventions to attenuate blood cell endothelial cell interactions underscores the importance of ROS in mediating the dysfunctional microvascular responses to oxidative stress.
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PMID:Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. 1266 63

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.
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PMID:Cytosolic and mitochondrial ROS in staurosporine-induced retinal cell apoptosis. 1464 98

Neurodegenerative diseases of the human brain comprise a variety of disorders that affect an increasing percentage of the population. Some of these are age dependent (e.g. Alzheimer's and Parkinson's diseases) and some are infection dependent, e.g. human immunodeficiency virus (HIV/AIDS). The vulnerable brain regions in HIV/AIDS individuals include the dentate nucleus in the cerebellum, the red nucleus, substantia nigra (SN) in the mid-brain, the subthalamic nucleus, thalamic fasciculus in the diencephalons, the globus pallidus and striatum (or neostriatum, which consists of caudate and putamen) in the forebrain. Lesion in these regions may lead to progressive dementia, which is similar to what is observed in Alzheimer's disease and Parkinson's disease. The entry of calcium into the cytoplasm of cells at concentrations that can activate oxidative enzymes such as phospholipase A(2) and xanthine oxidase, deplete cells of cysteine and glutathione, cause mitochondrial release of free radicals and cell death. Glutamate and its receptors are key molecular elements at the interface between neurons and glia. Dietary factors can modulate physiological functions (including brain function) thereby increasing the economic productivity of a population as a function of health. A greater understanding of the molecular mechanisms of neuroprotection, oxidative stress and immune function will facilitate definition of the prophylactic potentials of diet, nutritional/food supplements, medicinal plants and herbal extracts.
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PMID:Neuroprotection by bioactive components in medicinal and food plant extracts. 1464 22

The formation of reactive oxygen species (ROS) has been suggested to be associated with excitotoxicity but the involvement of cytoplasmic enzymes in ROS formation is not clearly known. In the present study, we examined the role of xanthine oxidase (XO), nitric oxide synthase (NOS) and phospholipase A(2) (PLA(2)) in glutamate-induced oxidative stress in rat cortical slices. Glutamate-induced ROS formation and mitochondrial depolarization were measured in rat cortical slices in presence of allopurinol, L-NAME and 4-bromophenacylbromide, the specific inhibitors of XO, NOS and PLA(2), respectively. Upon stimulation of slices with glutamate, a significant increase in ROS formation and mitochondrial depolarization was observed. However, pretreatment of slices with allopurinol, L-NAME and 4-bromophenacylbromide inhibited the glutamate-induced ROS formation and mitochondrial depolarization. The glutamate-induced ROS formation was dependent on the concentration of these inhibitors and also on the duration of the treatment. Allopurinol was found to be less effective as compared to L-NAME and 4-bromophenacylbromide. The combined treatment of slices with these enzyme inhibitors showed further inhibition in ROS formation and mitochondrial depolarization. The inhibition in ROS formation as well as mitochondrial depolarization by allopurinol, L-NAME and 4-bromophenacylbromide clearly suggests that the activation of XO, NOS and PLA(2) by calcium during glutamate receptor stimulation may release some chemicals which depolarize mitochondria resulting in ROS formation.
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PMID:Xanthine oxidase, nitric oxide synthase and phospholipase A(2) produce reactive oxygen species via mitochondria. 1577 70

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

Mitochondrial Ca(2+) uptake and poly(ADP-ribose) polymerase-1 (PARP-1) activation are both required for glutamate-induced excitotoxic neuronal death. Since activation of the glutamate receptors can induce increased levels of reactive oxygen species (ROS), we investigated the relationship of mitochondrial Ca(2+) uptake and ROS generation, and the possibility that ROS increase is a required signal for PARP-1 activation in cultured striatal neurons. Based on the spatial profile of NMDA-induced ROS generation, we found that only mitochondria showed a significant ROS increase within 30 min after NMDA receptor activation. This ROS increase was inhibited by the mitochondrial complex inhibitors rotenone and oligomycin, but not by the cytosolic phospholipase A(2) or xanthine oxidase inhibitors. Mitochondrial ROS generation was also inhibited by both removal of Ca(2+) from extracellular medium and blockage of mitochondrial Ca(2+) uptake by either a mitochondrial uncoupler or a Ca(2+) uniporter inhibitor. Furthermore, both DNA damage and PARP-1 activation induced by NMDA treatment was inhibited by blocking mitochondrial Ca(2+) uptake or by antioxidants. Our results demonstrate that ROS production during the early stage of acute excitotoxicity derives primarily from mitochondria and is Ca(2+)-dependent. More importantly, the increase of mitochondrial ROS serves as a signal for PARP-1 activation, suggesting that concomitant mitochondrial Ca(2+) uptake and PARP-1 activation constitute a unified mechanism for excitotoxic neuronal death.
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PMID:Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. 1794 4

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

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

Oxidative stress has been suggested as a mechanism contributing to neuronal death induced by hypoglycemia, and an early production of reactive species (RS) during the hypoglycemic episode has been observed. However, the sources of reactive oxygen (ROS) and nitrogen (RNS) species have not been fully identified. In the present study we have examined the contribution of various enzymatic pathways to RS production and neuronal death induced by glucose deprivation (GD) in hippocampal cultures. We have observed a rapid increase in RS during GD, which depends on the activation of NMDA and non-NMDA receptors and on the influx of calcium from the extracellular space. Accordingly, intracellular calcium concentration [Ca(2+)](i) progressively increases more than 30-fold during the GD period. It was observed that superoxide production through the activation of the calcium-dependent enzymes, phospholipase A(2) (cPLA(2)) and xanthine oxidase (XaO), contributes to neuronal damage, while nitric oxide synthase (NOS) is apparently not involved. Inhibition of cPLA(2) decreased RS at early times of GD whereas inhibition of XaO diminished RS at more delayed times. The antioxidants trolox and ebselen also showed a protective effect against neuronal death and diminished RS generation. Inhibition of NADPH oxidase also contributed to the early generation of superoxide. Taking together, the present results suggest that the early activation of calcium-dependent ROS producing pathways is involved in neuronal death associated with glucose deprivation.
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PMID:Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons. 2022 35


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