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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phagocyte-derived reactive oxygen species have been implicated in the clearance of malaria infections. We investigated the progression of five different strains of murine malaria in gp91(phox-/-) mice, which lack a functional NADPH oxidase and thus the ability to produce phagocyte-derived reactive oxygen species. We found that the absence of functional NADPH oxidase in the gene knockout mice had no effect on the parasitemia or total parasite burden in mice infected with either resolving (Plasmodium yoelii and Plasmodium chabaudi K562) or fatal (Plasmodium berghei ANKA, Plasmodium berghei K173 and Plasmodium vinckei vinckei) strains of malaria. This lack of effect was apparent in both primary and secondary infections with P. yoelii and P. chabaudi. There was also no difference in the presentation of clinical or pathological signs between the gp91(phox-/-) or wild-type strains of mice infected with malaria. Progression of P. berghei ANKA and P. berghei K173 infections was unchanged in glutathione peroxidase-1 gene knockout mice compared to their wild-type counterparts. The rates of parasitemia progression in gp91(phox-/-) mice and wild-type mice were not significantly different when they were treated with l-N(G)-methylarginine, an inhibitor of nitric oxide synthase. These results suggest that phagocyte-derived reactive oxygen species are not crucial for the clearance of malaria parasites, at least in murine models.
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PMID:Phagocyte-derived reactive oxygen species do not influence the progression of murine blood-stage malaria infections. 1604 Oct 8

Microglial cells are the resident immune cells of the central nervous system. These cells defend the central nervous system against invading microorganisms and clear the debris from damaged cells. Upon activation, microglial cells produce a large number of neuroactive substances that include cytokines, proteases, and prostanoids. In addition, activated microglial cells release radicals, such as superoxide and nitric oxide, that are products of the enzymes NADPH oxidase and inducible nitric oxide synthase, respectively. Microglia-derived radicals, as well as their reactive reaction products hydrogen peroxide and peroxynitrite, have the potential to harm cells and have been implicated in contributing to oxidative damage and neuronal cell death in neurological diseases. For self-protection against oxidative damage, microglial cells are equipped with efficient antioxidative defense mechanisms. These cells contain glutathione in high concentrations, substantial activities of the antioxidative enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, as well as NADPH-regenerating enzymes. Their good antioxidative potential protects microglial cells against oxidative damage that could impair important functions of these cells in defense and repair of the brain.
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PMID:Oxidative and antioxidative potential of brain microglial cells. 1611 27

Experiments were designed to test the hypothesis that elevated levels of endothelin 1 (ET-1) in the vasculature activate NADPH oxidase and/or uncoupled nitric-oxide synthase (NOS), resulting in O2-* production, and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of superoxide dismutase (SOD), ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (Nomega-nitro-L-arginine methyl ester) (NOS inhibitor), tetrahydrobiopterin (BH4) (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] and A-192621 [[2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]], respectively). O2-* production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased O2-* production compared with vehicle. SOD, ebselen, and apocynin inhibited the ET-1-induced increase in O2-* in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1-induced increase in O2-* in intact tissue, whereas these two compounds had no effect on ET-1-induced O2-* in endothelium-denuded aorta. Preincubation with BQ-123 or A-192621, individually, had no effect on ET-1-induced O2-*; however combining both antagonists inhibited the ET-1-stimulated increase in O2-*. Rat aortic rings were incubated with ET-1 or vehicle in the presence or absence of sepiapterin (BH4 synthesis substrate) or apocynin and mounted on wire myographs to determine isometric force generation in response to increasing KCl concentrations. ET-1 increased the contractile response to KCl compared with vehicle. Treatment with either sepiapterin or apocynin attenuated the ET-1-mediated increase with no effect of sepiapterin or apocynin alone. These data support the hypothesis that ET-1 increases vascular tone, in part, through ETA/ETB receptor activation of O2-* production from NADPH oxidase and NOS uncoupling.
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PMID:Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. 1614 72

Senescence marker protein 30 (SMP30), an important aging marker molecule, has been identified functionally as a calcium regulatory protein. Recent evidence showed its new assumed role as an effective anti-oxidative property. However, the role of SMP30 in the brain has not been explored. To delineate its role in the brain, we utilized SMP30 knock-out (SMP30 KO) mice in the current study. We focused on the oxidative status of the brain by examining selected oxidative markers in brains of SMP30 KO mice. Results showed that the generation of reactive species (RS) and NADPH oxidase activities were significantly elevated in SMP30 deficient brain. The increased oxidative status in these mice was further confirmed by increased oxidatively modified proteins such as dityrosine formation and carbonylation in the cortex of SMP30 KO mice. Moreover, SMP30 deficient brain showed the increased Mac-1 protein and myeloperoxidase (MPO) activity in the brain, supporting the putative anti-oxidative action of SMP30. Interestingly, the activities of major antioxidant enzymes, superoxide dismutase, catalase and reduced glutathione peroxidase in the brain were not affected by SMP30 depletion. Our results documented that brain SMP30 has a protective action against oxidative damage, without influencing antioxidant enzyme status.
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PMID:SMP30 deficiency causes increased oxidative stress in brain. 1650 Jun 93

Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 microg/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059+/-130 to 422+/-80 (oxyethidium fluorescence units) and mean arterial pressure from 175+/-4 to 157+/-6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13(BN). We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.
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PMID:NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats. 1650 10

Data from numerous studies demonstrate that oxidative stress plays an important role in the pathogenesis of vascular disease. Oxidative stress leads to many pathologic events, such as inactivation of nitric oxide, lipid oxidation, enhanced mitogenicity and apoptosis of vascular cells, and increased expression and activation of redox-sensitive genes, which contribute to atherogenesis at all stages of the disease. Multiple enzymes are expressed in vascular cells that are involved in the elimination and production of reactive oxygen species, including the superoxide dismutases, catalase, thioredoxin reductase, glutathione peroxidase, NAD(P)H oxidase, xanthine oxidase, myeloperoxidase, and endothelial nitric oxide synthase. Several agonists and pathologic conditions that predispose to vascular disease induce changes in the expression and activity levels of these antioxidant and oxidant enzyme systems, leading to modulation of vascular oxygen radical load. Identification of key enzymes and mechanisms of vascular oxidative stress is important for the development of novel, specific pharmacologic interventions.
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PMID:Regulation of antioxidant and oxidant enzymes in vascular cells and implications for vascular disease. 1660 Jan 62

Mitochondrial P450 type enzymes catalyze central steps in steroid biosynthesis, including cholesterol conversion to pregnenolone, 11beta and 18 hydroxylation in glucocorticoid and mineralocorticoid synthesis, C-27 hydroxylation of bile acids, and 1alpha and 24 hydroxylation of 25-OH-vitamin D. These monooxygenase reactions depend on electron transfer from NADPH via FAD adrenodoxin reductase and 2Fe-2S adrenodoxin. These systems can function as a futile NADPH oxidase, oxidizing NADPH in absence of substrate, and leak electrons via adrenodoxin and P450 to O(2), producing superoxide and other reactive oxygen species (ROS). The degree of uncoupling depends on the P450 and steroid substrate. Studies with purified proteins and overexpression in cultured cells show consistently that adrenodoxin, but not reductase, is responsible for ROS production that can lead to apoptosis. In the ovary and corpus luteum, antioxidant enzyme activities superoxide dismutase, catalase, and glutathione peroxidase parallel steroidogenesis. Antioxidant beta-carotene, alpha-tocopherol, and ascorbate can protect against oxidative damages of P450 systems. In testis Leydig cells, steroidogenesis is associated with aging of the steroidogenic capacity.
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PMID:Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells. 1668 56

The study aim was to investigate the interaction of physical conditioning and chronic ethanol ingestion on blood pressure (BP), heart rate (HR), nitric oxide (NO) and oxidants/antioxidants balance in the plasma of rats. Male Fisher rats were divided into four groups of seven animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks; (2) ethanol (4 g kg(-1), orally) daily for 12 weeks; (3) exercise training on treadmill plus sucrose daily for 12 weeks and (4) exercise training on treadmill followed by ethanol (4 g kg(-1), orally) daily for 12 weeks. The body weight, BP and HR were recorded every week. The animals were sacrificed under ether anesthesia after 12 weeks, blood collected in heparinzed vials, plasma isolated and analyzed. The results show that exercise training significantly lowered the weight gain 6-12 weeks in ethanol treated rats compared to ethanol alone or control rats. The mean arterial BP was significantly elevated 6-12 weeks after ethanol ingestion without significant alterations in HR. Exercise training lowered the BP close to the normal control values in ethanol fed rats. Ethanol significantly decreased the plasma NO levels, reduced to oxidized glutathione ratio (GSH/GSSG) and antioxidant enzymes-superoxide dismutase (CuZn-SOD, and Mn-SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities while plasma NADPH oxidase activity and malondialdehyde (MDA) levels were significantly elevated compared to control. Exercise training significantly restored the depletion of plasma NO levels, GSH/GSSG ratio, and antioxidant enzyme activities and normalized the MDA levels and NADPH oxidase activity in the plasma of ethanol treated rats. The study concluded that physical conditioning attenuates the chronic ethanol-induced hypertension by augmenting the NO bioavailability and reducing the oxidative stress response in the plasma of rats.
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PMID:Physiological basis for effect of physical conditioning on chronic ethanol-induced hypertension in a rat model. 1671 71

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

Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca(2+) concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with hypertension.
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PMID:Redox signaling in hypertension. 1676 37


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