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)

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

Competition for cellular iron (Fe) is a vital component of the interaction between host and intracellular pathogen. The host cell requires Fe for the execution of antimicrobial effector mechanisms, whereas most bacteria have an obligate requirement for Fe to sustain growth and intracellular survival. In this study, we show that chelation of host Fe in vivo exacerbates murine salmonellosis, resulting in increased bacterial load and decreased survival times. We further demonstrate that host Fe deprivation results in an inability to induce the NADPH oxidase-dependent production of reactive oxygen, an essential host defense mechanism for the early control of Salmonella typhimurium infection. Thus, altering the equilibrium of intracellular Fe influences the course of infection to the benefit of the pathogen.
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PMID:Iron chelation via deferoxamine exacerbates experimental salmonellosis via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase-dependent respiratory burst. 1190 5

The cytotoxicity of asbestos has been related to its ability to increase the production of reactive oxygen species (ROS), via the iron-catalyzed reduction of oxygen and/or the activation of NADPH oxidase. The pentose phosphate pathway (PPP) is generally activated by the cell exposure to oxidant molecules. Contrary to our expectations, asbestos (crocidolite) fibers caused a dose- and time-dependent inhibition of PPP and decreased its activation by an oxidative stress in human lung epithelial cells A549. In parallel, the intracellular activity of the PPP rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD), was significantly diminished by crocidolite exposure. This inhibition was selective, as the activity of other PPP and glycolysis enzymes was not modified, and was not attributable to a decreased expression of G6PD. On the opposite, the incubation with glass fibers MMVF10 did not modify PPP and G6PD activity. PPP and G6PD inhibition did not correlate with the increased nitric oxide (NO) production elicited by crocidolite in A549 cells. Experiments with the purified enzyme suggest that crocidolite inhibits G6PD by directly interacting with the protein. We propose here a new mechanism of asbestos-evoked oxidative stress, wherein fibers increase the intracellular ROS levels also by inhibiting the main antioxidant pathway of the cell.
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PMID:Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells. 1197 96

Chronic inflammation and production of DNA-damaging reactive oxygen species (ROS) may be involved in silica-induced lung cancer. Studies to date have largely focused on silica-induced production of ROS by lung phagocytes. In this study, we investigated the hypothesis that particulate silica (DQ12) can also induce elevations in intracellular ROS in a cancer-target cell type, i.e., human bronchial epithelial cells (BECs), via an indirect mechanism that involves ROS-inducing extracellular factor(s) that occur upon the interaction of silica with culture medium. The intracellular production of hydrogen peroxide (H(2)O(2)) in BECs was assessed by flow cytometry via monitoring dichlorofluorescein (DCF) fluorescence. Culture medium containing 10% human serum was incubated with silica particles in concentrations ranging from 10 to 50 microg/ml, and following incubation for 1 h and removal of the particles, the resulting supernatants were added to BECs. Silica-treated medium induced significant increases in intracellular H(2)O(2) after the medium had been treated with as little as 10 microg/ml of the particles. Further, the level of ROS increases in BECs in response to silica-treated medium was found to be virtually identical to that induced in cells that were directly treated with silica in suspension. Based on enzyme inhibitory studies, the mechanism for this increased generation of intracellular ROS appears to involve both mitochondrial respiration and a NAD(P)H oxidase-like system. Spectrofluorimetric experiments with the antioxidant enzymes superoxide dismutase and catalase showed that superoxide anions (O2*-) and H(2)O(2) are generated in silica-treated medium, but these ROS do not fully account for the induction of the intracellular ROS response. Iron, on the other hand, was found to be crucial to the process. Our collective results suggest silica-aqueous medium interactions can lead to the generation of factor(s) that induce the intracellular production of potentially DNA-damaging ROS in BECs in a manner that does not require direct particle-cell interactions.
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PMID:Silica-induced generation of extracellular factor(s) increases reactive oxygen species in human bronchial epithelial cells. 1201 87

Alveolar macrophages have been implicated in the pathogenesis of a number of acute and chronic lung disorders. We have previously shown that normal human alveolar macrophages exhibit decreased DNA binding activity of the transcription factor, AP-1, compared with monocytes. Furthermore, this decrease in AP-1 DNA binding appears to be due to a decrease in the redox active protein, redox factor (Ref)-1. Ref-1 is an important redox regulator of a number of transcription factors, including NF-kappaB and AP-1. In this study we evaluated the role of asbestos, a prototypic model of chronic fibrotic lung disease, in Ref-1 expression and activity. We found that incubation with low concentrations of crocidolite asbestos (0.5-1.25 microg/cm(2)) resulted in an increase in nuclear Ref-1 protein after 5 min, with a persistent elevation in protein up to 24 h. Additionally, an increase in nuclear Ref-1 could be induced by treating the cells with an oxidant-generating stimulus (iron loading plus PMA) and inhibited by diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. The asbestos-induced accumulation of nuclear Ref-1 was associated with an increase in AP-1 DNA binding activity. These findings suggest that an exposure associated with fibrotic lung disease, i.e., asbestos, modulates accumulation of nuclear Ref-1 in macrophages, and that this effect is mediated by an oxidant stimulus.
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PMID:Oxidant-mediated increases in redox factor-1 nuclear protein and activator protein-1 DNA binding in asbestos-treated macrophages. 1202 66

Oncogenic transformed fibroblasts are characterized by extracellular superoxide anion generation through a membrane-associated NADPH oxidase. After cellular glutathione depletion, extracellular reactive oxygen species (ROS) generated by transformed fibroblasts exhibit a strong apoptosis-inducing potential. As apoptosis induction under glutathione depletion is inhibited by catalase, the NADPH oxidase inhibitor apocynin, superoxide dismutase, the hydroxyl radical scavenger terephthalate and the iron chelator deferoxamine, the metal-catalysed Haber-Weiss reaction seems to be the responsible signaling mechanism. In contrast to extracellular ROS, intracellular ROS play no role for apoptosis induction in glutathione-depleted transformed fibroblasts initially, since a high level of intracellular catalase scavenges intracellular hydrogen peroxide. Intracellular catalase seems to be induced by extracellular hydrogen peroxide, as pretreatment of transformed fibroblasts with exogenous catalase downmodulates endogenous catalase and renders glutathione-depleted transformed cells susceptible for the effect of endogenous hydrogen peroxide. In contrast to transformed fibroblasts, nontransformed glutathione-depleted fibroblasts do not generate substantial extracellular ROS, but apoptosis is efficiently induced in these cells by intracellular ROS. Our data show that extracellular ROS of transformed fibroblasts exhibit redox-related signaling and at the same time represent a potential apoptosis-inducing hazard through the metal-catalysed Haber-Weiss reaction.
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PMID:Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts. 1218 88

Treatment of carcinoma cell lines with 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma, has been reported to induce apoptosis and/or inhibit proliferation. In this study, we investigated the cytotoxic effect and the action mechanisms of 15d-PGJ2 in a thyroid papillary cancer cell line, CG3. The results indicate that 15d-PGJ2 caused cytotoxicity and increased the amount of intracellular reactive oxygen species (ROS) in these cells. Mitochondrial oxidative phosphorylation inhibitors (carbonyl cyanide m-chloro-phenylhydrazone, oligomycin, cyclosporin A and rotenone), NADPH oxidase inhibitor (diphenyleneiodonium), xanthine oxidase inhibitor (allopurinol) and NO synthase inhibitor (N-monomethyl-L-arginine acetate) did not reduce the generation of ROS. However, catalase, N-acetyl-cysteine and the iron chelator desferri-oxamine decreased the intracellular ROS of 15d-PGJ2-treated CG3 cells. Furthermore, 15d-PGJ2 enhanced the accumulation of iron in the CG3 cells. These data suggest that 15d-PGJ2 induces the generation of ROS by enhancing the accumulation of intracellular iron and that the increased oxidative stress may cause apoptosis of CG3 cells.
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PMID:15-Deoxy-delta12,14-prostaglandin J2 induces apoptosis of a thyroid papillary cancer cell line (CG3 cells) through increasing intracellular iron and oxidative stress. 1218 33

The modification of low-density lipoprotein (LDL) by normal, myeloperoxidase (MPO)-deficient and NADPH oxidase-deficient granulocytes was investigated using the monoclonal antibody (mAb) OB/04, which was originally generated against copper-oxidized LDL. Incubation of LDL with normal granulocytes increased the reactivity of LDL with mAb OB/04. These effects were even more pronounced using MPO-deficient granulocytes. Inhibitors of oxidative reactions (the NADPH oxidase inhibitor diphenyleneiodonium chloride [DPI], catalase, superoxide dismutase [SOD]) did not significantly reduce LDL oxidation by normal granulocytes. Furthermore, granulocytes of a patient with NADPH oxidase deficiency were almost equally effective as normal granulocytes, indicating that oxidative burst-derived reactive oxygen species are of only minor importance in the generation of mAb OB/04-detectable new epitopes on LDL in vitro. In contrast, incubation of LDL with iron and copper prior to and during incubation with normal granulocytes markedly enhanced the generation of OB/04-detectable epitopes. It is supposed that, besides superoxide (in normal and MPO-deficient granulocytes) or instead of superoxide (in NADPH oxidase-deficient granulocytes), lytic enzymes released by activated granulocytes may enhance the availability of transition metals for oxidation of LDL. Our results support the concept that transition-metal-dependent pathways of LDL oxidation in combination with degranulation products of granulocytes are important.
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PMID:Low-density lipoprotein modification by normal, myeloperoxidase-deficient and NADPH oxidase-deficient granulocytes and the impact of redox active transition metal ions. 1218 57

Oxidative stress is induced by a wide range of environmental factors including UV stress, pathogen invasion (hypersensitive reaction), herbicide action and oxygen shortage. Oxygen deprivation stress in plant cells is distinguished by three physiologically different states: transient hypoxia, anoxia and reoxygenation. Generation of reactive oxygen species (ROS) is characteristic for hypoxia and especially for reoxygenation. Of the ROS, hydrogen peroxide (H(2)O(2)) and superoxide (O(2)(.-)) are both produced in a number of cellular reactions, including the iron-catalysed Fenton reaction, and by various enzymes such as lipoxygenases, peroxidases, NADPH oxidase and xanthine oxidase. The main cellular components susceptible to damage by free radicals are lipids (peroxidation of unsaturated fatty acids in membranes), proteins (denaturation), carbohydrates and nucleic acids. Consequences of hypoxia-induced oxidative stress depend on tissue and/or species (i.e. their tolerance to anoxia), on membrane properties, on endogenous antioxidant content and on the ability to induce the response in the antioxidant system. Effective utilization of energy resources (starch, sugars) and the switch to anaerobic metabolism and the preservation of the redox status of the cell are vital for survival. The formation of ROS is prevented by an antioxidant system: low molecular mass antioxidants (ascorbic acid, glutathione, tocopherols), enzymes regenerating the reduced forms of antioxidants, and ROS-interacting enzymes such as SOD, peroxidases and catalases. In plant tissues many phenolic compounds (in addition to tocopherols) are potential antioxidants: flavonoids, tannins and lignin precursors may work as ROS-scavenging compounds. Antioxidants act as a cooperative network, employing a series of redox reactions. Interactions between ascorbic acid and glutathione, and ascorbic acid and phenolic compounds are well known. Under oxygen deprivation stress some contradictory results on the antioxidant status have been obtained. Experiments on overexpression of antioxidant production do not always result in the enhancement of the antioxidative defence, and hence increased antioxidative capacity does not always correlate positively with the degree of protection. Here we present a consideration of factors which possibly affect the effectiveness of antioxidant protection under oxygen deprivation as well as under other environmental stresses. Such aspects as compartmentalization of ROS formation and antioxidant localization, synthesis and transport of antioxidants, the ability to induce the antioxidant defense and cooperation (and/or compensation) between different antioxidant systems are the determinants of the competence of the antioxidant system.
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PMID:Antioxidants, oxidative damage and oxygen deprivation stress: a review. 1250 39

Iron- or copper-mediated catalysis leads to the generation of reactive oxygen species (ROS) that can attack biomolecules directly, with the consequent enhancement in membrane lipid peroxidation, DNA damage, and protein oxidation. Reactive nitrogen species (RNS) can also be formed, leading to nitration of aromatic structures in addition to the oxidative deterioration of cellular components. Kupffer cells, the resident macrophages of the liver, play significant roles in immunomodulation, phagocytosis, and biochemical attack. Upon stimulation, liver macrophages release biologically active products related to cell injury, namely, ROS, RNS, and both immunomodulatory and fibrogenic cytokines, with production of chemokines and adhesion molecules by other cells of the liver sinusoid. Iron and copper alter the functional status of Kupffer cells by enhancing their respiratory burst activity without modifying particle phagocytosis. This effect is probably due to extra O2 equivalents used in the oxidation of biomolecules and/or in the activating action of iron/copper on nitric oxide synthase, in addition to those employed by NADPH oxidase activity. Changes in gene expression of Kupffer cells may also be accomplished by iron and copper through modulation of the activity of transcription factors such as NF-kappaB, which signals the production of cytotoxic, proinflammatory, or fibrogenic mediators. Thus, iron/copper-induced hepatotoxicity is a multifactorial phenomenon underlying actions due to the generation of ROS and RNS that may alter essential biomolecules with loss of their biological functions, modulate gene expression of Kupffer cells with production of cytotoxic mediators, or both.
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PMID:Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. 1257 70


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