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)

We previously showed that "ischemia" (abrupt cessation of flow) leads to rapid membrane depolarization and increased generation of reactive oxygen species (ROS) in lung microvascular endothelial cells. This response is not associated with anoxia but, rather, reflects loss of normal shear stress. This study evaluated whether a similar response occurs in aortic endothelium. Plasma membrane potential and production of ROS were determined by fluorescence microscopy and cytochrome c reduction in flow-adapted rat or mouse aorta or monolayer cultures of rat aortic endothelial cells. Within 30 s after flow cessation, endothelial cells that had been flow adapted showed plasma membrane depolarization that was inhibited by pretreatment with cromakalim, an ATP-sensitive K(+) (K(ATP)) channel agonist. Flow cessation also led to ROS generation, which was inhibited by cromakalim and the flavoprotein inhibitor diphenyleneiodonium. Aortic endothelium from mice with "knockout" of the K(ATP) channel (K(IR)6.2) showed a markedly attenuated change in membrane potential and ROS generation with flow cessation. In aortic endothelium from mice with knockout of NADPH oxidase (gp91(phox)), membrane depolarization was similar to that in wild-type mice but ROS generation was absent. Thus rat and mouse aortic endothelial cells respond to abrupt flow cessation by K(ATP) channel-mediated membrane depolarization followed by NADPH oxidase-mediated ROS generation, possibly representing a cell-signaling response to altered mechanotransduction.
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PMID:Membrane depolarization and NADPH oxidase activation in aortic endothelium during ischemia reflect altered mechanotransduction. 1533 75

Increased oxidative stress may play a key role in the progressive deterioration of pancreatic beta-cells and the development of diabetes. However, the underlying mechanism is not well understood. Exposure of pancreatic beta-cell line, MIN6 cells, to elevated glucose level for 2h induced an increase in reactive oxygen species (ROS) production, as evaluated by the staining of 2',7'-dichlorofluorescein diacetate. This effect was completely blocked by NAD(P)H oxidase inhibitor (diphenylene iodonium) and protein kinase C (PKC) inhibitor (calphostin C), but not affected by other flavoprotein inhibitors (rotenone, oxypurinol, or l-N-monomethyl arginine). Glibenclamide also stimulated ROS production in a dose-dependent manner. This effect was again blocked by diphenylene iodonium and calphostin C. In conclusion, insulin secretagogues, both glibenclamide and elevated glucose level, stimulated ROS production in beta-cells through a PKC-dependent activation of NAD(P)H oxidase. This mechanism may be a novel therapeutic target for preventing the progression of beta-cell deterioration.
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PMID:Sulfonylurea as well as elevated glucose levels stimulate reactive oxygen species production in the pancreatic beta-cell line, MIN6-a role of NAD(P)H oxidase in beta-cells. 1556 52

The dual oxidase (Duox)2 flavoprotein is strongly expressed in the thyroid gland, where it plays a critical role in the synthesis of thyroid hormones by providing thyroperoxidase with H2O2. DUOX2 mRNA was recently detected by RT-PCR and in-situ hybridization experiments in other tissues, such as rat colon and rat and human epithelial cells from the salivary excretory ducts and rectal glands. We examined Duox2 expression at the protein level throughout the porcine digestive tract and in human colon. Western blot analysis identified Duox2 as the same two molecular species (M(r) 165 and 175 kDa) as detected in the thyroid. It was expressed in all the tissues tested, but the highest levels were found in the cecum and sigmoidal colon. Immunohistochemical studies showed that Duox2 protein is mainly present in these parts of the gut and located at the apical membrane of the enterocytes in the brush border, indicating that it is expressed only in highly differentiated cells. A Ca2+/NADPH-dependent H2O2-generating system was associated with Duox2 protein expression, which had the same biochemical characteristics as the NADPH oxidase in the thyroid. Indeed, treatment of the thyroid and cecum particulate fractions with phenylarsine oxide resulted in complete calcium desensitization of both enzymes. A marked increase in DUOX2 expression was also found during spontaneous differentiation of postconfluent Caco-2 cells. The discovery of Duox2 as a novel source of H2O2 in the digestive tract, particularly in the cecum and colon, makes it a new candidate mediator of physiopathological processes.
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PMID:Dual oxidase2 is expressed all along the digestive tract. 1559 Nov 62

Reactive oxygen species (ROS) has been increasingly recognised as intracellular messengers in signal transduction following receptor activation by a variety of bioactive peptides including growth factors, cytokines and hormones. In this study ROS production and glucose transport activity were evaluated in the growth factor dependent M07e cells and in B1647 cells, not requiring additional hematopoietic cytokines for growth: the aim was to investigate whether ROS could be involved in the regulation of Glut1-mediated glucose uptake in both cell lines. The effect of the synthetic superoxide and hydrogen peroxide scavenger EUK-134 on DOG uptake activity and intracellular ROS formation supports the concept of reactive oxygen species as signalling molecules. In order to investigate ROS generation sources, diphenyleneiodonium, an inhibitor of flavoprotein centres and apocynin, an inhibitor of NAD(P)H oxidase, were used: they inhibit both ROS production and glucose uptake activation. All these data support the hypothesis that ROS can contribute to the regulation of glucose transport, not only in M07e cells but also in B1647 cells; we could speculate that one possible source of ROS, linked somehow with Glut1 activity, can be a NAD(P)H oxidase similar to that one present in phagocytic cells.
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PMID:ROS production and Glut1 activity in two human megakaryocytic cell lines. 1570 59

The extracellular tissue penetrating protozoan parasite Entamoeba histolytica has been known to induce host cell apoptosis. However, the intracellular signaling mechanism used by the parasite to trigger apoptosis is poorly understood. In this study, we investigated the roles of reactive oxygen species (ROS), and of MAPKs in the Entamoeba-induced apoptosis of human neutrophils. The neutrophils incubated with live trophozoites of E. histolytica revealed a marked increase of receptor shedding of CD16 as well as phosphatidylserine (PS) externalization on the cell surface. The Entamoeba-induced apoptosis was effectively blocked by pretreatment of cells with diphenyleneiodonium chloride (DPI), a flavoprotein inhibitor of NADPH oxidase. A large amount of intracellular ROS was detected after exposure to viable trophozoites, and the treatment with DPI strongly inhibited the Entamoeba-induced ROS generation. However, a mitochondrial inhibitor rotenone did not attenuate the Entamoeba-induced ROS generation and apoptosis. Although E. histolytica strongly induced activation of ERK1/2 and p38 MAPK in neutrophils, the activation of ERK1/2 was closely associated with ROS-mediated apoptosis. Pretreatment of neutrophils with MEK1 inhibitor PD98059, but not p38 MAPK inhibitor SB202190, prevented Entamoeba-induced apoptosis. Moreover, DPI almost completely inhibited Entamoeba-induced phosphorylation of ERK1/2, but not phosphorylation of p38 MAPK. These results strongly suggest that NADPH oxidase-derived ROS-mediated activation of ERK1/2 is required for the Entamoeba-induced neutrophil apoptosis.
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PMID:NADPH oxidase-derived reactive oxygen species-mediated activation of ERK1/2 is required for apoptosis of human neutrophils induced by Entamoeba histolytica. 1577 91

Matrix metalloproteinase-9 (MMP-9) is involved in physiological tissue remodelling processes as well as in tumor invasion and metastasis. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increases MMP-9 secretion from normal human epidermal keratinocytes (NHEK) in vivo and in vitro. Here we show that the flavoprotein inhibitor diphenyleneiodinium (DPI) and the NADPH oxidase inhibitor apocynin block TPA-induced MMP-9 secretion of NHEK in vitro. Furthermore, N-acetyl-L-cysteine and L-cysteine lowered TPA-induced MMP-9 secretion, suggesting an involvement of reactive oxygen species(ROS). TPA exerts its effect on MMP-9 gene expression and secretion via the superoxide-producing enzyme NADPH oxidase: TPA rapidly stimulates generation of superoxide anion as well as gene expression of two cytosolic NADPH oxidase subunits (p47-phox and p67-phox) after 2 h, which is followed by induction of MMP-9 gene expression after 4 h. Taken together, the novel finding herein is the TPA-induced MMP-9 secretion from normal human epidermal keratinocytes through a NADPH oxidase dependent pathway.
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PMID:Tumor promoter TPA stimulates MMP-9 secretion from human keratinocytes by activation of superoxide-producing NADPH oxidase. 1578 29

In afferent arteriolar vascular smooth muscle cells, ANG II induces a rise in cytosolic Ca(2+) ([Ca(2+)](i)) via inositol trisphosphate receptor (IP(3)R) stimulation and by activation of the adenine diphosphate ribose (ADPR) cyclase to form cyclic ADPR, which sensitizes the ryanodine receptor (RyR) to Ca(2+). We hypothesize that ANG II stimulation of NAD(P)H oxidases leads to the formation of superoxide anion (O(2)-*, which, in turn, activates ADPR cyclase. Afferent arterioles were isolated from rat kidney with the magnetized microsphere and sieving technique and loaded with fura-2 to measure [Ca(2+)](i). ANG II rapidly increased [Ca(2+)](i) by 124 +/- 12 nM. In the presence of apocynin, a specific inhibitor of NAD(P)H oxidase assembly, the [Ca(2+)](i) response was reduced to 35 +/- 5 nM (P < 0.01). Tempol, a superoxide dismutase mimetic, did not alter the [Ca(2+)](i) response to ANG II at a concentration of 10(-4) M (99 +/- 12 nM), but 10(-3) M tempol reduced the response to 32 +/- 3 nM (P < 0.01). The addition of nicotinamide, an inhibitor of ADPR cyclase, to apocynin or tempol (10(-3) M) resulted in no further inhibition. Measurement of superoxide production with the fluorescent probe tempo 9-AC showed that ANG II caused an increase of 48 +/- 20 arbitrary units; apocynin or diphenyl iodonium (an inhibitor of flavoprotein oxidases) inhibited the response by 94%. Hydrogen peroxide (H(2)O(2)) was studied at physiological (10(-7) M) and higher concentrations. In the presence of H(2)O(2) (10(-7) M), neither baseline [Ca(2+)](i) nor the response to ANG II was altered (125 +/- 15 nM), whereas H(2)O(2) (10(-6) and 10(-5) M) inhibited the [Ca(2+)](i) response to ANG II by 35 and 46%, respectively. We conclude that ANG II rapidly activates NAD(P)H oxidases of afferent arterioles, leading to the formation of O(2)-*, which then stimulates ADPR cyclase to form cADPR. cADPR, by sensitizing the RyR to Ca(2+), augments the Ca(2+) response (calcium-induced calcium release) initiated by activation of the IP(3)R.
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PMID:Angiotensin II, reactive oxygen species, and Ca2+ signaling in afferent arterioles. 1594 49

AMID (apoptosis-inducing factor-homologous mitochondrion-associated inducer of death; also known as PRG3 (p53-responsive gene 3)) is a human caspase-independent pro-apoptotic protein with some similarity to apoptosis-inducing factor. AMID was purified from a recombinant bacterial host, enabling biochemical analysis of the protein. AMID is a flavoprotein; possesses NAD(P)H oxidase activity; and catalyzes NAD(P)H-dependent reduction of cytochrome c and other electron acceptors, including molecular oxygen. NADPH binds approximately 10-fold tighter than NADH. AMID binds 6-hydroxy-FAD (a cofactor that accumulates only adventitiously and at low abundance in other flavoprotein enzymes) to form a stoichiometric cofactor.protein complex. AMID has a distinctive electronic spectrum due to the modified flavin. NAD(P)+ binding perturbed the spectrum, enabling determination of K(d) values for these coenzymes. 6-Hydroxy-FAD could be removed from AMID and the apoprotein reconstituted with FAD. FAD was converted to 6-hydroxy-FAD in reconstituted AMID during aerobic turnover with NADPH. AMID is a DNA-binding protein that lacks apparent DNA sequence specificity. Formation of the protein.DNA complex (i) effected a major protein conformational change and (ii) was prevented in the presence of nicotinamide coenzyme. Apo-AMID retains DNA binding activity. Our studies establish a link between coenzyme and DNA binding that likely impacts on the physiological role of AMID in cellular apoptosis.
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PMID:The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity. 1595 87

Oxidant stress plays a crucial role in the triggering of cardioprotection involving ischemic preconditioning (IPC). We have used biotin-tagged cysteine to probe for redox-modified proteins in IPC protocols. Cysteine was biotinylated and introduced into isolated rat hearts. S-Thiolated proteins were detected and quantified using nonreducing western blots probed with streptavidin-horseradish peroxidase. Controls (15 min of aerobic perfusion plus 5 min of 0.5 mM biotin-cysteine plus 5 min of aerobic perfusion) showed low-level protein S-thiolation. Hearts preconditioned with 5 min of ischemia and reperfused for 5 min with biotin-cysteine plus 5 min of aerobic perfusion showed increased thiolation (160%) that was fully blocked by the antioxidant mercaptopropionylglycine, which is also known to block IPC. "Preconditioning" agonists (phorbol 12-myristate 13-acetate or phenylephrine) or oxidants (hydrogen peroxide or diamide) administered during aerobic preparations to biotin-cysteine-loaded hearts induced efficient protein S-thiolation. Preconditioning agonist-induced S-thiolation was significantly attenuated by diphenyleneiodonium (a flavoprotein inhibitor) or by the protein kinase C inhibitor bisindolylmaleimide I. Additional studies testing the role of a Nox2-containing NAD(P)H oxidase as the source of the oxidant stress essential to the triggering IPC showed that protein S-thiolation was the same in wild-type and Nox2 knockout mice.
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PMID:Ischemic preconditioning: a potential role for protein S-thiolation? 1599 43

Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-beta1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF-beta1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF-beta1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving Smad 2/3 but not mitogen-activated protein (MAP) kinases. TGF-beta1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase flavoprotein inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF-beta1, Nox4 was present in freshly cultured cells but progressively lost with each passage in culture, paralleling a decrease in ROS production by HPASMC over time. At a later time point (72 h), TGF-beta1 promoted HPASMC proliferation in a manner partially inhibited by Nox4 small interfering RNA and dominant negative Smad 2/3, indicating that TGF-beta1 stimulates HPASMC growth in part by a redox-dependent mechanism mediated through induction of Nox4. HPASMC activation of the MAP kinases ERK1/2 was reduced by the NAD(P)H oxidase inhibitors DPI and 4-(2-aminoethyl)benzenesulfonyl fluoride, suggesting that TGF-beta1 may facilitate proliferation by upregulating Nox4 and ROS production, with transient oxidative inactivation of phosphatases and augmentation of growth signaling cascades. These findings suggest that Nox4 is the relevant Nox homolog in HPASMC. This is the first observation that TGF-beta1 regulates Nox4, with important implications for mechanisms of pulmonary vascular remodeling.
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PMID:Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. 1622 20


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