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)

Elevated cardiovascular risk is associated with an increased number of small, dense low-density lipoprotein (LDL) particles, which exhibit increased susceptibility to lipid oxidation, however, the mechanism determining LDL particle size has never been fully elucidated. We have examined the association between the C242T polymorphism of the p22 phox gene, which is a small subunit of vascular NAD(P)H oxidase, and both LDL particle size and clinical characteristics in 260 healthy subjects. Peak LDL particle diameter (LDL-PPD) was measured by continuous disk polyacrylamide gel electrophoresis. Twenty-one of the 217 subjects with the CC genotype showed pattern B (median LDL-PPD under 25.5 nm), whereas, none of the 43 subjects with TC + TT genotypes showed pattern B. The pattern B fraction was significantly larger in the CC group than in the TC + TT group (p = 0.030). The subjects with the CC genotype also showed a significantly higher fasting glucose level, plasma insulin level, and insulin resistance index of homeostasis model assessment (HOMA-R) than those with the TC + TT genotype. Our data demonstrate that variation in the small NAD(P)H oxidase subunit p22 phox gene substantially influences LDL particle size and may also reflect differences in the insulin sensitivity of non-diabetic subjects.
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PMID:NAD (P) H oxidase p22 phox C242T polymorphism affects LDL particle size and insulin resistance in Japanese subjects. 1222 52

Application of the elicitor cryptogein to tobacco (cv Xanthi) is known to evoke external medium alkalinization, active oxygen species production, and phytoalexin synthesis. These are all dependent on an influx of calcium. We show here that cryptogein also induces calcium-dependent plasma membrane depolarization, chloride efflux, cytoplasm acidification, and NADPH oxidation without changes in NAD+ and ATP levels, indicating that the elicitor-activated redox system, responsible for active oxygen species production, uses NADPH in vivo. NADPH oxidation activates the functioning of the pentose phosphate pathway, leading to a decrease in glucose 6-phosphate and to the accumulation of glyceraldehyde 3-phosphate, 3- and 2-phosphoglyceric acid, and phosphoenolpyruvate. By inhibiting the pentose phosphate pathway, we demonstrate that the activation of the plasma membrane NADPH oxidase is responsible for active oxygen species production, external alkalinization, and acidification of the cytoplasm. A model is proposed for the organization of the cryptogein responses measured to date.
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PMID:Early Events Induced by the Elicitor Cryptogein in Tobacco Cells: Involvement of a Plasma Membrane NADPH Oxidase and Activation of Glycolysis and the Pentose Phosphate Pathway. 1223 54

Diabetes is a major risk factor for premature atherosclerosis, and oxidative stress appears to be an important mechanism. Previously, we showed that diabetic monocytes produce increased superoxide anion (O(2)(-)), and alpha-tocopherol (AT) supplementation decreases this. The aim of this study was to elucidate the mechanism(s) of O(2)(-) release and inhibition by AT under hyperglycemic (HG) conditions in monocytes. O(2)(-) release, protein kinase C (PKC) activity, and translocation of PKC-alpha and -betaII and p47phox were increased in THP-1 cells (human monocytic cell line) under HG (15 mmol/l glucose) conditions, whereas AT supplementation inhibited these changes. AT, NADPH oxidase inhibitors (apocynin and diphenyleneiodonium chloride [DPI]), and an inhibitor to PKC-alpha and other isoforms (2,2',3,3',4,4'-hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether [HBDDE]) but not PKC-beta II (LY379196) decreased O(2)(-) release and p47phox translocation. Antisense oligodeoxynucleotides to PKC-alpha and p47phox but not to PKC-betaII inhibited HG-induced O(2)(-) release and p47phox translocation in THP-1 cells. Under HG conditions, reactive oxygen species release from monocytes was not inhibited by agents affecting mitochondrial metabolism but was inhibited in human endothelial cells. We conclude that under HG conditions, monocytic O(2)(-) release is dependent on NADPH oxidase activity but not the mitochondrial respiratory chain; HG-induced O(2)(-) release is triggered by PKC-alpha, and AT inhibits O(2)(-) release via inhibition of PKC-alpha.
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PMID:Alpha-tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-alpha. 1235 46

We present a two-compartment model to explain the oscillatory behavior observed experimentally in activated neutrophils. Our model is based mainly on the peroxidase-oxidase reaction catalyzed by myeloperoxidase with melatonin as a cofactor and NADPH oxidase, a major protein in the phagosome membrane of the leukocyte. The model predicts that after activation of a neutrophil, an increase in the activity of the hexose monophosphate shunt and the delivery of myeloperoxidase into the phagosome results in oscillations in oxygen and NAD(P)H concentration. The period of oscillation changes from >200 s to 10-30 s. The model is consistent with previously reported oscillations in cell metabolism and oxidant production. Key features and predictions of the model were confirmed experimentally. The requirement of the hexose monophosphate pathway for 10 s oscillations was verified using 6-aminonicotinamide and dexamethasone, which are inhibitors of glucose-6-phosphate dehydrogenase. The role of the NADPH oxidase in promoting oscillations was confirmed by dose-response studies of the effect of diphenylene iodonium, an inhibitor of the NADPH oxidase. Moreover, the model predicted an increase in the amplitude of NADPH oscillations in the presence of melatonin, which was confirmed experimentally. Successful computer modeling of complex chemical dynamics within cells and their chemical perturbation will enhance our ability to identify new antiinflammatory compounds.
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PMID:A model of the oscillatory metabolism of activated neutrophils. 1252 66

Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelial dysfunction in diabetes. To clarify whether glucose-modified HDL affects the function of endothelial cells, we first examined herein the level of H(2)O(2) generation from cultured human aortic endothelial cells (HAECs) exposed to a glycated oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation for 48 hours with 100 microg/mL of gly-ox-HDL induced significant release of H(2)O(2) from cells and gly-ox-HDL-induced H(2)O(2) formation was inhibited in the presence of diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, stimulation of HAECs with gly-ox-HDL for 48 hours elicited a marked downregulation of catalase and Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD), suggesting H(2)O(2) formation by gly-ox-HDL to be due to a disturbance involving oxidant and antioxidant enzymes in the cells. Treatment of HAECs with gly-ox-HDL attenuated the expression of endothelial nitric oxide synthase (eNOS), but not inducible nitric oxide synthase (iNOS), and this was followed by decreased production of nitric oxide (NO) by the cells. Furthermore, in vitro experiments with glycated HDL (gly-HDL) in the presence of 2 mmol/L EDTA and Cu(2+)-oxidized HDL suggested the effect of gly-HDL on endothelial function to be possibly potentiated by additional oxidative modification. Taking all of the above findings together, gly-ox-HDL may lead to the deterioration of vascular function through altered production of reactive oxygen species and reactive nitrogen species in endothelial cells.
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PMID:Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells. 1252 61

Reactive oxygen species (ROS) have been implicated in the pathogenesis of vascular dysfunction in diabetes mellitus, and NAD(P)H oxidase is known as the most important source of ROS in the vasculatures. To determine whether NAD(P)H oxidase is a major participant in the critical intermediary signaling events in high glucose (HG, 25 mM)-induced proliferation of vascular smooth muscle cells (VSMC), we investigated in explanted aortic VSMC from rats the role of NAD(P)H oxidase on the HG-related cellular proliferation and superoxide production. VSMC under HG condition had increased proliferative capacity that was inhibited by tiron (1 mM), a cell membrane permeable superoxide scavenger, but not by SOD, which is not permeable to cell membrane. The nitroblue tetrazolium staining in the HG-exposed VSMC was more prominent than that of VSMC under normal glucose (5.5 mM) condition, which was significantly inhibited by DPI (10 microM), an NAD(P)H oxidase inhibitor, but not by inhibitors for other oxidases such as NADH dehydrogenase, xanthine oxidase, and nitric oxide synthase. In the VSMC under HG condition, the enhanced NAD(P)H oxidase activity with increased membrane translocation of Rac1 was observed, but the protein expression of p22phox and gp91phox was not increased. These data suggest that HG-induced changes in VSMC proliferation are related to the intracellular production of superoxide through enhanced activity of NAD(P)H oxidase.
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PMID:NAD(P)H oxidase participates in the signaling events in high glucose-induced proliferation of vascular smooth muscle cells. 1267 89

Oxidative stress is associated with diabetes mellitus: a role of vascular NADPH oxidase as a source of superoxide has been demonstrated. We determined whether in type 2 diabetes mononuclear cells, NADPH oxidase and the inducible hemeoxygenase (HO-1) gene expressions are activated. In monocytes from 25 outpatients with type 2 diabetes, p22(phox) gene expression was higher (0.71 +/- 0.09 p22(phox)/beta-actin gene expression ratio) than that observed in 19 controls (0.56 +/- 0.09, P < 0.001). Similarly, HO-1 gene expression was significantly higher in diabetic patients (0.77 +/- 0.12 HO-1/beta-actin gene expression ratio) than in controls (0.41 +/- 0.14, P < 0.001). The p22(phox) and HO-1 gene expressions were also determined during (plasma glucose 363 +/- 40 mg/dl) and after (125 +/- 11 mg/dl) metabolic decompensation in 10 type 2 diabetic patients. The correction of the metabolic milieu was associated with a 19% +/- 3% (P < 0.01) and 30% +/- 3% (P < 0.01) decrease in the p22(phox) and HO-1 gene expressions, respectively. In a multivariate analysis, age was independently associated to p22(phox) gene expression in circulating monocytes in type 2 diabetics [13% (adjusted R(2)), P < 0.05]. Decompensated type 2 diabetes is associated with increased p22(phox) and HO-1 gene expressions in circulating monocytes; the metabolic normalization reduces but does not normalize this activation. These findings suggest that these cells, which play a crucial role in the earliest events of atherosclerotic lesion, are subjected to an increased oxidative stress.
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PMID:Monocyte NADPH oxidase subunit p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress. 1267 69

H2O2 generation is a limiting step in thyroid hormone biosynthesis. Biochemical studies have confirmed that H2O2 is generated by a thyroid Ca2+/NADPH-dependent oxidase. Decreased H2O2 availability may be another mechanism of inhibition of thyroperoxidase activity produced by thioureylene compounds, as propylthiouracil (PTU) and methimazole (MMI) are antioxidant agents. Therefore, we analyzed whether PTU or MMI could scavenge H2O2 or inhibit thyroid NADPH oxidase activity in vitro. Our results show that PTU and thiourea did not significantly scavenge H2O2. However, MMI significantly scavenged H2O2 at high concentrations. Only MMI was able to decrease the amount of H2O2 generated by the glucose-glucose oxidase system. On the other hand, both PTU and MMI were able to partially inhibit thyroid NADPH oxidase activity in vitro. As PTU did not scavenge H2O2 under the conditions used here, we presume that this drug may directly inhibit thyroid NADPH oxidase. Also, at the concentration necessary to inhibit NADPH oxidase activity, MMI did not scavenge H2O2, also suggesting a direct effect of MMI on thyroid NADPH oxidase. In conclusion, this study shows that MMI, but not PTU, is able to scavenge H2O2 in the micromolar range and that both PTU and MMI can impair thyroid H2O2 generation in addition to their potent thyroperoxidase inhibitory effects.
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PMID:Thyroid Ca2+/NADPH-dependent H2O2 generation is partially inhibited by propylthiouracil and methimazole. 1275 90

The presence of a phagocyte-like NAD(P)H oxidase in pancreatic beta-cells was investigated. Three NAD(P)H oxidase components were found in pancreatic islets by RT-PCR: gp91(PHOX), p22(PHOX), and p47(PHOX). The components p67(PHOX) and p47(PHOX) were also demonstrated by Western blotting. Through immunohistochemistry, p47(PHOX) was mainly found in the central area of the islet, confirming the expression of this component by insulin-producing cells. Activation of NAD(P)H oxidase complex in the beta-cells was also examined by immunohistochemistry. The pancreatic islets presented slower kinetics of superoxide production than HIT-T15 cells, neutrophils, and macrophages, but they reached 66% that of the neutrophil nitroblue tetrazolium (NBT) reduction after 2 h of incubation. Glucose (5.6 mmol/l) increased NBT reduction by 75% when compared with control. The involvement of protein kinase C (PKC) in the stimulatory effect of glucose was confirmed by incubation of islets with phorbol myristate acetate (a PKC activator) and bysindoylmaleimide (GF109203X) (a PKC-specific inhibitor). Diphenylene iodonium [an NAD(P)H oxidase inhibitor] abolished the increase of NBT reduction induced by glucose, confirming the NAD(P)H oxidase activity in pancreatic islets. Because reactive oxygen species are involved in intracellular signaling, the phagocyte-like NAD(P)H oxidase activation by glucose may play an important role for beta-cell functioning.
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PMID:Pancreatic beta-cells express phagocyte-like NAD(P)H oxidase. 1276 57

Angiotensin II (Ang II), protein kinase C (PKC), reactive oxygen species (ROS) generated by NADPH oxidase, the activation of Janus kinase 2 (JAK2), and the polyol pathway play important parts in the hyperproliferation of vascular smooth muscle cells (VSMC), a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between the polyol pathway, PKC-beta, ROS, JAK2, and Ang II in the development of diabetic macroangiopathy. VSMC cultured in high glucose (HG; 25 mm) showed significant increases in the tyrosine phosphorylation of JAK2, production of ROS, and proliferation activities when compared with VSMC cultured in normal glucose (5.5 mm (NG)). Both the aldose reductase specific inhibitor (zopolrestat) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of JAK2, the production of ROS, and proliferation of VSMC induced by HG, but it had no effect on the Ang II-induced activation of these parameters in both NG and HG. However, transfection with PKC-beta antisense oligonucleotide, preincubation with a PKC-beta-specific inhibitor (LY379196) or apocynin (NADPH oxidase-specific inhibitor), or electroporation of NADPH oxidase antibodies blocked the Ang II-induced JAK2 phosphorylation, production of ROS, and proliferation of VSMC in both NG and HG. These observations suggest that the polyol pathway hyperactivity induced by HG contributes to the development of diabetic macroangiopathy through a PKC-beta-ROS activation of JAK2.
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PMID:High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway. 1277 86


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