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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 was present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.
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PMID:The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus. 1940 74

Insulin stimulates superoxide (O(2)(-)) production in monocytes and macrophages. However, the mechanisms through which insulin induces O(2)(-) production are not completely understood. In this study, we (a) characterized the enzyme and the pathways involved in insulin-stimulated O(2)(-) production in human monocytes and murine macrophages, and (b) analyzed the consequences of insulin-stimulated O(2)(-) production on the cellular phenotype in these cells. We showed that insulin stimulated O(2)(-) production, and promoted p47(phox) translocation to the plasma membrane. Insulin-induced O(2)(-) production and p47(phox) translocation were prevented in the presence of specific inhibitors of PI3K and PKC. Insulin-mediated NADPH oxidase activation stimulated MMP-9 activation in monocytes and cell proliferation in macrophages. The effect of insulin on these phenotypic responses was mediated through NFkappaB, p38MAPK, and ERK 1/2 activation. Small-interfering RNA-specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression, decreased insulin-induced O(2)(-) production, inhibited the turn on of NFkappaB, p38MAPK, and ERK 1/2, and reduced cell proliferation in macrophages. These findings suggest a pivotal role for NADPH oxidase in insulin-induced proliferation and proteolytic activation in monocytes and macrophages, respectively, and identify a pathway that may play a pathological role in hyperinsulinemic states.
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PMID:Insulin-induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes/macrophages. 1943 31

Treatment of bovine pulmonary smooth muscle cells with the TxA(2) mimetic, U46619 stimulated [Ca(2+)](i), which was inhibited upon pretreatment with apocynin (NADPH oxidase inhibitor). Pretreatment with cromakalim (K(V) channel opener) or nifedepine (L-VOCC inhibitor) inhibited U46619 induced increase in [Ca(2+)](i), indicating a role of K(V)-LVOCC axis in this scenario. Neither cromakalim nor nifedepine inhibited U46619 induced increase in NADPH oxidase activity, suggesting that the NADPH oxidase activation is proximal to the K(V)-LVOCC axis in the cells. Pretreatment with calphostin C (PKC inhibitor) markedly reduced U46619 induced increase in NADPH oxidase activity and [Ca(2+)](i) in the cells. Calphostin C pretreatment also markedly reduced p(47phox) phosphorylation and translocation to the membrane and association with p(22phox), a component of Cyt.b(558) of NADPH oxidase in the membrane. Overall, PKC plays an important role in NADPH oxidase derived O(2)(-)-mediated regulation of K(V)-LVOCC axis leading to an increase in [Ca(2+)](i) by U46619 in the cells.
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PMID:Role of protein kinase C in NADPH oxidase derived O2*(-)-mediated regulation of KV-LVOCC axis under U46619 induced increase in [Ca2+]i in pulmonary smooth muscle cells. 1949 96

Activation of circulating monocytes by hyperglycemia is bound to play a role in inflammatory and atherosclerosis. In this study, we examined whether flavonoids (catechin, EGCG, luteolin, quercetin, rutin) - phytochemicals that may possible belong to a new class of advanced glycation end products (AGEs) inhibitors - can attenuate high glucose (15 mmol/L, HG)-induced inflammation in human monocytes. Our results show that all flavonoids significantly inhibited HG-induced expression of proinflammatory genes and proteins, including TNF-alpha, interleukin-1beta (IL-1beta), and cyclooxygenase (COX)-2, at a concentration of 20 microM. Flavonoids also prevented oxidative stress in activated monocytes, as demonstrated by their inhibitory effects on intracellular reactive oxygen species (ROS) and N(epsilon)-(carboxymethyl)lysine formation caused by HG. These inhibitory effects may involve inhibition of nuclear factor-kappaB activation and may be supported by downregulation of the following: i) PKC-dependent NADPH oxidase pathway; ii) phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase, and iii) mRNA expression of receptor of AGEs. In addition, we found for the first time that lower levels of Bcl-2 protein under HG conditions could be countered by the action of flavonoids. Our data suggest that, along with their antioxidant activities, flavonoids possess anti-inflammatory properties and might therefore have additional protective effects against glycotoxin-related inflammation.
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PMID:Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. 1955 21

The present study investigates cadmium (Cd) ability to enhance superoxides (O(2-)) and nitric oxide (NO) production (as nitrites) in haemocytes of mussel Mytilus galloprovincialis as well as the possible involvement of Na(+)/H(+) exchanger (NHE) in the induction of NADPH oxidase and NO synthase activity. PMA, a well-known PKC-mediated NADPH oxidase as well as NO synthase stimulator was also used, in order to verify Cd effects on both O(2-) and NO generation. According to the results of the present study, micromolar concentrations of Cd (0.05, 5, 10 and 50 microM) seemed to enhance O(2-) and NO generation in haemocytes of mussels. Moreover, O(2-) and NO generation in haemocytes exposed to Cd could be enhanced by its ability to induce reactive oxygen species (ROS) but respiratory burst activation as well. Inhibition of NO synthase with 10 microM l-NAME, significantly attenuated Cd ability to enhance O(2-) production and diminished NO generation, thus leading to the suggestion that Cd toxic effects, started at concentration of 50 muM, could enhance NADPH oxidase and NO synthase stimulation in haemocytes of mussels. NHE seems to play a regulatory role in the induction of either O(2-) or NO generation in haemocytes exposed to the metal, since its inhibition with the use of 10 microM EIPA significantly decrease both O(2-) and NO production. The involvement of NHE in the induction of O(2-) and NO generation, probably via PKC-mediated NADPH oxidase and NO synthase activation, is likely to be crucial to haemocytes exposed to heavy metals, such as Cd.
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PMID:Production of superoxides and nitric oxide generation in haemocytes of mussel Mytilus galloprovincialis (Lmk.) after exposure to cadmium: a possible involvement of Na(+)/H(+) exchanger in the induction of cadmium toxic effects. 1956 97

Macrophages produce a large volume of ROS (reactive oxygen species) through respiratory burst. However, the influence of iNOS [inducible NOS (nitric oxide synthase)] activation on ROS production remains unclear. In the present study, the kinetic generation of ROS in RAW264.7 murine macrophages was monitored by chemiluminescence. PMA induces a robust chemiluminescence in RAW264.7 cells, suggesting PKC (protein kinase C)-related assembly and activation of NOX (NADPH oxidase). The effects of iNOS induction on ROS production were examined. Induction of iNOS expression in RAW264.7 cells with LPS (lipopolysaccharide; 1 microg/ml) causes a significant increase in PMA-induced chemiluminescence, which could be enhanced by the NOS substrate, L-arginine, and could be abolished by the NOS inhibitor, L-NNA (NG-nitro-L-arginine). Further experiments reveal that induction of iNOS expression enhances the PMA-stimulated phosphorylation of the p47phox subunit of NOX, and promotes the relocalization of cytosolic p47phox and p67phox subunits to the membrane. Inhibition of PKCzeta by its myristoylated pseudosubstrate significantly decreased the PMA-stimulated phosphorylation of the p47phox in LPS-pretreated cells, suggesting that PKCzeta is involved in the iNOS-dependent assembly and activation of NOX. Taken together, the present study suggests that the induction of iNOS upregulates the PMA-induced assembly of NOX and leads to the enhanced production of ROS via a PKCzeta-dependent mechanism.
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PMID:Induction of inducible nitric oxide synthase increases the production of reactive oxygen species in RAW264.7 macrophages. 1967 2

In human neutrophils, TNF-elicited O(2)(-) production requires adherence and integrin activation. How this cooperative signaling between TNFRs and integrins regulates O(2)(-) generation has yet to be fully elucidated. Previously, we identified delta-PKC as a critical early regulator of TNF signaling in adherent neutrophils. In this study, we demonstrate that inhibition of delta-PKC with a dominant-negative delta-PKC TAT peptide resulted in a significant delay in the onset time of TNF-elicited O(2)(-) generation but had no effect on Vmax, indicating an involvement of delta-PKC in the initiation of O(2)(-) production. In contrast, fMLP-elicited O(2)(-) production in adherent and nonadherent neutrophils was delta-PKC-independent, suggesting differential regulation of O(2)(-) production. An important step in activation of the NADPH oxidase is phosphorylation of the cytosolic p47phox component. In adherent neutrophils, TNF triggered a time-dependent association of delta-PKC with p47phox, which was associated with p47phox phosphorylation, indicating a role for delta-PKC in regulating O(2)(-) production at the level of p47phox. Activation of ERK and p38 MAPK is also required for TNF-elicited O(2)(-) generation. TNF-mediated ERK but not p38 MAPK recruitment to p47phox was delta-PKC-dependent. delta-PKC activity is controlled through serine/threonine phosphorylation, and phosphorylation of delta-PKC (Ser643) and delta-PKC (Thr505) was increased significantly by TNF in adherent cells via a PI3K-dependent process. Thus, signaling for TNF-elicited O(2)(-) generation is regulated by delta-PKC. Adherence-dependent cooperative signaling activates PI3K signaling, delta-PKC phosphorylation, and delta-PKC recruitment to p47phox. delta-PKC activates p47phox by serine phosphorylation or indirectly through control of ERK recruitment to p47phox.
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PMID:Regulation of TNF-induced oxygen radical production in human neutrophils: role of delta-PKC. 1980

It is generally accepted that reactive oxygen species (ROS) act as signalling molecules and regulate various physiological processes, including proliferation, differentiation, apoptosis and migration. The initiation and proper functioning of several signalling pathways leading to the effective motility rely on the action of several growth factors and cytokines, which induce generation of ROS, among others by NADPH oxidase. ROS modify the activity of several key enzymes, resulting in the reorganization of actin cytoskeleton, adhesion and stimulation of migration. There is an evidence that ROS can oxidase such critical target molecules as PKC, MAPK, PI3K, tyrosine phospatases (PTPs) and PTEN. In this review, some ROS-dependent transduction pathways, involved in regulation of cell migration are discussed. Moreover, the thioredoxin/thioredoxin reductase system, which is responsible for reduction of oxidised proteins has been described and some data concerning the effect of thioredoxin reductase on the regulation of PKC-dependent cell motility have been presented.
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PMID:[Reactive oxygen species in regulation of cell migration. The role of thioredoxin reductase]. 1982 70

Epidermal growth factor receptor (EGFR) activation by GPCRs regulates many important biological processes. ADAM metalloprotease activity has been implicated as a key step in transactivation, yet the regulatory mechanisms are not fully understood. Here, we investigate the regulation of transforming growth factor-alpha (TGF-alpha) shedding by reactive oxygen species (ROS) through the ATP-dependent activation of the P2Y family of GPCRs. We report that ATP stimulates TGF-alpha proteolysis with concomitant EGFR activation and that this process requires TACE/ADAM17 activity in both murine fibroblasts and CHO cells. ATP-induced TGF-alpha shedding required calcium and was independent of Src family kinases and PKC and MAPK signaling. Moreover, ATP-induced TGF-alpha shedding was completely inhibited by scavengers of ROS, whereas calcium-stimulated shedding was partially inhibited by ROS scavenging. Hydrogen peroxide restored TGF-alpha shedding after calcium chelation. Importantly, we also found that ATP-induced shedding was independent of the cytoplasmic NADPH oxidase complex. Instead, mitochondrial ROS production increased in response to ATP and mitochondrial oxidative complex activity was required to activate TACE-dependent shedding. These results reveal an essential role for mitochondrial ROS in regulating GPCR-induced growth factor shedding.
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PMID:Mitochondrial reactive oxygen species mediate GPCR-induced TACE/ADAM17-dependent transforming growth factor-alpha shedding. 1984 66

This study investigated the role of Na(+)/H(+) exchanger (NHE) and signalling molecules, such as cAMP, PKC, PI 3-kinase, and immune defence enzymes, NADPH oxidase and nitric oxide synthase, in the induction of protein glutathionylation and carbonylation in cadmium-treated haemocytes of mussel Mytilus galloprovincialis. Glutathionylation was detected by western blot analysis and showed actin as its main target. A significant increase of both actin glutathionylation and protein carbonylation, were observed in haemocytes exposed to micromolar concentration of cadmium chloride (5 micromol l(-1)). Cadmium seems to cause actin polymerization that may lead to its increased glutathionylation, probably to protect it from cadmium-induced oxidative stress. It is therefore possible that polymerization of actin plays a signalling role in the induction of both glutathionylation and carbonylation processes. NHE seems to play a regulatory role in the induction of oxidative damage and actin glutathionylation, since its inhibition by 2 micromol l(-1) cariporide, significantly diminished cadmium effects in each case. Similarly, attenuation of cadmium effects were observed in cells pre-treated with either 11 micromol l(-1) GF-109203X, a potent inhibitor of PKC, 50 nmol l(-1) wortmannin, an inhibitor of PI 3-kinase, 0.01 mmol l(-1) forskolin, an adenylyl cyclase activator, 10 micromol l(-1) DPI, a NADPH oxidase inhibitor, or 10 micromol l(-1) L-NAME, a nitric oxide synthase inhibitor, suggesting a possible role of PKC, PI 3-kinase and cAMP, as well as NADPH oxidase and nitric oxide synthase in the enhancement of cadmium effects on both actin glutathionylation and protein carbonylation.
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PMID:The role of signalling molecules on actin glutathionylation and protein carbonylation induced by cadmium in haemocytes of mussel Mytilus galloprovincialis (Lmk). 1988 Jul 21


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