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)

Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.
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PMID:Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells. 918 53

Peritoneal dialysis effluent (PDE) contains a low-molecular-weight substance that is able to prime human neutrophils for the release of arachidonic acid and superoxide anion. Conventional priming agents, such as tumor necrosis factor alpha (TNF-alpha), are known to signal via mitogen-activated protein (MAP) kinases; at least one possible substrate for MAP kinases is cytosolic phospholipase A(2) (cPLA(2)). Phosphorylation of this enzyme results in arachidonic acid release, and this fatty acid is a potent primer and activator of the human neutrophil NADPH oxidase. Because of the striking similarities between the priming of neutrophils with agents such as TNF-alpha and PDE, we have investigated the signalling pathways evoked by PDE and explored the possibility that cPLA(2) is a target for activated MAP kinases. Our results show that PDE treatment of human neutrophils results in the phosphorylation of the p38 kinase rather than the p42 and p44 kinases. Phosphorylation of p38 is transient with maximal activity being observed 1 min after exposure to PDE. We were unable to demonstrate that activation of p38 resulted in phosphorylation of cPLA(2); furthermore, translocation of this enzyme to a membrane-containing fraction was not enhanced in PDE-treated neutrophils. Taken together, these data suggest that, in a manner similar to that of TNF-alpha, PDE primes human neutrophils by the activation of the p38 kinase. However, unlike the cytokine, the activation of this protein does not result in phosphorylation or activation of cPLA(2).
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PMID:Role of p38 in the priming of human neutrophils by peritoneal dialysis effluent. 1054 80

Bradykinin stimulates proliferation of aortic vascular smooth muscle cells (VSMCs). We investigated the action of bradykinin on the phosphorylation state of the mitogen-activated protein kinases p42(mapk) and p44(mapk) in VSMCs and tested the hypothesis that reactive oxygen species (ROS) might be involved in the signal transduction pathway linking bradykinin activation of nuclear transcription factors to the phosphorylation of p42(mapk) and p44(mapk). Bradykinin (10(-8) mol/L) rapidly increased (4- to 5-fold) the phosphorylation of p42(mapk) and p44(mapk) in VSMCs. Preincubation of VSMCs with either N-acetyl-L-cysteine and/or alpha-lipoic acid significantly decreased bradykinin-induced cytosolic and nuclear phosphorylation of p42(mapk) and p44(mapk). In addition, the induction c-fos mRNA levels by bradykinin was completely abolished by N-acetyl-L-cysteine and alpha-lipoic acid. Using the cell-permeable fluorescent dye dichlorofluorescein diacetate, we determined that bradykinin (10(-8) mol/L) rapidly increased the generation of ROS in VSMCs. The NADPH oxidase inhibitor diphenylene iodonium (DPI) blocked bradykinin-induced c-fos mRNA expression and p42(mapk) and p44(mapk) activation, implicating NADPH oxidase as the source for the generation of ROS. These findings demonstrate that the phosphorylation of cytosolic and nuclear p42(mapk) and p44(mapk) and the expression of c-fos mRNA in VSMCs in response to bradykinin are mediated via the generation of ROS and implicate ROS as important mediators in the signal transduction pathway through which bradykinin promotes VSMC proliferation in states of vascular injury.
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PMID:Role of reactive oxygen species in bradykinin-induced mitogen-activated protein kinase and c-fos induction in vascular cells. 1077 66

Angiotensin II (AngII) induces G(1) phase arrest and hypertrophy of cultured renal proximal tubular cells. In previous studies, it was shown that these effects depend on oxygen radical-mediated induction of p27(Kip1), an inhibitor of cyclin-dependent kinases. The present study was undertaken to investigate whether mitogen-activated protein (MAP) kinases serve as signaling intermediates between AngII-induced oxidative stress and induction of p27(Kip1). AngII (10(-7) M) induces a biphasic phosphorylation pattern of p44/42 MAP kinase with an early phosphorylation after 2 min and a later, second phosphorylation peak after prolong incubation (12 h) in cultured proximal tubular cells from two different species (MCT and LLC-PK(1) cells). Total protein expression of MAP kinase was not changed by AngII. These phosphorylation patterns of p44/42 MAP kinase caused activation of the enzyme, as detected by phosphorylated MAP substrate Elk-1 after immuno-precipitation of MAP kinase. Exogenous H(2)O(2) also stimulates a biphasic phosphorylation of p44/42 MAP kinase. The flavoprotein inhibitor diphenylene iodinium, as well as the antioxidant N-acetylcysteine, prevented AngII-induced p44/42 MAP kinase phosphorylation, indicating involvement of reactive oxygen species generated by membrane-bound NAD(P)H oxidase. The MAP kinase kinase inhibitor PD98059 completely inhibits AngII-induced p27(Kip1) expression and (3)[H]leucine incorporation into proteins as a previously established marker of cell hypertrophy. PD98059 did not attenuate AngII-stimulated intracellular synthesis of oxygen radicals. Transient transfection with p44/42 MAP kinase antisense, but not sense, phosphorothioate-modified oligonucleotides also prevented AngII-induced MAP kinase phosphorylation, p27(Kip1) expression, and cell hypertrophy. Furthermore, induction of p27(Kip1) by H(2)O(2) was also abolished in the presence of PD98059. Although AngII induces phosphorylation of the stress-activated p38 MAP kinase, inhibition of this enzyme with SB203580 failed to attenuate induced p27(Kip1) expression and hypertrophy. These data provide evidence that AngII- mediated oxygen stress leads to the phosphorylation of p44/42 MAP kinase in proximal tubular cells. Activation of this enzyme is essential for p27(Kip1) expression, G(1) phase arrest, and hypertrophy of proximal tubular cells. These findings may lead to new concepts concerning interference of the development of proximal tubular hypertrophy, which may eventually turn into a maladaptive process in vivo leading ultimately to tubular atrophy and tubulointerstitial fibrosis.
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PMID:Reactive oxygen species stimulate p44/42 mitogen-activated protein kinase and induce p27(Kip1): role in angiotensin II-mediated hypertrophy of proximal tubular cells. 1090 52

Sialic acid containing glycosphingolipids (gangliosides) are expressed on the surface of all mammalian cells and have been implicated in regulating various biological phenomena; however, the detailed signaling mechanisms involved in this process are not known. We report here a novel aspect of disialoganglioside, GD3-mediated regulation of cell proliferation and cell death via the recruitment of reactive oxygen species (ROS). A low concentration (2.5-10 microm) of GD3, incubated with human aortic smooth muscle cells for a short period of time (10-30 min), stimulates superoxide generation via the activation of both NADPH oxidase and NADH oxidase activity. This leads to downstream signaling leading to cell proliferation and apoptosis. However, [(3)H]GD3 incubated with the cells under such conditions was found in a trypsin-sensitive fraction that was separable from endogenous GD3. The exact mechanism causing ROS generation and downstream signaling remains to be elucidated. The uptake of GD3 was accompanied by a 2.5-fold stimulation in the activity of mitogen-activated protein (MAP) kinase and 5-fold stimulation in cell proliferation. Preincubation of cells with membrane-permeable antioxidants, pyrrolidine dithiocarbamate, and N-acetylcysteine abrogated the superoxide generation and cell proliferation. In contrast, at higher concentrations (50-200 microm) GD3 inhibited the generation of superoxides but markedly stimulated the generation of nitric oxide (NO) (10-fold compared with control). This in turn stimulated mitochondrial cytochrome c release and intrachromosomal DNA fragmentation, which lead to apoptosis. In sum, at a low concentration, GD3 recruits superoxides to activate p44 MAPK and stimulates cell proliferation. In contrast, at high concentrations GD3 recruits nitric oxide to scavenge superoxide radicals that triggered signaling events that led to apoptosis. These observations might have relevance in regard to the potential role of GD3 in aortic smooth muscle cell proliferation and apoptosis that may contribute to plaque rupture in atherosclerosis.
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PMID:GD3 recruits reactive oxygen species to induce cell proliferation and apoptosis in human aortic smooth muscle cells. 1186 54

Neurodegenerative disorders in humans may be triggered or exacerbated by exposure to occupational or environmental agents. Here, we show that a brief exposure to methylisothiazolinone, a widely used industrial and household biocide, is highly toxic to cultured neurons but not to glia. We also show that the toxic actions of this biocide are zinc dependent and require the activation of p44/42 extracellular signal-regulated kinase (ERK) via a 12-lipoxygenase-mediated pathway. The cell death process also involves activation of NADPH oxidase, generation of reactive oxygen species, DNA damage, and overactivation of poly(ADP-ribose) polymerase, all occurring downstream from ERK phosphorylation. The toxic effects of methylisothiazolinone and related biocides on neurons have not been reported previously. Because of their widespread use, the neurotoxic consequences of both acute and chronic human exposure to these toxins need to be evaluated.
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PMID:In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway. 1219 62

This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47(phox) to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47(phox) and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.
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PMID:Complement-induced impairment of innate immunity during sepsis. 1221 41

Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific beta1-antagonist with weak beta2-agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-kappaB (NF-kappaB), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-kappaB phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-kappaB, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-beta1 gene expression. In conclusion, celiprolol suppresses VCAM-1 expression because of inhibition of oxidative stress, NF-kappaB, and signal transduction, while increasing eNOS via stimulation of the PI3K-Akt signaling pathway and improving cardiovascular remodeling.
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PMID:Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 Via NF-kappaB induced by oxidative stress. 1455 79

Cellular insulin stimulation generates a burst of H(2)O(2) that modulates protein-tyrosine phosphorylation in the insulin action pathway, in part by the inhibition of redox-sensitive protein-tyrosine phosphatases [J. Biol. Chem. 276 (2001) 21938]. Blocking the insulin-induced rise in H(2)O(2) with the NADPH oxidase inhibitor diphenyleneiodonium (DPI) strongly attenuated the activation of phosphatidylinositol 3' (PI 3')-kinase, Akt and GLUT4 translocation by insulin in 3T3-L1 adipocytes; however, under identical conditions, we observed a paradoxical increase in the activation of p42/p44 mitogen-activated protein (MAP) kinase. DPI inhibited the insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1/2, and also reduced the association of Grb2 with IRS-1, suggesting that the effect of DPI on MAP kinase activation occurred downstream of the IR and IRS proteins. DPI increased the insulin-stimulated phosphorylation of p42/p44 MAP kinase with no change in basal, and increased insulin-stimulated MAP kinase kinase (MEK) activity by a similar degree. DPI enhanced basal Grb2-Sos binding and reduced the effect of insulin to potentiate the dissociation of the Grb2-Sos complex, suggesting that the effect of DPI was mediated upstream of Raf-1. Cell treatment with dibutyryl cAMP significantly reduced the enhancement of MAP kinase activation in the presence of DPI. However, forskolin, acting in a PKA-independent manner, increased the insulin stimulation of MAP kinase and MEK, but fully abrogated the effect of DPI to enhance these insulin responses. PLCgamma inhibition with U73122 blocked the insulin stimulation of MAP kinase and MEK as well as the enhancing effect of DPI on these responses. PKC activation strongly stimulated MAP kinase and MEK activation, even in the presence of U73122, consistent with PKC acting downstream of PLCgamma. These data show that the insulin-stimulated oxidant signal differentially affects the two major downstream components of the insulin signaling pathway, PI 3'-kinase and MAP kinase, and cross-talk between insulin action, PLCgamma and, to a lesser extent, PKA modulates the net cellular effects of insulin-stimulated cellular H(2)O(2).
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PMID:Integration of multiple downstream signals determines the net effect of insulin on MAP kinase vs. PI 3'-kinase activation: potential role of insulin-stimulated H(2)O(2). 1468 62

The superoxide anion-generating effect of celecoxib (4-[5-(4-methylpheny)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); SC58633), a selective cyclooxygenase-2 inhibitor, on human neutrophils was evaluated in this study. Celecoxib induced superoxide anion generation in a concentration-dependent manner in human neutrophils. The EC50 value of celecoxib on superoxide anion generation was 15.5+/-2.5 microM. A NADPH oxidase inhibitor, diphenyliodonium (20 microM), and superoxide dismutase (150 U/ml) completely inhibited the free radical generation caused by celecoxib, indicating that the respiratory burst was activated by celecoxib. 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM;10 microM) and staurosporine (200 nM) completely inhibited the superoxide anion release caused by celecoxib, respectively. These data indicated that celecoxib increased superoxide anion release by increasing intracellular calcium and protein kinase C activation. Moreover, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-C)-carbazole (Go-6976; 1 microM) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide, methane sulfate (Ro-31-8220; 0.5 microM), specific inhibitors of conventional protein kinase C isotypes (alpha, beta(I) and beta(II)), significantly inhibited superoxide anion release caused by celecoxib. Rottlerin (5 microM), a protein kinase C delta inhibitor, did not affect the free radical generation caused by celecoxib. Celecoxib caused translocation of protein kinase C alpha, beta(I) and beta(II) from the cytosol to the cellular membrane. 2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one (PD98059; 20 microM) and wortmannin (100 nM) did not decrease the superoxide anion generation caused by celecoxib, indicating that Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3 kinase) were not involved in the respiratory burst induced by celecoxib. Pertussis toxin (2 microg/ml), a Gi-protein sensitive inhibitor, significantly inhibited superoxide anion release. Moreover, pertussis toxin significantly inhibited intracellular calcium mobilization and protein kinase C alpha, beta(I) and beta(II) translocation from the cytosol to the membrane. Celecoxib increased beta(2)-integrin expression on human neutrophils and this effect was inhibited by BAPTA/AM (10 microM), superoxide dismutase (150 U/ml), genistein (25 microM) and PD98059 (20 microM). This information indicated that intracellular calcium, superoxide anion, tyrosine kinase and MAP kinase are involved in beta(2)-integrin expression. Furthermore, BAPTA/AM, superoxide dismutase and genistein inhibited celecoxib-increased MAP kinase activity, indicating that MAP kinase is a downstream signal for beta(2)-integrin expression. In conclusion, celecoxib stimulates superoxide anion release from human neutrophils by activating pertussis toxin sensitive G-protein. An increase in intracellular calcium and protein kinase C alpha, beta(I) and beta(II) is involved in this process. Celecoxib also regulates beta(2)-integrin expression through superoxide anion release, tyrosine kinase and p42/p44 MAP kinase on human neutrophils.
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PMID:Celecoxib simulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for beta 2-integrin expression on human neutrophils. 1472 79


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