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)

Paraoxonase 2 (PON2) is a member of the paraoxonases gene family. PON2 is ubiquitously present in cells, including macrophages, and it was shown to protect against cellular oxidative stress. The aim of the present study was to analyze mechanisms involved in PON2 expression during monocyte/macrophage differentiation. PON2 expression was analyzed in vitro in THP-1 cells differentiated with 1alpha,25-dihydroxyvitamin D3 and in vivo in mouse peritoneal macrophages (MPM) isolated at increasing time intervals after intraperitoneal thioglycollate injection. PON2 expression (mRNA and protein) and activity gradually increased during monocyte/macrophage differentiation, up to five fold and eight fold in vitro and in vivo, respectively. This effect was associated with a gradual increase in cellular superoxide anion production. Supplementation of vitamin E to Balb/C mice inhibited the reduced nicotinamide adenine dinuleotide phosphate (NADPH)-oxidase-dependent increase in cellular superoxide anion production by 50% and down-regulated PON2 mRNA expression and activity by 30 and 60%, respectively. Furthermore, PON2 expression was lower by nine fold in MPM isolated from P47(phox-/-) (inactive NADPH oxidase) mice, in comparison to MPM from control mice. PON2 expression was found to be regulated, at least in part, by the transcription factor AP-1, as suggested by decreased JDP2 (AP-1 repressor) protein expression in the nucleus and by decreased PON2 expression in the presence of a Jun N-terminal kinase inhibitor (SP600125). The present study demonstrates, for the first time, that PON2 expression increases in monocytes during their maturation into macrophage as a result of NADPH-oxidase activation, and this process is partly regulated by the transcription factor AP-1. PON2 stimulation may represent a compensatory mechanism against the increase in cellular superoxide anion production and atherogenesis.
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PMID:Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. 1554 23

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxi-dative stress and apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 microM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (100 microM), the p38 mito-gen-activated protein kinase inhibitor SB203580 (2.5 microM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 microM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 microM), and antioxidants alpha-tocopherol (5 microg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride staining, annexin-V phosphatidyl- serine/propidium iodide, and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored Hcy-induced apoptosis. JNK inhibitor II, alpha-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580 and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively, our results suggested that Hcy may induce oxidative stress and apopto-sis through an NADPH oxidase and/or JNK-dependent mechanism(s).
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PMID:Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells. 1573 81

In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the Galpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Galpha(12/13), but not by an RGS domain specific for Galpha(q). Constitutively active Galpha(12)- or Galpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Galpha(13), which was completely inhibited by the Galpha(12/13)-specific RGS domain. Furthermore, the Galpha(12/13)-specific but not the Galpha(q)-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by Galpha(12/13)-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that Galpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.
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PMID:G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. 1574 61

Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH2-terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II-induced augmentations of the NAD(P)H oxidase complex formation (p47phox, p22phox, and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.
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PMID:Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. 1583 27

Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts. Reactive oxygen species (ROS) produced by Ang II stimulation are assumed to play pivotal roles in this process. Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts. Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47(phox), and an inhibitor of Galpha(12/13) (Galpha(12/13)-specific regulator of G protein signaling domain of p115RhoGEF, p115-regulator of G protein signaling (RGS)). Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47(phox)-dependent manner. Because p115-RGS suppressed Ang II-induced Rac activation, Ang II receptor-coupled Galpha(12/13) mediated NFAT activation through ROS production by Rac activation. Ang II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium. The expression of constitutively active (CA)-Galpha(12/13), CA-G translocation alpha(13), or CA-Rac increased the nuclear of GFP-NFAT4. These results suggest that NFAT activity is regulated by both Ca(2+)-dependent and ROS-dependent pathways. Furthermore, activation of c-Jun NH(2)-terminal kinase (JNK) induced by Ang II stimulation is required for NFAT activation because Ang II-induced NFAT activation was inhibited by SP600125, a selective JNK inhibitor. These results indicate that Ang II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of Galpha(12/13), Rac, NADPH oxidase, and JNK and that Galpha(12/13)-mediated ROS production is essential for NFAT transcriptional activation.
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PMID:Galpha12/13-mediated production of reactive oxygen species is critical for angiotensin receptor-induced NFAT activation in cardiac fibroblasts. 1582 47

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91phox (Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47phox. gp91phox (Nox 2) and p47phox were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta). These inhibitors and p47phox protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCzeta are upstream events of the CD95L-induced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to N-acetylcysteine, inhibitors of NADPH oxidase, PKCzeta, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCzeta, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47phox, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCzeta-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation.
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PMID:Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. 1591 50

Genipin, the aglycone of geniposide, exhibits anti-inflammatory and anti-angiogenic activities. Here we demonstrate that genipin induces apoptotic cell death in FaO rat hepatoma cells and human hepatocarcinoma Hep3B cells, detected by morphological cellular changes, caspase activation and release of cytochrome c. During genipin-induced apoptosis, reactive oxygen species (ROS) level was elevated, and N-acetyl-l-cysteine (NAC) and glutathione (GSH) suppressed activation of caspase-3, -7 and -9. Stress-activated protein kinase/c-Jun NH2-terminal kinase 1/2(SAPK/JNK1/2) but neither MEK1/2 nor p38 MAPK was activated in genipin-treated hepatoma cells. SP600125, an SAPK/JNK1/2 inhibitor, markedly suppressed apoptotic cell death in the genipin-treated cells. The FaO cells stably transfected with a dominant-negative c-Jun, TAM67, was less susceptible to apoptotic cell death triggered by genipin. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, inhibited ROS generation, apoptotic cell death, caspase-3 activation and JNK activation. Consistently, the stable expression of Nox1-C, a C-terminal region of Nox1 unable to generate ROS, blocked the formation of TUNEL-positive apoptotic cells, and activation of caspase-3 and JNK in FaO cells treated with genipin. Our observations imply that genipin signaling to apoptosis of hepatoma cells is mediated via NADPH oxidase-dependent generation of ROS, which leads to downstream of JNK.
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PMID:Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. 1614 11

Trilinolein, isolated from the traditional Chinese herb Sanchi (Panax notoginseng), has been shown to have myocardial protective effects via its antioxidant ability. However, the cellular and molecular mechanisms of the protective effect of trilinolein in the heart remain to be elucidated. Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We previously reported that ET-1 induces ROS generation via the ET(A) receptor and ROS modulates c-fos gene expression. We have therefore examined whether trilinolein attenuates ROS production and ET-1-induced c-fos gene expression in cardiomyocytes. Cultured neonatal rat cardiomyocytes were stimulated with ET-1 (10 nM), and c-fos gene expression was examined. Trilinolein (1 and 10 microM) inhibited ET-1-induced c-fos gene expression in cardiomyocytes. We also examined the effects of trilinolein on ET-1-increased NADPH oxidase activity and superoxide formation. Trilinolein inhibited ET-1-increased NADPH oxidase activity and superoxide formation in a concentration-dependent manner. This increase in superoxide production by ET-1 was significantly inhibited by trilinolein, diphenyleneiodonium, or N-acetylcysteine. Trilinolein also decreased ET-1- or H2O2-induced extracellular signal-regulated kinase (ERK) phosphorylation, c-Jun NH2-terminal kinase (JNK) phosphorylation, and activator protein-1 activation. These data indicate that trilinolein inhibits ET-1-induced ERK phosphorylation, JNK phosphorylation, and c-fos gene expression via attenuating superoxide production in cardiomyocytes.
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PMID:Inhibitory effect of trilinolein on endothelin-1-induced c-fos gene expression in cultured neonatal rat cardiomyocytes. 1618 2

Vanadate is a transition metal widely distributed in the environment. It has been reported that vanadate associated with air pollution particles can modify DNA synthesis, causing cell growth arrest, and apoptosis. Moreover, vanadium exposure was also found to cause the synthesis of inflammatory cytokines, such as interleukin-1, tumor necrosis factor-alpha, and prostaglandin E(2). Here, we found that exposure of A549 human lung carcinoma cells to vanadate led to extracellular signal-regulated kinase, c-Jun NH(2)-terminal protein kinases (JNKs), p38 mitogen-activated protein kinase (p38) activation, and COX-2 protein expression in a dose-dependent manner. SB203580, a p38 MAPK inhibitor, but not PD098059 and SP600125, specific inhibitor of MKK1 and selective inhibitor of JNK, respectively, suppressed COX-2 expression. Furthermore, the epithelial growth factor (EGF) receptor specific inhibitor (PD153035) reduced vanadate-induced COX-2 expression. However, scavenging of vanadate-induced reactive oxygen species by catalase, a specific H(2)O(2) inhibitor, or DPI, an NADPH oxidase inhibitor, resulted in no inhibition on COX-2 expression. Together, we suggested that EGF receptor and p38 MAPK signaling pathway may be involved in vanadate-induced COX-2 protein expression in A549 human lung carcinoma cell line.
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PMID:Induction of COX-2 protein expression by vanadate in A549 human lung carcinoma cell line through EGF receptor and p38 MAPK-mediated pathway. 1630 Jul 28

Epidermal growth factor (EGF) is a survival signal for transforming growth factor-beta (TGF-beta)-induced apoptosis in hepatocytes, phosphatidylinositol 3-kinase (PI 3-K) being involved in this effect. Here, we analyze the possible cross talks between EGF and TGF-beta signals to understand how EGF impairs the early pro-apoptotic events induced by TGF-beta. Data have indicated that neither SMAD nor c-Jun NH2 Terminal Kinase (JNK) activations are altered by EGF, which clearly interferes with events directly related to the radical oxygen species (ROS) production, impairing oxidative stress, p38 MAP kinase activation, and cell death. Activation of a NADPH-oxidase-like system, which is responsible for the early ROS production by TGF-beta, is completely inhibited by EGF, through a PI 3-K-dependent mechanism. Activity of RAC1 increases by TGF-beta, but also by EGF, and both act synergistically to get maximum effects. Fetal rat hepatocytes express nox4, in addition to nox1 and nox2, and TGF-beta clearly upregulates nox4. EGF blocks up-regulation of nox4 by TGF-beta. Interestingly, in the presence of PI 3-K inhibitors, EGF is not able to counteract the nox4 upregulation by TGF-beta. Taking together these results indicate that impairment of TGF-beta-induced NADPH oxidase activation by EGF is a RAC1-independent process and correlates with an inhibition of the mechanisms that address the increase of nox4 mRNA levels by TGF-beta.
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PMID:EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. 1633 83


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