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)

Endothelial cells (ECs) under hemodynamic forces increase intracellular reactive oxygen species (ROS) that modulate gene expression. We previously showed that NO attenuated the shear flow-induced gene level. The present study explored the role of endothelial NO in cyclic strain-treated ECs. Treatment of ECs with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, reduced cyclic strain-induced monocyte chemotactic protein (MCP)-1 expression. Conversely, exposure of ECs to an NO synthase inhibitor augmented MCP-1 mRNA levels. NO attenuated the binding of activator protein-1 to the 12-O-tetradecanoylphobol-13-acetate-responsive element (TRE) in the MCP-1 promoter region. ECs overexpressed with endothelial NO synthase (eNOS) inhibited cyclic strain-induced MCP-1 expression and MCP-1 promoter (-540 bp) activity. Consistently, ECs treated with SNAP or infected with adenovirus carrying eNOS reduced strain-induced superoxide levels. These strain-induced superoxide and MCP-1 expressions were greatly blunted by treating ECs with an NADPH oxidase inhibitor, diphenyleneiodonium chloride or apocynine, but not with a xanthine oxidase inhibitor. ECs infected with adenovirus carrying the dominant-negative mutant of Rac (RacN17), a component of NADPH oxidase, reduced the strain-induced superoxide and MCP-1 expression. In contrast, ECs transfected with a constitutively active Rac (RacV12) increased MCP-1 and 4x TRE promoter activities. However, ECs cotransfected with eNOS and RacV12 reduced those promoter activities. Consistently, the increases of superoxide levels and MCP-1 expression by overexpression of RacV12 were abolished after infecting ECs with eNOS. Our results show that NO from eNOS-inhibiting redox-sensitive MCP-1 expression is mediated via Rac-dependent NADPH oxidase by reducing ROS. This study provides a molecular basis to support the notion that endothelial NO acts as an antioxidant by negatively regulating redox-sensitive gene expression in ECs constantly under hemodynamic influence.
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PMID:NO modulates monocyte chemotactic protein-1 expression in endothelial cells under cyclic strain. 1174 68

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.
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PMID:Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. 1457 80

Our previous study demonstrated that homocysteine (Hcy) mediated the expression and secretion of MCP-1 and IL-8 in human monocytes. In the present study, we investigated whether the responsiveness of isolated monocytes to lipopolysaccharide (LPS)-induced chemokine secretion was enhanced in patients with hyperhomocysteinemia (HHcy), and if so, whether this enhanced response could be inhibited by folic acid treatment. We studied 38 control subjects and 40 patients with HHcy. The results showed that MCP-1 secretion from isolated monocytes in response to low-dose LPS in patients with HHcy was significantly higher than that in controls. After patients with HHcy underwent low-dose folic acid treatment (0.8 mg/d) for 6 months, plasma Hcy levels were decreased and the hyper-responsiveness of MCP-1 and IL-8 secreted by isolated monocytes was significantly reversed. Furthermore, folic acid treatment at high concentrations (5 microM) significantly reduced the elevated levels of reactive oxygen species, NADPH oxidase activity and chemokines in response to Hcy in cultured human monocytes. HHcy may contribute to atherogenesis through enhancing the responsiveness of monocytes to inflammatory stimuli and promoting leukocyte recruitment into atherosclerotic plaque. In addition to lowering the plasma levels of Hcy, low-dose folic acid treatment exerts beneficial effects on patients with HHcy by inhibiting pro-inflammatory responses such as chemokine secretion from human monocytes.
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PMID:Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia. 1577 59

AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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PMID:Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice. 1592 10

The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In the case of Leishmania donovani infection, the impairment of PKC-mediated signaling is one of the crucial events for the establishment of parasite into the macrophages. Earlier reports established that C-C chemokines mediated protection against leishmaniasis via the generation of nitric oxide after 48 h. In this study, we investigated the role of MIP-1alpha and MCP-1 in the regulation of impaired PKC activity in the early hours (6 h) of infection. These chemokines restored Ca2+-dependent PKC activity and inhibited Ca2+-independent atypical PKC activity in L. donovani-infected macrophages under both in vivo and in vitro conditions. Pretreatment of macrophages with chemokines induced superoxide anion generation by activating NADPH oxidase components in infected cells. Chemokine administration in vitro induced the migration of infected macrophages and triggered the production of reactive oxygen species. In vivo treatment with chemokines significantly restricted the parasitic burden in livers as well as in spleens. Collectively, these results indicate a novel regulatory role of C-C chemokines in controlling the intracellular growth and multiplication of L. donovani, thereby demonstrating the antileishmanial properties of C-C chemokines in the disease process.
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PMID:Regulation of impaired protein kinase C signaling by chemokines in murine macrophages during visceral leishmaniasis. 1629 31

The role of polymorphonuclear neutrophils (PMN) in mediating diabetic tissue damage to the periodontium was investigated in a novel model of chronic hyperglycemia, the Akita mouse. Induction of acute peritoneal inflammation in wild-type (WT) and Akita mice resulted in exaggerated IL-6 response in Akita mice (2.9-fold increase over WT values) and a markedly increased chemokine response (KC, 2.6-fold; MCP-1, 2.6-fold; and MIP-1alpha, 4.4-fold increase over WT values). Chemotaxis to both fMLP and WKYMVm was significantly reduced in isolated Akita PMN compared with WT PMN as measured in a Boyden chamber. Superoxide release in contrast was significantly increased in Akita PMN as measured with cytochrome c reduction. Bone marrow-derived Akita PMN showed partial translocation of p47phox to the cell membrane without external stimulation, suggesting premature assembly of the superoxide-producing NADPH oxidase in hyperglycemia. In vivo studies revealed that ligature-induced periodontal bone loss is significantly greater in Akita mice compared with WT. Moreover, intravital microscopy of gingival vessels showed that leukocyte rolling and attachment to the vascular endothelium is enhanced in periodontal vessels of Akita mice. These results indicate that chronic hyperglycemia predisposes to exaggerated inflammatory response and primes leukocytes for marginalization and superoxide production but not for transmigration. Thus, leukocyte defects in hyperglycemia may contribute to periodontal tissue damage by impairing the innate immune response to periodontal pathogens as well as by increasing free radical load in the gingival microvasculature.
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PMID:Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice. 1708 43

Monocyte chemoattractant protein (MCP)-1 plays a key role in atherosclerosis and inflammation associated with visceral adiposity by inducing mononuclear cell migration. Evidence shows that mouse peritoneal macrophages (MPM) express a 12-lipoxygenase (12/15-LO) that has been clearly linked to accelerated atherosclerosis in mouse models and increased monocyte endothelial interactions in both rodent and human cells. However, the role of 12/15-LO products in regulating MCP-1 expression in macrophages has not been clarified. In this study, we tested the role of 12/15-LO products using MPM and the mouse macrophage cell line, J774A.1 cells. We found that 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] increased MCP-1 mRNA and protein expression in J774A.1 cells and MPM. In contrast, 12(R)-HETE, a lipid not derived from 12/15-LO, did not affect MCP-1 expression. 15(S)-HETE also increased MCP-1 mRNA expression, but the effect was less compared with 12(S)-HETE. MCP-1 mRNA expression was upregulated in a macrophage cell line stably overexpressing 12/15-LO (Plox-86 cells) and in MPM isolated from a 12/15-LO transgenic mouse. In addition, the expression of MCP-1 was downregulated in MPM isolated from 12/15-LO knockout mice. 12(S)-HETE-induced MCP-1 mRNA expression was attenuated by specific inhibitors of protein kinase C (PKC) and p38 mitogen-activated protein kinase (p38). 12(S)-HETE also directly activated NADPH oxidase activity. Two NADPH oxidase inhibitors, apocynin and diphenyleneiodonium chloride, blocked 12(S)-HETE-induced MCP-1 mRNA. Apocynin attenuated 12(S)-HETE-induced MCP-1 protein secretion. These data show that 12(S)-HETE increases MCP-1 expression by inducing PKC, p38, and NADPH oxidase activity. These results suggest a potentially important mechanism linking 12/15-LO activation to MCP-1 expression that induces inflammatory cell infiltration.
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PMID:Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages. 1829 57

Reactive oxygen species (ROS) play a crucial role in ischemia-reperfusion (IR) injury after lung transplantation. We hypothesized that NADPH oxidase derived from bone marrow (BM) cells contributes importantly to lung IR injury. An in vivo mouse model of lung IR injury was employed. Wild-type C57BL/6 (WT) mice, p47(phox) knockout (p47(phox)-/-) mice, or chimeras created by BM transplantation between WT and p47(phox)-/- mice were assigned to either Sham (left thoracotomy) or six study groups that underwent IR (1 h left hilar occlusion and 2 h reperfusion). After reperfusion, pulmonary function was assessed using an isolated, buffer-perfused lung system. Lung injury was assessed by measuring vascular permeability (via Evans blue dye), edema, neutrophil infiltration (via myeloperoxidase [MPO]), lipid peroxidation (via malondialdyhyde [MDA]), and expression of proinflammatory cytokines. Lung IR resulted in significantly increased MDA in WT mice, indicative of oxidative stress. WT mice treated with apocynin (an NADPH oxidase inhibitor) and p47(phox)-/- mice displayed significantly reduced pulmonary dysfunction and injury (vascular permeability, edema, MPO, and MDA). In BM chimeras, significantly reduced pulmonary dysfunction and injury occurred after IR in p47(phox)-/--->WT chimeras (donor-->recipient) but not WT-->p47(phox)-/- chimeras. Induction of TNF-alpha, IL-17, IL-6, RANTES (CCL5), KC (CXCL1), MIP-2 (CXCL2), and MCP-1 (CCL2) was significantly reduced after IR in NADPH oxidase-deficient mice and p47(phox)-/--->WT chimeras but not WT-->p47(phox)-/- chimeras. These results indicate that NADPH oxidase-generated ROS specifically from BM-derived cells contributes importantly to lung IR injury. NADPH oxidase may represent a novel therapeutic target for the treatment of IR injury after lung transplantation.
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PMID:NADPH oxidase in bone marrow-derived cells mediates pulmonary ischemia-reperfusion injury. 1878 74

Previous study showed that mulberry (Morus Alba L.) leaf (ML) ameliorates atherosclerosis in apoE(-/-) mice. Although the adipocytokine dysregulation is an important risk factor for atherosclerotic cardiovascular disease, the effect of ML on metabolic disorders related to adipocytokine dysregulation and inflammation has not been studied. Therefore, we studied the effects of ML in metabolic disorders and examined the mechanisms by which ML ameliorates metabolic disorders in db/db mice. We treated db/db mice with ML, pioglitazone, or both for 12 weeks and found that ML decreased blood glucose and plasma triglyceride. Co-treatment with ML and pioglitazone showed additive effects compared with pioglitazone. Moreover, their co-treatment attenuated the body weight increase observed under the pioglitazone treatment. ML treatment also increased the expression of adiponectin, and decreased the expression of TNF-alpha, MCP-1, and macrophage markers in white adipose tissue (WAT). Furthermore, ML decreased lipid peroxides and the expression of NADPH oxidase subunits in WAT and liver. Their co-treatment enhanced these effects. Thus, ML ameliorates adipocytokine dysregulation at least in part through inhibiting oxidative stress in WAT of db/db mice, and that ML may be a basis for a pharmaceutical for the treatment of the metabolic syndrome as well as reducing adverse effects of pioglitazone.
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PMID:Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice. 1907 Aug 57

MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of heart failure that is known to involve apoptosis. How MCP-1 contributes to cell death involved in the development of heart disease is not understood. In the present study we show that MCP-1 causes death in cardiac myoblasts, H9c2 cells, by inducing oxidative stress which causes ER stress leading to autophagy via a novel zinc-finger protein, MCPIP (MCP-1-induced protein). MCPIP expression caused cell death, and knockdown of MCPIP attenuated MCP-1-induced cell death. It caused induction of iNOS (inducible NO synthase), translocation of the NADPH oxidase subunit phox47 from the cytoplasm to the membrane, production of ROS (reactive oxygen species), and induction of ER (endoplasmic reticulum) stress markers HSP40 (heat-shock protein 40), PDI (protein disulfide-isomerase), GRP78 (guanine-nucleotide-releasing protein 78) and IRE1alpha (inositol-requiring enzyme 1alpha). It also caused autophagy, as indicated by beclin-1 induction, cleavage of LC3 (microtubule-associated protein 1 light chain 3) and autophagolysosome formation, and apoptosis, as indicated by caspase 3 activation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) assay. Inhibitors of oxidative stress, including CeO2 nanoparticles, inhibited ROS formation, ER stress, autophagy and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death as did knockdown of the ER stress signalling protein IRE1. Knockdown of beclin-1 and autophagy inhibitors prevented cell death. This cell death involved caspase 2 and caspase 12, as specific inhibitors of these caspases prevented MCPIP-induced cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK (c-Jun N-terminal kinase) and p38 and induction of p53 and PUMA (p53 up-regulated modulator of apoptosis). Taken together, these results suggest that MCPIP induces ROS/RNS (reactive nitrogen species) production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1alpha-JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure.
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PMID:MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. 1992 54


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