Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils are implicated in the damage of lung tissue in many disease states, including infectious diseases and environmental insults. These effects may be due to oxidative or nonoxidative functions of the neutrophil or both. We examined the role of neutrophils in pulmonary damage during infection with the opportunistic fungal pathogen Pneumocystis sp. in four mouse models of neutrophil dysfunction. These were (i) a knockout of the gp91(phox) component of NADPH oxidase, in which reactive oxygen species (ROS) production is greatly reduced; (ii) a double knockout of gp91(phox) and inducible nitric oxide synthase, in which ROS and nitric oxide production is greatly decreased; (iii) a knockout of the chemokine receptor CXCR2, in which accumulation of intra-alveolar neutrophils is severely diminished; and (iv) antibody depletion of circulating neutrophils in wild-type mice with the monoclonal antibody RB6. Surprisingly, in each case, indicators of pulmonary damage (respiratory rates, arterial oxygen partial pressures, and intra-alveolar albumin concentrations) were the same in knockout mice and comparable wild-type mice. Therefore, whereas neutrophils are a valid correlative marker of lung damage during Pneumocystis infection, neither neutrophils nor ROS appear to be the causative agent of tissue damage. We also show that there is no difference in Pneumocystis burdens between wild-type and knockout mice, which supports the idea that neutrophils do not have a major role in the clearance of this organism.
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PMID:Neither neutrophils nor reactive oxygen species contribute to tissue damage during Pneumocystis pneumonia in mice. 1538 71

Microglia, the major immune effector cells in the central nervous system, are activated when the brain suffers injury. A number of studies indicate that gangliosides activate microglia. However, the signaling mechanisms involved in microglial activation are not yet to be elucidated. Our results show that gangliosides induce the expression of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in rat brain microglia and BV2 murine microglia via protein kinase C (PKC) and NADPH oxidase. Expression of IL-1beta, TNF-alpha, and iNOS in ganglioside-treated cells was significantly reduced in the presence of inhibitors of PKC (GF109203X, Go6976, Ro31-8220, and rottlerin) and NADPH oxidase (diphenyleneiodonium chloride [DPI]). In response to gangliosides, PKC-alpha, betaII, and delta and NADPH oxidase p67(phox) translocated from the cytosol to the membrane. ROS generation was also activated within 5 min of ganglioside treatment. Ganglioside-induced ROS generation was blocked by PKC inhibitors. Furthermore, ganglioside-induced activation of NF-kappaB, an essential transcription factor that mediates the expression of IL-1beta, TNF-alpha, and iNOS, was reduced in the presence of GF109203X and DPI. Our results collectively suggest that gangliosides activate microglia via PKC and NADPH oxidase, which regulate activation of NF-kappaB.
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PMID:Gangliosides activate microglia via protein kinase C and NADPH oxidase. 1539 Jan 22

The present study tested the hypothesis that free radicals were involved in the pathogenesis of lung injury caused by diesel exhaust particles (DEP) and bacterial lipopolysaccharides (LPS). Intratracheal coinstillation of DEP and LPS in rat lungs resulted in synergistic enhancement of free radical generation in the lungs. The radical metabolites were characterized as lipid-derived by electron spin resonance (ESR). The free radical generation was paralleled by a synergistic increase in total protein and by infiltration of neutrophils in the bronchoalveolar lavage (BAL) fluid of the lungs. Experiments with NADP-reduced (NADPH) oxidase and iNOS knockout mice showed that NADPH oxidase and iNOS did not contribute to free radical generation. However, pretreatment with the macrophage toxicant GdCl(3), the xanthine oxidase (XO) inhibitor allopurinol, and the Fe(III) chelator Desferal resulted in a marked decrease in free radical generation, lung inflammation, and lung injury. These effects were concomitant with the inhibition of XO activity in BAL, suggesting that the activated macrophages and the activity of XO contributed to the generation of free radicals caused by DEP and LPS. This is the first demonstration that DEP and LPS work synergistically to enhance free radical generation in lungs, mediated by the activation of local XO.
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PMID:Synergistic production of lung free radicals by diesel exhaust particles and endotoxin. 1547 98

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors controlling lipid and glucose metabolism as well as inflammation. PPARs are expressed in macrophages, cells that also generate reactive oxygen species (ROS). In this study, we investigated whether PPARs regulate ROS production in macrophages. Different PPAR-alpha, but not PPAR-gamma agonists, increased the production of ROS (H2O2 and ) in human and murine macrophages. PPAR-alpha activation did not induce cellular toxicity, but significantly decreased intracellular glutathione levels. The increase in ROS production was not attributable to inherent prooxidant effects of the PPAR-alpha agonists tested, but was mediated by PPAR-alpha, because the effects were lost in bone marrow-derived macrophages from PPAR-alpha-/- mice. The PPAR-alpha-induced increase in ROS was attributable to the induction of NADPH oxidase, because (1) preincubation with the NADPH oxidase inhibitor diphenyleneiodinium prevented the increase in ROS production; (2) PPAR-alpha agonists increased production measured by superoxide dismutase-inhibitable cytochrome c reduction; (3) PPAR-alpha agonists induced mRNA levels of the NADPH oxidase subunits p47(phox), p67phox, and gp91phox and membrane p47phox protein levels; and (4) induction of ROS production was abolished in p47phox-/- and gp91phox-/- macrophages. Finally, induction of NADPH oxidase by PPAR-alpha agonists resulted in the formation of oxidized LDL metabolites that exert PPAR-alpha-independent proinflammatory and PPAR-alpha-dependent decrease of lipopolysaccharide-induced inducible nitric oxide synthase expression in macrophages. These data identify a novel mechanism of autogeneration of endogenous PPAR-alpha ligands via stimulation of NADPH oxidase activity.
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PMID:Peroxisome proliferator-activated receptor alpha induces NADPH oxidase activity in macrophages, leading to the generation of LDL with PPAR-alpha activation properties. 1559 Dec 35

Alzheimer's disease can be considered a protein misfolding disease. In particular, inappropriate processing of a proteolytic fragment of amyloid precursor protein, amyloid beta-protein (Abeta), in early stages of Alzheimer's disease may lead to stabilization of small oligomers that are highly mobile and have a potential to be extremely toxic assemblies. Recently, the importance of such soluble species of Abeta in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Abeta both in vitro and in vivo. This review focuses on the mechanisms of Abeta inhibition of long-term potentiation at synapses in the rodent hippocampus from two complimentary perspectives. Firstly, we examine evidence that the synaptic activity of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Abeta species. Secondly, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Abeta is emphasised. These mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of Alzheimer's disease.
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PMID:Mechanisms of the inhibitory effects of amyloid beta-protein on synaptic plasticity. 1558 82

Solute carrier family 11a member 1 (Slc11a1; formerly natural resistance-associated macrophage protein 1) encodes a late endosomal/lysosomal protein/divalent cation transporter, which regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 exerts pleiotropic effects on gene regulation and function, including generation of nitric oxide (NO) via inducible NO synthase (iNOS; encoded by Nos2A) and of reactive oxygen intermediates (ROI) via the phagocyte oxidase complex. As NO and ROI have potent antimicrobial activity in macrophages, it was assumed that their activities would contribute to Slc11a1-regulated innate resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani. By intercrossing mice with gene disruptions at Nos2A and Cybb (encoding gp91phox, the heavy chain subunit of cytochrome b-245 and an essential component of phagocyte NADPH oxidase) onto equivalent Slc11a1 wild-type and mutant genetic backgrounds, we demonstrate that neither iNOS nor gp91phox activity is required for Slc11a1-mediated innate resistance to either infection. Functional gp91phox and iNOS are required to control S. enterica serovar Typhimurium in non-Slc11a1-regulated phases of infection. For L. donovani, an organ-specific requirement for iNOS to clear parasites from the spleen was observed at 50 days post-infection, but neither iNOS nor gp91phox influenced late-phase infection in the liver. This contrasted with Leishmania major infection, which caused rapid lesion growth and death in iNOS knockout mice and some exacerbation of disease with gp91phox deficiency. This highlights the adaptive differences in tissue and cellular tropisms between L. donovani and L. major and the different genes and mechanisms that regulate visceral versus cutaneous forms of the disease.
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PMID:Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity. 1560 66

Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, a fulminant microglial-mediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the Abeta-stimulated expression of interleukin-1beta and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal Abeta production and microglia-directed inflammation.
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PMID:3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. 1564 73

Recently we have reported that glucose deprivation induces the potentiated death and loss of ATP in immunostimulated astroglia via the production of NO and eventually peroxynitrite. This study examined the role of the ERK1/2 signaling pathways in the glucose deprivation-induced death of immunostimulated astroglia. Immunostimulation with LPS+IFN-gamma induced the sustained activation of ERK1/2 for up to 48 h. Glucose deprivation caused the loss of ATP and consequently cell death in immunostimulated astroglia, which was significantly blocked by the treatment with the ERK kinase (MEK1) inhibitor, PD98059 (10-40 microM), to inhibit the ERK1/2 pathways. The systems for generating NO (iNOS) or superoxide (NADPH oxidase) were regulated by the ERK1/2 signaling pathways because the addition of PD98059 reduced the level of both. Interestingly, glucose deprivation caused an approximately two-fold increase in the level of peroxynitrite formation in immunostimulated astroglia, which was significantly reduced by the PD98059 treatment. This demonstrates that the ERK1/2 signaling pathways play an important role in glucose deprivation-induced death in immunostimulated astroglia by regulating the generation of NO, superoxide and their reaction product, peroxynitrite.
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PMID:Role of MAPK/ERK1/2 in the glucose deprivation-induced death in immunostimulated astroglia. 1572 Dec 16

We have recently shown that superoxide and hydrogen peroxide are putative inducers of angiogenesis in vivo, possibly through up regulation of inducible nitric oxide synthase (NOS) and increased production of endogenous nitric oxide (NO). The aim of the present work was to elucidate the implication of reactive oxygen species in endothelial cell functions, using cultures of human umbilical vein endothelial cells (HUVEC). Superoxide dismutase (SOD), tempol (membrane permeable SOD mimetic) and the NADPH oxidase inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride and apocynin, but not allopurinol, inhibited HUVEC proliferation and migration, as well as activity of endothelial NOS (eNOS). Catalase and the intracellular hydrogen peroxide scavenger sodium pyruvate decreased, while hydrogen peroxide increased HUVEC proliferation, migration and activity of eNOS. Dexamethasone induced the proliferation and migration of HUVEC and activated eNOS. Nomega-nitro-L-arginine methyl ester (L-NAME), but not Nomega-nitro-D-arginine methyl ester, decreased endothelial cell functions and reversed the effects of dexamethasone and hydrogen peroxide. N5-(1-iminoethyl)-L-ornithine dihydrochloride, but not the inducible NOS specific inhibitor N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide dihydrochloride also decreased endothelial cell functions, similarly to L-NAME. The guanylate cyclase inhibitor 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one inhibited HUVEC proliferation in a concentration-dependent manner and completely reversed hydrogen peroxide-induced proliferation, migration and cGMP accumulation. In conclusion, superoxide and hydrogen peroxide seem to play a significant role in promoting endothelial cell proliferation and migration, possibly through regulation of eNOS activity.
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PMID:Antioxidants inhibit human endothelial cell functions through down-regulation of endothelial nitric oxide synthase activity. 1574 Jul 22

The NF-kappaB/iNOS pathway stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway and diverse antioxidants block muscle differentiation. Therefore, we here investigated whether Nox 2 links those two myogenic pathways in H9c2 and C2C12 myoblasts. Compared with the proliferation stage, ROS generation was enhanced from the early stage of differentiation and gradually increased as differentiation progressed. Antioxidants suppressed the activated NF-kappaB/iNOS pathway during muscle differentiation. Nox 2 activity was also increased during muscle differentiation. Treatment with DPI and apocynin, two inhibitors of NADPH oxidase, and suppression of Nox 2 expression using siRNA, but not Nox 1, inhibited NADPH oxidase activity, muscle differentiation, and the NF-kappaB/iNOS pathway. Inhibition of PI 3-kinase and p38 MAPK suppressed the Nox 2/NF-kappaB/iNOS pathway. Nitric oxide restored muscle differentiation blocked by treatment with antioxidants or suppression of the Nox 2/NF-kappaB/iNOS pathway. In conclusion, Nox 2 stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway by activating the NF-kappaB/iNOS pathway via ROS generation.
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PMID:Nox 2 stimulates muscle differentiation via NF-kappaB/iNOS pathway. 1578 Jul 57


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