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)

Sepsis is a complex clinical syndrome that results from a harmful host response to infection, in which foreign bacteria and lipopolysaccharide (LPS) are potent activators of different immune cells, including monocytes and macrophages. To date, there are currently few effective adjuvant therapies in clinical use except activated protein C focusing on the coagulation system. Mastoparans (MPs) are wasp venom cationic amphiphilic tetradecapeptides; these are capable of modulating various cellular activities, including stimulation of GTP-binding protein, phospholipase C and can bind to a phospholipid bilayer. Masroparan-1 (MP-1, INLKAIAALAKKLL-NH2), a tetradecapeptide toxin isolated from hornet venom, was synthesized chemically. In this study, Escherichia coli 25922 (E. coli 25922) and LPS were used to induce sepsis in an animal model. We found that MP-1 treatment at 3 mg/kg protected mice from otherwise lethal bacteria and LPS challenges. MP-1 has antibacterial capabilities against Gram-negative and Gram-positive bacteria. Its antibacterial action against E. coli may result from the destruction of bacterial membrane structures. In addition, treatment of murine peritoneal macrophages with MP-1 potently inhibited the respiratory burst. This effect maybe related to an inhibition of NADPH oxidase in the membrane. Furthermore, MP-1, bound with high-affinity to LPS and lipid A with dissociation equilibrium constants of 484 and 456 nM, respectively, and neutralized LPS in a dose-dependent manner. MP-1 also significantly reduced the expression of TLR4, TNF-alpha and IL-6 mRNA and the release of cytokines in LPS-stimulated murine peritoneal macrophages. Our results shows that the MP-1-mediated protection of mice from lethal challenge by live bacteria and LPS was associated with its bactericidal action and inhibition of inflammatory responses by macrophages to both bacteria and LPS (the release of cytokines and reactive oxygen species).
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PMID:A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro. 1593 30

We previously conducted screening tests of the chloroform extracts from a total of 89 species of Japanese plant food items for their suppressive effects on superoxide (O(2) ()) generation through both NADPH oxidase and xanthine oxidase, and reported that mioga ginger (Zingiber mioga Roscoe) indicated the strongest suppressive activities. In this study, the suppressive effects of mioga ginger constituents, aframodial, and galanal B, together with [6]-gingerol and galanolactone occurring in ginger, on free radical generation and inducible proinflammatory gene expressions were investigated. Of these constituents, aframodial (20 microM) exhibited marked suppressive effects on 12-O-tetradecanoylphorbol-13-acetate-induced O(2) () generation in HL-60 cells and lipopolysaccharide (LPS)/interferon-gamma-induced nitric oxide (NO) generation in RAW264.7 cells (inhibition rates [IRs]=84.6% and 95.9%, respectively). Aframodial also strongly suppressed the stimulated HL-60 cell-induced mutagenicity in AS52 cells (IR=95.9%). The LPS-induced expression of inducible proinflammatory genes such as inducible NO synthase, interleukin (IL)-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor was significantly abolished (IRs=99.1%, 74.6%, 74.0%, and 64.4%, respectively) by aframodial. In addition, degradation of the inhibitor of nuclear factor kappaB was suppressed by this compound (IR=100%), suggesting that the suppression of nuclear factor kappaB activation, at least in part, is involved. Taken together, these results suggest that aframodial has potent antioxidative and anti-inflammatory potentials, and may be a promising candidate in prevention and/or therapy for chronic inflammationassociated carcinogenesis.
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PMID:Suppressive effects of mioga ginger and ginger constituents on reactive oxygen and nitrogen species generation, and the expression of inducible pro-inflammatory genes in macrophages. 1635 25

Cardiomyogenesis in differentiating mouse embryonic stem (ES) cells is promoted by cardiotrophin-1 (CT-1), a member of the IL-6 interleukin superfamily that acts through the tall gp130 cytokine receptor. We show that prooxidants (menadione, hydrogen peroxide) as well as chemical (CoCl2) and physiological (1% O2) hypoxia increased CT-1 as well as HIF-1alpha protein and mRNA expression in embryoid bodies, indicating that CT-1 expression is regulated by reactive oxygen species (ROS) and hypoxia. Treatment with either prooxidants or chemical hypoxia increased gp130 phosphorylation and protein expression of NADPH oxidase subunits p22-phox, p47-phox, p67-phox, as well as Nox1 and Nox4 mRNA. Consequently, inhibition of NADPH oxidase activity by diphenylen iodonium chloride (DPI) and apocynin abolished prooxidant- and chemical hypoxia-induced upregulation of CT-1. Prooxidants and chemical hypoxia activated ERK1,2, JNK and p38 as well as PI3-kinase. The proxidant- and CoCl2-mediated upregulation of CT-1 was significantly inhibited in the presence of the ERK1,2 antagonist UO126, the JNK antagonist SP600125, the p38 antagonist SKF86002, the PI3-kinase antagonist LY294002, the Jak-2 antagonist AG490 as well as in the presence of free radical scavengers. Moreover, developing embryoid bodies derived from HIF-1alpha-/- ES cells lack cardiomyogenesis, and prooxidants as well as chemical hypoxia failed to upregulate CT-1 expression. Our results demonstrate that CT-1 expression in ES cells is regulated by ROS and HIF-1alpha and imply a crucial role of CT-1 in the survival and proliferation of ES-cell-derived cardiac cells.
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PMID:Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1alpha and intracellular reactive oxygen species. 1650 96

Overexpression of constitutively active (CA)-G alpha13 significantly increased the expression of interleukin (IL)-1beta and IL-6 mRNAs and proteins in rat cardiac fibroblasts. IL-1beta mRNA induction by CA-G alpha13 was suppressed by diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, but not by BAPTA-AM, an intracellular Ca2+ chelator. In contrast, IL-6 mRNA induction by CA-G alpha13 was suppressed by BAPTA-AM but not by DPI. However, both IL-1beta and IL-6 mRNA induction was suppressed by nuclear factor kappaB (NF-kappaB) inhibitors. The CA-G alpha13-induced NF-kappaB activation was suppressed by DPI and BAPTA-AM, but not C3 toxin and the Rho-kinase inhibitor Y27632. IL-6 mRNA induction by CA-G alpha13 was suppressed by SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), an inhibitor of receptor-activated nonselective cation channels, and the expression of CA-G alpha13 increased basal Ca2+ influx. These results suggest that G alpha13 regulates IL-1beta mRNA induction through the reactive oxygen species-NF-kappaB pathway, while it regulates IL-6 mRNA induction through the Ca2+-NF-kappaB pathway.
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PMID:Heterotrimeric G protein G alpha13-induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts. 1677 60

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its cardioprotective effects are not completely understood. Because TNF-alpha-induced endothelial activation and vascular inflammation play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits TNF-alpha-induced signal transduction in human coronary arterial endothelial cells (HCAECs). We found that TNF-alpha significantly increased adhesiveness of the monocytic THP-1 cells to HCAECs, an effect that could be inhibited by pretreatment with resveratrol and the NF-kappaB inhibitor pyrrolidine dithiocarbamate. Previously, we found that TNF-alpha activates NAD(P)H oxidases, and our recent data showed that TNF-alpha-induced endothelial activation was prevented by the NAD(P)H oxidase inhibitor apocynin or catalase plus SOD. Resveratrol also inhibited H(2)O(2)-induced monocyte adhesiveness. Using a reporter gene assay, we found that, in HCAECs, TNF-alpha significantly increased NF-kappaB activity, which could be inhibited by resveratrol (>50% inhibition at 10(-6) mol/l) and pyrrolidine dithiocarbamate. Resveratrol also inhibited TNF-alpha-induced, NF-kappaB-driven luciferase expression in rat aortas electroporated with the reporter gene construct. In TNF-alpha-treated HCAECs, resveratrol (in the submicromolar range) significantly attenuated expression of NF-kappaB-dependent inflammatory markers inducible nitric oxide synthase, IL-6, bone morphogenetic protein-2, ICAM-1, and VCAM. Thus resveratrol at nutritionally relevant concentrations inhibits TNF-alpha-induced NF-kappaB activation and inflammatory gene expression and attenuates monocyte adhesiveness to HCAECs. We propose that these anti-inflammatory actions of resveratrol are responsible, at least in part, for its cardioprotective effects.
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PMID:Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. 1697 25

We investigated whether the cytokines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) are neuroprotective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3/43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. The activated microglia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD and LBD, but those of BDNF mRNA and protein drastically decreased specifically in LBD, in which neuronal loss was observed not only in the nigro-striatum but also in the hippocampus. The results suggest activated microglia in the hippocampus to be probably neuroprotective in PD, but those to be neurotoxic in LBD. As an evidence supporting this hypothesis, two subsets of microglia were isolated from mouse brain by cell sorting: one subset with high production of reactive oxygen species (ROS) and the other with no production of ROS. When co-cultured with neuronal cells, one microglia clone with high ROS production was neurotoxic, but another clone with no ROS production neuroprotective. On the other hand, Sawada with coworkers found that a neuroprotective microglial clone in a culture experiment converted to a toxic microglial clone by transduction of the HIV-1 Nef protein with increasing NADPH oxidase activity. Taken together, all these results suggest that activated microglia may change in vivo from neuroprotective to neurotoxic subtsets as degeneration of dopamine neurons in the SN progresses in PD. We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD. Toxic change of activated microglia may also occur in Alzheimer's disease and other neurodegenerative diseases in which inflammatory process is found.
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PMID:Role of cytokines in inflammatory process in Parkinson's disease. 1701 56

Free 8-hydroxydeoxyguanosine (oh(8)dG), a nucleoside of 8-hydroxyguanine (oh(8)Gua), present in cytosol is not incorporated into DNA. However, nothing is known about its biological function when it presents in cytosol as a free form. We demonstrate here for the first time that oh(8)dG inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production and cyclooxygenase-2 (COX-2) activity, and both gene transcriptions in microglia. Furthermore, oh(8)dG reduced mRNA levels of pro-inflammatory cytokine, such as IL-1beta, IL-6, and TNF-alpha, in activated BV2 cells. We also found that oh(8)dG suppressed reactive oxygen species (ROS) production through reduction of NADPH oxidase activity and blocked Rac1/STATs signal cascade. Finally, oh(8)dG suppressed recruitment of STATs and p300 to the iNOS and COX-2 promoters, and inhibited H3 histone acetylation. Taken together, these results provide new aspects of oh(8)dG as an anti-inflammatory agent.
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PMID:8-hydroxydeoxyguanosine suppresses NO production and COX-2 activity via Rac1/STATs signaling in LPS-induced brain microglia. 1702 66

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

Although the cardiovascular morbidity and mortality induced by cigarette smoking exceed those attributable to lung cancer, the molecular basis of smoking-induced vascular injury remains unclear. To test the link between cigarette smoke, oxidative stress, and vascular inflammation, rats were exposed to the smoke of five cigarettes per day (for 1 wk). Also, isolated arteries were exposed to cigarette smoke extract (CSE; 0 to 40 microg/ml, for 6 h) in organoid culture. We found that smoking impaired acetylcholine-induced relaxations of carotid arteries, which could be improved by the NAD(P)H oxidase inhibitor apocynin. Lucigenin chemiluminescence measurements showed that both smoking and in vitro CSE exposure significantly increased vascular O(2)(*-) production. Dihydroethidine staining showed that increased O(2)(*-) generation was present both in endothelial and smooth muscle cells. CSE also increased vascular H(2)O(2) production (dichlorofluorescein fluorescence). Vascular mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha and that of inducible nitric oxide synthase was significantly increased by both smoking and CSE exposure, which could be prevented by inhibition of NAD(P)H oxidase (diphenyleneiodonium and apocynin) or scavenging of H(2)O(2). In cultured endothelial cells, CSE elicited NF-kappaB activation and increased monocyte adhesiveness, which were prevented by apocynin and catalase. Thus we propose that water-soluble components of cigarette smoke (which are likely to be present in the bloodstream in vivo in smokers) activate the vascular NAD(P)H oxidase. NAD(P)H oxidase-derived H(2)O(2) activates NF-kappaB, leading to proinflammatory alterations in vascular phenotype, which likely promotes development of atherosclerosis, especially if other risk factors are also present.
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PMID:Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation. 1707 26

Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 microg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1beta, IL-6, IL-12 tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma levels in supernatants were analysed by the beadlyte cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3.2 with acteoside versus 5.2 with phosphate-buffered saline (PBS) (P < 0.02). In chronic colitis both 120 microg (3.3 versus 5.2) or 600 microg acteoside (3.0 versus 5.2) significantly ameliorated colitis (both P < 0.02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-gamma secretion (195 pg/ml with 600 microg acteoside versus 612 pg/ml with PBS, P < 0.02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted.
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PMID:In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis. 1743 25


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