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)

Fas-mediated apoptosis plays an important role in normal tissue homeostasis, and disruption of this death pathway contributes to many human diseases. Induction of apoptosis via Fas activation has been associated with reactive oxygen species (ROS) generation and down-regulation of FLICE inhibitory protein (FLIP); however, the relationship between these two events and their role in Fas-mediated apoptosis are unclear. We show herein that ROS are required for FLIP down-regulation and apoptosis induction by Fas ligand (FasL) in primary lung epithelial cells. ROS mediate the down-regulation of FLIP by ubiquitination and subsequent degradation by proteasome. Inhibition of ROS by antioxidants or by ectopic expression of ROS-scavenging enzymes glutathione peroxidase and superoxide dismutase effectively inhibited FLIP down-regulation and apoptosis induction by FasL. Hydrogen peroxide is a primary oxidative species responsible for FLIP down-regulation, whereas superoxide serves as a source of peroxide and a scavenger of NO, which positively regulates FLIP via S-nitrosylation. NADPH oxidase is a key source of ROS generation induced by FasL, and its inhibition by dominant-negative Rac1 expression or by chemical inhibitor decreased the cell death response to FasL. Taken together, our results indicate a novel pathway of FLIP regulation by an interactive network of reactive oxygen and nitrogen species that provides a key mechanism of apoptosis regulation in Fas-induced cell death and related apoptosis disorders.
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PMID:The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation. 1829 30

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.
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PMID:[The role for oxidative stress in neurodegenerative diseases]. 1830 64

Tanshinone IIA is one of the most abundant constituents of the root of Salvia miltiorrhiza BUNGE which exerts antioxidant and anti-inflammatory actions in many experimental disease models. In the present study, we demonstrated that the standardized fraction of S. miltiorrhiza (Sm-SF) was able to protect RAW 264.7 cells from ethanol-and lipopolysaccharide (LPS)-induced production of superoxide radical, activation of NADPH oxidase and subsequently death of the cells. Among four main components of Sm-SF, tanshinone IIA was the most potent in protecting cells from LPS-and ethanol-induced cytotoxicity. LPS or ethanol induced the expression of CD14, iNOS, and SCD1 and decreased RXR-alpha, which was completely reversed by tanshinone IIA. In H4IIEC3 cells, 10 microM tanshinone IIA effectively blocked ethanol-induced fat accumulation as evidenced by Nile Red binding assay. These results indicate that tanshinone IIA may have potential to inhibit alcoholic liver disease by reducing LPS-and ethanol-induced Kupffer cell sensitization, inhibiting synthesis of reactive oxygen/nitrogen species, inhibiting fatty acid synthesis and stimulating fatty acid oxidation.
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PMID:Effects of tanshinone IIA on the hepatotoxicity and gene expression involved in alcoholic liver disease. 1848 Oct 25

A wide variety of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical and hydrogen peroxide, and reactive nitrogen species such as nitric oxide (NO) and peroxynitrite are known to be involved in pathophysiology of bronchial asthma. We have investigated, in this study, the status of NADPH oxidase (NOX), a major source of superoxide anion production, in peripheral blood lymphocytes (PBL) from asthmatic patients in relation to salbutamol treatment. PBL isolated from patients with bronchial asthma were found to have a significantly increased activity of NOX. Plasma levels of malondialdehyde (MDA), an index of lipid peroxidation, and NO were also markedly elevated in asthmatic patients compared to control samples. A significantly decreased catalase activity observed in PBL from our patients underscored the severity of oxidative stress during asthma. Treatment of PBL with salbutamol (10 microg ml(-1)), prevented the attenuation of catalase activity but significantly increased the levels of NO and NOX activity. Levels of NOX-1 mRNA were significantly (p < 0.001) increased in PBL following treatment with NO donor (500 microM), S-nitroso-N-acetyl penicillamine (SNAP). Western blot analysis revealed that gp91phox protein was also significantly (twofold-threefold) increased following treatment with SNAP. The observed transcriptional regulation of NOX-1 and gp91phox by NO was observed to result in an increased NOX activity as well. This study concludes that salbutamol treatment enhances superoxide anion production in asthma patients through NO-mediated mechanisms, however it exerts beneficial antioxidant effects through activation of catalase and attenuation of lipid peroxidation.
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PMID:Nitric oxide-mediated activation of NADPH oxidase by salbutamol during acute asthma in children. 1850 84

Cystathionine beta synthase deficiency induces hyperhomocysteinemia which is considered as a risk factor for vascular diseases. Studies underlined the importance of altered cellular redox reactions in hyperhomocysteinemia-induced vascular pathologies. Nevertheless, hyperhomocysteinemia also induces hepatic dysfunction which may accelerate the development of vascular pathologies by modifying cholesterol homeostasis. The aim of the present study was to analyze the modifications of redox state in the liver of heterozygous cystathionine beta synthase-deficient mice, a murine model of hyperhomocysteinemia. In this purpose, we quantified levels of reactive oxygen and nitrogen species and we assayed activities of main antioxidant enzymes. We found that cystathionine beta synthase deficiency induced NADPH oxidase activation. However, there was no accumulation of reactive oxygen (superoxide anion, hydrogen peroxide) and nitrogen (nitrite, peroxynitrite) species. On the contrary, hepatic hydrogen peroxide level was decreased independently of an activation of glutathione-dependent mechanisms. In fact, cystathionine beta synthase deficiency had no effect on glutathione peroxidase, glutathione reductase and glutathione S-transferase activities. However, we found a 50% increase in hepatic catalase activity without any variation of expression. These findings demonstrate that cystathionine beta synthase deficiency initiates redox disequilibrium in the liver. However, the activation of catalase attenuates oxidative impairments.
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PMID:Cystathionine beta synthase deficiency induces catalase-mediated hydrogen peroxide detoxification in mice liver. 1854 Nov 57

Hemodynamics, specifically, fluid shear stress, modulates the focal nature of atherosclerosis. Shear stress induces vascular oxidative stress via the activation of membrane-bound NADPH oxidases present in vascular smooth muscle cells, fibroblasts, and phagocytic mononuclear cells. Shear stress acting on the endothelial cells at arterial bifurcations or branching points regulates both NADPH oxidase and nitric oxide (NO) synthase activities. The former is considered a major source of oxygen-centered radicals (i.e., superoxide anion [O2(.-)]) that give rise to oxidative stress; the latter is a source of nitrogen-centered radicals (i.e., nitric oxide [NO]) that give rise to nitrative/nitrosative stress. In addition to conventional biochemical analyses, the emerging microelectromechanical systems (MEMS) provide spatial and temporal resolutions to investigate the mechanisms whereby the characteristics of shear stress regulate the biological activities of endothelial cells at the complicated arterial geometry. In parallel, the development of MEMS liquid chromatography (LC) provides a new venue to measure circulating oxidized low-density lipoprotein (ox-LDL) particles as a lab-on-a chip platform. Nanowire-based field effect transistors further pave the way for a high throughput approach to analyze the LDL redox state. Integration of MEMS with oxidative biology is synergistic in assessing vascular oxidative stress. The MEMS LC provides an emerging lab-on-a-chip platform for ox-LDL analysis. In this context, this chapter has integrated expertise from the fields of vascular biology and oxidative biology to address the dynamics of inflammatory responses.
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PMID:Monitoring oxidative stress in vascular endothelial cells in response to fluid shear stress: from biochemical analyses to micro- and nanotechnologies. 1855 32

The cross talk between reactive oxygen species (ROS) and reactive nitrogen species (RNS) plays a pivotal role in the regulation of myocardial and vascular function. Both nitric oxide and redox-based signaling involve the posttranslational modification of proteins through S-nitrosylation and oxidation of specific cysteine residues. Disruption of this cross talk between ROS and RNS contributes to the pathogenesis of heart failure. Therefore, the elucidation of these complex chemical interactions may improve our understanding of cardiovascular pathophysiology. This chapter discusses the significant role of spatial confinement of nitric oxide synthases, NADPH oxidase, and xanthine oxidoreductase in the regulation of myocardial excitation-contraction coupling. This chapter describes techniques for assessing oxidative and nitrosative stress. A variety of assays have been developed that quantify S-nitrosylated proteins. Among them, the biotin-switch method directly evaluates endogenously nitrosylated proteins in a reproducible way. Identification of the biotinylated or S-nitrosylated proteins subjected to the biotin-switch assay are described and evaluated with a one-dimensional gel (Western blot) or with the newly developed two-dimensional fluorescence difference gel electrophoresis proteomic analysis. Quantifying the number of free thiols with the monobromobimane assay in a protein of interest allows estimation of cysteine oxidation and, in turn, the state of nitroso-redox balance of effector molecules. In summary, this chapter reviews the biochemical methods that assess the impact of nitroso/redox signaling in the cardiovascular system.
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PMID:Nitric oxide and cardiobiology-methods for intact hearts and isolated myocytes. 1855 46

Methylglyoxal is a normal metabolite and has the potential to affect a wide variety of cellular processes. In particular, it can act selectively against malignant cells. The study described herein was to investigate whether methylglyoxal can enhance the non-specific immunity of the host against tumor cells. Methylglyoxal increased the number of macrophages in the peritoneal cavity of both normal and tumor-bearing mice. It also elevated the phagocytic capacity of macrophages in both these groups of animals. This activation of macrophages was brought about by increased production of Reactive Oxygen Intermediates (ROIs) and Reactive Nitrogen Intermediates (RNIs). The possible mechanism for the production of ROIs and RNIs can be attributed to stimulation of the respiratory burst enzyme NADPH oxidase and iNOS, respectively. IFN-gamma, which is a regulatory molecule of iNOS pathway also showed an elevated level by methylglyoxal. TNF-alpha, which is an important cytokine for oxygen independent killing by macrophage also increased by methylglyoxal in both tumor-bearing and non tumor-bearing animals. Methylglyoxal also played a role in the proliferation and cytotoxicity of splenic lymphocytes. In short, it can be concluded that methylglyoxal profoundly stimulates the immune system against tumor cells.
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PMID:Activation of macrophages and lymphocytes by methylglyoxal against tumor cells in the host. 1861 20

UVA should receive significant consideration as a human health risk as it is a large proportion of the solar spectrum that reaches the earth's surface and because of its ability to penetrate human skin. It is only relatively recently that this has been recognized and this previously under-researched part of the UV spectrum is becoming increasingly well characterized at doses that are quite low in relation to those experienced by humans. Absorption of UVA in a cell leads to the production of reactive oxygen and nitrogen species that can damage major biomolecules including DNA and membrane lipids. Various types of damage induced in these molecules lead to significant biological effects including cytotoxicity, mutations and alterations in cell signalling pathways. Longer-term effects such as persistent genomic instability and bystander effects have also been observed following UVA treatment of mammalian cells and, as with ionizing radiation, this changes some of the fundamental thinking around tissue effects of irradiation. Antioxidants have been assessed extensively for their ability to protect against the biological effects of UVA and a number have been shown to be successful at least in-vitro, for example vitamin E and epigallocatechin-3-gallate. Other potential targets for protection are suggested through the increased understanding of some of the signalling mechanisms activated following treatment, for example the inhibition of NADPH oxidase is seen to reduce a bystander effect. The search for appropriate and successful photoprotective agents remains an important area of research.
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PMID:Cellular effects of long wavelength UV light (UVA) in mammalian cells. 1864 90

Oxidative stress is a "privilege" of aerobic organisms. It can be induced by endogenous and exogenous factors. Most often, it is characterized by the production of free radicals and nonradical oxygen and nitrogen products, referred to under a single term "reactive species" (RS). Oxidative stress is a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins and DNA. However, reactive oxygen (ROS) and nitrogen species (RNS) are "two-faced" products. Produced in low/moderate concentrations as molecular signals that regulate a series of physiological processes, such as a defence against infectious agents, the maintenance of vascular tone, the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. Many of ROS-mediated responses protect cells against oxidative stress and maintain "redox homeostasis". Then, both reactive species are produced by strictly regulated enzymes, such as nitric oxide synthase (NOS), and isoforms of NADPH oxidase, or as by-products from not so well regulated sources, such as the mitochondrial electron-transport chain. An excessive increase in ROS production has been implicated in the pathogenesis of atherosclerosis, cardiovascular diseases, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative and immuno-inflammatory diseases. Within the cells, ROS can act as secondary messengers in intracellular signalling cascades, which can induce the oncogenic phenotype of cancer cells, cellular senescence and apoptosis.
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PMID:[Oxidative stress in human diseases]. 1892 87


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