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

---

Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO)-1 is a stress-inducible rate-limiting enzyme in heme degradation that confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system-stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. We report that LTA is an inducer of HO-1 expression mediated through the signaling pathways in human tracheal smooth muscle cells (HTSMCs). LTA-induced HO-1 protein levels, mRNA expression, and promoter activity were attenuated by transfection with dominant negative mutants of TLR2 and MyD88, by pretreatment with the inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride (DPI) and apocynin (APO)), and reactive oxygen species (ROS) scavenger (N-acetyl-l-cysteine) or by transfection with small interfering RNAs of Src and NF-E2-related factor 2 (Nrf2). LTA-stimulated translocation of p47(phox) and Nrf2 or ROS production was attenuated by transfection with dominant negative mutants of TLR2, MyD88, and c-Src and by pretreatment with DPI or APO. Furthermore, LTA-induced TLR2, MyD88, TNFR-associated factor (TRAF)6, c-Src, and p47(phox) complex formation was revealed by immunoprecipitation using an anti-TLR2 or anti-c-Src Ab followed by Western blot analysis against an anti-TLR2, anti-MyD88, anti-TRAF6, anti-c-Src, or anti-p47(phox) Ab. These results demonstrated that LTA-induced ROS generation was mediated through the TLR2/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO-1 expression in HTSMCs.
...
PMID:Lipoteichoic acid induces HO-1 expression via the TLR2/MyD88/c-Src/NADPH oxidase pathway and Nrf2 in human tracheal smooth muscle cells. 1880 14

Nimodipine, a calcium channel blocker, has been used mainly in the therapy of cardiovascular diseases. Recently, its indications have been extended experimentally to a wider range of disorders especially some central nervous system (CNS) disorders. In this study, we investigated whether nimodipine is neuroprotective to inflammation-mediated neurodegenerative diseases. Pretreatment with nimodipine reduced the degeneration of dopaminergic (DA) neurons induced by LPS in mesencephalic neuron-glia cultures in a dose-dependent manner. The neuroprotective effect of nimodipine was attributed to the inhibition of microglial activation, since nimodipine significantly inhibited the production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and prostaglandin E(2) (PGE(2)) from LPS-stimulated microglia. Moreover, nimodipine was not neuroprotective to 1-methyi-4-phenylpyridinium (MPP(+))-induced DA neurotoxicity in the absence of microglia. Mechanistic study showed that nimodipine failed to protect the degeneration of neurons in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Taken together these results suggest that nimodipine is protective to DA neurodegeneration via inhibiting the microglial-mediated oxidative stress and inflammatory response. Thus, nimodipine may be a potential therapeutic agent for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.
...
PMID:Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. 1904 11

Oxidative stress is recognized to be involved in many pathological conditions, such as inflammation, arteriosclerosis, and neurodegenerative diseases. Reactive oxygen species (ROS), which induce oxidative stress responses, appear to induce different biochemical and cellular changes in each pathological condition. To elucidate the roles of ROS in these diverse pathological conditions, the measurement and evaluation of oxidative stress at subcellular levels would be very effective. We have developed EPR probes for oxidative stress in organelles, which are tagged with a fluorescent function, and assessed oxidative stress of the membrane and mitochondria using chemical probes for the corresponding organelles. These probes are localized to the expected cellular regions confirmed by confocal fluorescent microscopy, and for demonstration, the probes are employed to detect oxidative stress in RAW264.7 cells stimulated with LPS/IFN-gamma. From the radical clearance rate of the probes localized in both the membrane and mitochondria, oxidative stress has been found to be consistently more severe in the membrane region, where NADPH oxidase is known to be upregulated by LPS/IFN-gamma treatment. These specific probes have depicted each organelle under different oxidative stress conditions by a specific exogenous oxidative stimulus.
...
PMID:2,2,6,6-tetramethylpiperidin-1-oxyl probes for evaluating oxidative stress on the cell membrane and mitochondria. 1908 42

Oxidative stress is commonly observed in the elderly and could be involved in age-related diseases. However, the determinants of superoxide anion overproduction are not clearly understood. Superoxide anion production was evaluated using a lucigenin-based chemiluminescence method in 478 elderly subjects (304 women, 174 men; 79.5+/-7.1 years). Homocysteine (HCy) metabolism (homocysteinemia, vitamin B12, plasma, and erythrocyte folates), inflammation (CRP, fibrinogen, alpha-1 acid glycoprotein), lipid parameters (total cholesterol, triglycerides, HDL and LDL cholesterol), and nutritional parameters (albumin, transthyretin) were determined. The results show that HCy levels (p<0.001) and superoxide anion production (p=0.04) increase with aging, but CRP does not. Highest HCy (>20 microM) (OR 1.83 (1.09-3.07), p=0.02) and CRP over 5 mg/L (adjusted OR 2.01 (1.15-3.51), p=0.01) are the main determinants in superoxide anion production in the elderly. These clinical data are confirmed in an in vitro study using THP-1 monocyte-like cells. Incubation with HCy thiolactone (HTL) (0-200 microM) and LPS (0-20 ng/ml) dramatically enhances NADPH oxidase expression and activation. Moreover, a synergic action was evidenced for low concentrations of HTL (20 microM) and LPS (5 ng). Taken together, the clinical data and in vitro experiments support the hypothesis that moderate homocysteinemia and low-grade inflammation synergically enhance NADPH oxidase activity in the elderly.
...
PMID:Homocysteine and inflammation as main determinants of oxidative stress in the elderly. 1908 60

Several S100 Ca(2+)-binding proteins undergo various post-translational modifications that may alter their intracellular and extracellular functions. S100A8 and S100A9, two members of this family, are particularly susceptible to oxidative modification. These proteins, abundantly expressed in neutrophils and activated macrophages, are associated with acute and chronic inflammatory conditions, including microbial infections, cystic fibrosis, rheumatoid arthritis, and atherosclerosis. They have diverse intracellular roles including NADPH oxidase activation and arachidonic acid transport and can be secreted via a Golgi-independent pathway to exert extracellular functions. Many pro-inflammatory functions have been described for S100A8 and S100A9, but they are also implicated in anti-inflammatory roles in wound-healing and protection against excessive oxidative tissue damage,the latter as a result of their exquisite capacity to scavenge oxidants. Similarly, their genes are induced by proinflammatory (LPS and TNF-alpha) stimuli, but induction is IL-10-dependent, and anti-inflammatory glucocorticoids induce or amplify expression. S100A8 and S100A9 were described recently as damage-associated molecular pattern molecules, which provide a novel, conceptual framework for understanding their functions. However, because of this designation, recent reviews focus solely on their pro-inflammatory functions. Here, we summarize the mounting evidence from functional and gene regulation studies that these proteins may also play protective roles. This review offers an explanation for the disparate, functional roles of S100A8 and S100A9 based on emerging data that post-translational, oxidative modifications may act as a regulatory switch.
...
PMID:Oxidative modifications of S100 proteins: functional regulation by redox. 1923 40

Damage to nuclear DNA in human peripheral blood mononuclear cells was studied after in vitro treatment with bacterial endotoxin by alkaline comet assay. It was found that LPS induced DNA damage as soon as over the first 30 min of incubation, while by the 4th hour of incubation DNA damage was found in more than 95% cells. Exogenous superoxide dismutase completely protected DNA, which suggests that superoxide radical is the primary extracellular damaging agent. Polyphenol antioxidant (water-soluble lignin) and specific NADPH oxidase inhibitor (diphenyleneiodonium chloride) also produced a protective effect. Our results show that LPS-activated mononuclear cells can be used ex vivo as a convenient and adequate experimental system for evaluation of the efficiency of various substances in protection of lymphocyte DNA from the damaging effect of reactive oxygen species of LPS-stimulated monocytes.
...
PMID:DNA damage in human mononuclear cells induced by bacterial endotoxin. 1924 Aug 45

The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O(2)( )). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-kappaB essential modulator (NEMO or IkappaB kinase gamma) deficiency. We observed impaired O(2)( ) generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O(2)( ) in response to LPS-primed fMLP and translocated less p67(phox) than normal PMN, although p47(phox) and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.
...
PMID:Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. 1972 66

The purpose of this study was to investigate the role of Rac1 and estrogen in sex difference of cardiac tumor necrosis factor-alpha (TNF-alpha) expression during endotoxemia. Endotoxemia was induced in male and female mice by peritoneal injection of lipopolysaccharide (LPS, 4 mg/kg). Compared with female mice, male mice produced more TNF-alpha in the heart 4 h after LPS treatment, which were correlated with higher Rac1 and NADPH oxidase activity, more phosphorylation of ERK1/2 and p38 MAPK, and up-regulation of toll-like receptor-4 (TLR-4) expression in male mice. Cardiac specific Rac1 knockout or administration of 17beta-estradiol down-regulated Rac1 expression, attenuated gp91(phox)-NADPH oxidase expression and activity, decreased phosphorylation of ERK1/2/p38 MAPK and inhibited cardiac TNF-alpha expression induced by LPS, suggesting an important role of Rac1 and estrogen in LPS-stimulated TNF-alpha expression in the heart. More importantly, the sex difference in TNF-alpha expression was abrogated by Rac1 knockout or gp91(phox) knockout and by administration of apocynin or N-acetylcysteine in LPS-stimulated mice. To investigate the functional significance of sex difference in endotoxemia, heart function was measured in isolated hearts with a Langendorff system. Male mice exhibited worse myocardial dysfunction compared with female in endotoxemia. Treatment of male mice with 17beta-estradiol attenuated myocardial dysfunction during endotoxemia. In conclusion, LPS induces Rac1 activation, which contributes to NADPH oxidase activity and phosphorylation of ERK1/2/p38 MAPK, leading to TNF-alpha expression in the heart. The sex difference in TNF-alpha expression is estrogen-dependent and mediated via Rac1 dependent NADPH oxidase/ERK1/2 and p38 MAPK pathway in LPS-stimulated hearts.
...
PMID:Rac1 mediates sex difference in cardiac tumor necrosis factor-alpha expression via NADPH oxidase-ERK1/2/p38 MAPK pathway in endotoxemia. 1945 Jun 5

Toll-like receptor 4 (TLR4) senses bacterial LPS and is required for the control of systemic Salmonella enterica serovar Typhimurium infection in mice. The mechanisms of TLR4 activation and its downstream signalling cascades are well described, yet the direct effects on the pathogen of signalling via this receptor remain unknown. To investigate this we used microarray-based transcriptome profiling of intracellular S. Typhimurium during infection of primary bone marrow-derived macrophages from wild-type and TLR4-deficient mice. We identified 17 S. Typhimurium genes that were upregulated in the presence of functional TLR4. Nine of these genes have putative functions in oxidative stress resistance. We therefore examined S. Typhimurium gene expression during infection of NADPH oxidase-deficient macrophages, which lack normal oxidative killing mechanisms. We identified significant overlap between the 'TLR4-responsive' and 'NADPH oxidase-responsive' genes. This is new evidence for a link between TLR4 signalling and NADPH oxidase activity. Interestingly, with the exception of a dps mutant, S. Typhimurium strains lacking individual TLR4- and/or oxidative stress-responsive genes were not attenuated during intravenous murine infections. Our study shows that TLR4 activity, either directly or indirectly, induces the expression of multiple stress resistance genes during the intracellular life of S. Typhimurium.
...
PMID:Multiple redundant stress resistance mechanisms are induced in Salmonella enterica serovar Typhimurium in response to alteration of the intracellular environment via TLR4 signalling. 1954 4

Macrophages produce a large volume of ROS (reactive oxygen species) through respiratory burst. However, the influence of iNOS [inducible NOS (nitric oxide synthase)] activation on ROS production remains unclear. In the present study, the kinetic generation of ROS in RAW264.7 murine macrophages was monitored by chemiluminescence. PMA induces a robust chemiluminescence in RAW264.7 cells, suggesting PKC (protein kinase C)-related assembly and activation of NOX (NADPH oxidase). The effects of iNOS induction on ROS production were examined. Induction of iNOS expression in RAW264.7 cells with LPS (lipopolysaccharide; 1 microg/ml) causes a significant increase in PMA-induced chemiluminescence, which could be enhanced by the NOS substrate, L-arginine, and could be abolished by the NOS inhibitor, L-NNA (NG-nitro-L-arginine). Further experiments reveal that induction of iNOS expression enhances the PMA-stimulated phosphorylation of the p47phox subunit of NOX, and promotes the relocalization of cytosolic p47phox and p67phox subunits to the membrane. Inhibition of PKCzeta by its myristoylated pseudosubstrate significantly decreased the PMA-stimulated phosphorylation of the p47phox in LPS-pretreated cells, suggesting that PKCzeta is involved in the iNOS-dependent assembly and activation of NOX. Taken together, the present study suggests that the induction of iNOS upregulates the PMA-induced assembly of NOX and leads to the enhanced production of ROS via a PKCzeta-dependent mechanism.
...
PMID:Induction of inducible nitric oxide synthase increases the production of reactive oxygen species in RAW264.7 macrophages. 1967 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---