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)

In addition to their role in bacterial killing, reactive oxygen intermediates (ROI) produced by the NADPH oxidase may participate in the regulation of intracellular pathways. We have recently demonstrated that ROI produced by the oxidase regulate tyrosine phosphorylation in neutrophils, possibly by alterations in the cellular redox state. The purpose of the present study was to characterize the identities of certain of the redox-sensitive tyrosine-phosphorylated substrates and the significance of the increased phosphorylation. As a prominent 42-44-kDa phosphorylated band was noted in oxidant-treated cells, we investigated the possible phosphorylation and activation of mitogen-activated protein (MAP) kinase under these conditions. Immunoprecipitation of MAP kinase followed by immunoblotting with anti-phosphotyrosine antibodies indicated that a 42-44-kDa polypeptide was tyrosine-phosphorylated in response to treatment of cells, either with the oxidizing agent diamide or with H2O2 in cells where catalase was inhibited. Using an in vitro renaturation assay with myelin basic protein as the substrate, oxidant-induced stimulation of kinase activity of a 42-44-kDa band was observed in both whole cell extracts and in MAP kinase immunoprecipitates. The mechanism of redox-sensitive activation of MAP kinase was examined. First, exposure of cells to oxidants caused a significant increase in the activity of MEK (the putative activator of MAP kinase), as determined by an in vitro kinase assay using recombinant catalytically inactive glutathione S-transferase-MAP kinase as the substrate. Additionally, oxidant treatment of cells resulted in inhibition of the activity of CD45, a protein tyrosine phosphatase known to dephosphorylate and inactivate MAP kinase. We conclude that oxidant treatment of neutrophils can activate MAP kinase by stimulating its tyrosine and (presumably) threonine phosphorylation via MEK activation, a response that may be potentiated by inhibition of MAP kinase dephosphorylation by phosphatases such as CD45.
...
PMID:Activation of the mitogen-activated protein kinase signaling pathway in neutrophils. Role of oxidants. 798 67

To investigate the nature of the oxidative event that occurs during phagocytosis of retinal outer segments (ROS) by cultured human retinal pigment epithelial (RPE) cells, cells were incubated with isolated bovine ROS labeled with either the fluorescence probe carboxy-SNAFL-2 or the nonfluorescent, oxidizable probe 2',7'-dichlorodihydrofluorescein (H2DCF). The increase in fluorescence following phagocytosis was measured by a flow cytometer. Other measurements included: oxygen consumption using a Clark-type oxygen electrode, extracellular superoxide release by superoxide dismutase inhibitable lucigenin chemiluminescence, intracellular hydrogen peroxide (H2O2) production, and the effect of catalase inhibition on cellular thiobarbituric acid-reactive substances (TBARS) caused by phagocytosis. The activities of the enzymes NADPH oxidase and palmitoyl-CoA oxidase were also measured. H2DCF attached to bovine ROS was oxidized during phagocytosis with a time course suggesting oxidation subsequent to ROS uptake. Measurements of oxygen consumption showed a time-dependent increase of 10%, 4 h after ROS feeding, attributable to a doubling of the cyanide-resistant oxygen consumption. Intracellular H2O2 production also doubled 4 h after ROS phagocytosis. ROS uptake by RPE cells produced no significant extracellular superoxide, while extracellular superoxide production was readily demonstrated in a control macrophage cell line. Enzyme activity measurements showed that incubation of RPE cells with ROS doubled catalase activity without affecting superoxide dismutase or glutathione peroxidase activities. Inhibition of catalase during ROS uptake increased TBARS by 66%. Other enzyme activity measurements showed that human RPE cells possess both NADPH oxidase and palmitoyl-CoA oxidase activities. We conclude that ROS phagocytosis subjects RPE cells to an oxidative event on the same order of magnitude as measured in a macrophage. The event is not an extracellular macrophage-type respiratory burst and may be due to intracellular H2O2 resulting from an NADPH oxidase in the phagosome or from beta-oxidation of ROS lipids in peroxisomes. Irrespective of case, the enzyme catalase appears to be essential in protecting the RPE cell against reactive oxygen species produced during phagocytosis.
...
PMID:Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis. 808 27

Oxygen sensors in the body induce various cell activities to avoid any mismatch between oxygen demand and oxygen supply and to maintain an optimal level of oxygen partial pressure (PO2) in various organs. Oxygen sensing seems to be a well conserved process among procaryontic and eucaryontic cells. The molecular mechanism of oxygen sensing is unknown, but it has been suggested that a hemeprotein is involved that does not participate in the mitochondrial energy production. As examplified on the carotid body and on erythropoietin producing HepG2 cells, a cytochrome b was described for the NAD(P)H oxidase of neutrophiles might be an attractive candidate for this hemeprotein. It is hypothesised that hydrogen peroxide (H2O2) produced by this cytochrome b in direct correlation with cellular PO2, serves as a second messenger to regulate potassium channels or gene expression. One might forsee, that this new concept of oxygen sensing could have an impact on all processes in physiology and pathophysiology which are dealing with reactive oxygen intermediates.
...
PMID:Mechanisms and meaning of cellular oxygen sensing in the organism. 815 48

Platelets primed by exposure to subthreshold concentrations of arachidonic acid or collagen are known to be activated by nanomolar levels of hydrogen peroxide. We here demonstrate that this effect is mediated by hydroxyl radicals (OHzero) formed in an extracellular Fenton-like reaction. H2O2-induced platelet aggregation, serotonin release and thromboxane A2 productions were inhibited by OHzero scavengers and by the iron chelator desferrioxamine; hydroxyl radicals were detected directly by ESR measurements of the spin-trapped OHzero adduct. The role of OHzero was confirmed in experiments with exogenously added iron; free or EDTA-bound ferrous iron activated platelets in a process blocked by deoxyribose, mannitol or catalase, whereas ferric iron was without effect unless reductants were included. The activation by OHzero depended on concomitant release of arachidonic acid and was blocked by the phospholipase A2 inhibitors mepacrine and aristolochic acid, and by the Na+/K+ antiporter inhibitor ethylisopropylamiloride. In contrast, neomycin and staurosporin were without effects, indicating that phospholipase C and protein kinase C were not involved in the initial phase of activation. Neither radical formation nor arachidonic acid release was blocked by aspirin. In whole blood aggregation of platelets could be induced by H2O2 generated upon specific stimulation of neutrophils by N-formyl-methionyl-leucyl-phenylalanine; platelet activation and radical formation were blocked by the NADPH oxidase inhibitor diphenyliodonium as well as by catalase and mannitol. These results suggest that reactive oxygen species act as 'second messengers' during the initial phase of the platelet activation process.
...
PMID:Role of hydroxyl radicals in the activation of human platelets. 817 49

To characterize the perioperative alterations in polymorphonuclear leukocytes (PMN) function mediated by protein kinase C, we studied twenty six patients undergoing gastrointestinal surgery. Seventeen patients with thoracic esophageal cancer were underwent total thoracic esophagectomy through a right thoracotomy (severe surgical stress group). Nine patients underwent cholecystectomy (slight surgical stress group). Measurement of O2- production capacity was used as a reflection of the activity of NADPH oxidase, and the activity of myeloperoxidase-H2O2-halide system was evaluated using luminol-dependent chemiluminescence. O2- production stimulated by phorbol 12-myristate 13-acetate (PMA) was suppressed, reaching a minimum on POD 3. On the other hand, luminol dependent chemiluminescence increased significantly after surgery, reached a maximum on POD 3. These alterations were more remarkable in the severely stressed patients. These results suggest that postoperative PMN signal transduction mechanisms, mediated by protein kinase C, may activate myeloperoxidase-H2-O2-halide system but suppress NADPH oxidase system dependently of the degree of surgical stress, revealing a differential effect of protein kinase C activation on PMN microbicidal activity.
...
PMID:[Perioperative alterations in polymorphonuclear leukocyte function mediated by protein kinase C]. 817 96

The highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.
...
PMID:Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells. 819 1

In recent years it has become increasingly apparent that, in man, free radicals play a role in a variety of normal regulatory systems, the deregulation of which may play an important role in inflammation. As examples, we discuss the second messenger roles of: NO in the regulation of vascular tone, O2.- in fibroblast proliferation and H2O2 in the activation of transcription factors such as NF kappa B. Other control mechanisms, the physiological function of which may be perturbed in inflammation, include: the oxidative modification of low density lipoprotein, the oxidative inactivation of alpha-1-protease inhibitor, DNA damage/repair and heat shock protein synthesis. At sites of inflammation, increased free radical activity is associated with the activation of the neutrophil NADPH oxidase and/or the uncoupling of a variety of redox systems, including endothelial cell xanthine dehydrogenase. Although free radicals, thus produced, have the capacity to mediate tissue destruction, either alone or in concert with proteases, we argue that disturbances in the second messenger and regulatory activities of free radicals may also contribute significantly to the inflammatory process.
...
PMID:Free radicals in inflammation: second messengers and mediators of tissue destruction. 822 Oct 19

In order to understand the pathogenesis of mouse muscular dystrophy, we investigated the levels of the thiobarbituric acid-reactive substances (TBARS), H2O2 and NADPH oxidase activity, which were relative to the acceleration of oxidative conditions, in tongue and hindleg skeletal muscles from C57BL/6J-dy mice. The TBARS content (702 nmol/g protein) in skeletal muscles from 2-months-old dystrophic mice was increased significantly over that (384 nmol/g protein) in muscles from age-matched normal mice. The H2O2 concentration in dystrophic skeletal muscles was 30% higher than that in normal ones. Microsomal NADPH oxidase activity which was related to the production of superoxide anions, was similar between dystrophic muscles (4.66 nmol/10 min/mg protein) and normal muscles (4.11 nmol/10 min/mg protein). These results indicate that oxidation is accelerated in the dystrophic muscles. However, the TBARS content in the tongues of dystrophic mice was identical to that of normal mice. This finding supports our bone-muscle growth imbalance hypothesis for the pathogenesis of mouse muscular dystrophy.
...
PMID:Elevation of the level of thiobarbituric acid-reactive products in hindleg skeletal muscle of dystrophic mice, but non-elevation in tongue muscle. 822 42

Phagocytic cells respond to a variety of membrane stimulants by producing reactive oxygen intermediates (ROI), i.e. O2-, H2O2 and OH.metabolites. Plasma membrane activation is associated with superoxide generating NADPH oxidase, thereby causing the production of these toxic species. Stimulation of phagocytic cells also results in activation of purine catabolism, which directs the metabolic flux through xanthine oxidase to produce the superoxide anion. We previously observed that BL/LL macrophages (M phi) exhibited a premature inability to undergo tuftsin stimulated phagocytosis and microbicidal activity. The present study was undertaken to measure ROI levels in the absence and presence of 'tuftsin' pulsing as a function of in vitro culture age and also correlated these levels with adenosine deaminase (ADA) activity. The latter is known to be a contributor of O2- generation and is also involved in the maturation of the monocyte/macrophage system. The behaviour of normal and tuberculoid monocytes/macrophages were more or less the same, either in the presence or absence of tuftsin, i.e. they showed a progressive increase in ROI production until day 3, then tapered off in older cultures by day 7. In contrast, after day 1, the lepromatous macrophages were unable to undergo tuftsin mediated stimulation for the production of ROI and ADA activity. These findings indicate a defective M phi function in lepromatous patients towards tuftsin pulsing, thereby supporting our earlier observations. Thus BL/LL M phi behaved as if they were aged after 1 day of in vitro culture, which may account for an inability to handle Mycobacterium leprae for efficient killing.
...
PMID:Modulation of peripheral blood derived monocytes/macrophages from leprosy patients using 'tuftsin' for production of reactive oxygen intermediates. 823

The results of this study show that recombinant interleukin-8 (IL-8) enhances the intracellular killing of Mycobacterium fortuitum by human granulocytes. This chemokine did not stimulate the phagocytosis of M. fortuitum by granulocytes at various bacterium-to-cell ratios. The killing process was not affected by the NADPH oxidase inhibitor diphenyleneiodonium bisulfate, which indicates that recombinant IL-8 stimulates oxygen-independent mycobactericidal mechanisms of granulocytes. IL-8 did not stimulate H2O2 production in granulocytes but primed the cells for enhanced H2O2 production upon stimulation with preopsonized M. fortuitum. In sum, the chemokine IL-8 not only is involved in the recruitment of granulocytes to the site of infection but also facilitates the elimination of microorganisms by increasing the efficiency of the bactericidal activity of granulocytes.
...
PMID:Interleukin-8 enhances nonoxidative intracellular killing of Mycobacterium fortuitum by human granulocytes. 833 40


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

---