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)

We previously reported that phorbol 12-myristate 13-acetate (PMA)-induced superoxide (O2.-) generation of neutrophils was inhibited by hypericin, a photosensitizing pigment found in St. Johnswort (herb Hypericin triquetrifolium Turra), via a mechanism involving protein kinase C (PKC). To obtain further insights into the mechanism of inhibition, the effects of hypericin on stimulation-dependent O2.- generation and related enzymes of neutrophils were investigated. Hypericin inhibited O2.- generation of neutrophils induced by PKC-dependent and -independent stimuli in a light- and concentration-dependent manner. Oxygen was required for the light-dependent inhibition by hypericin. NADPH oxidase activity in a cell-free system and TNF-alpha-induced tyrosyl phosphorylation of neutrophil proteins were also inhibited by hypericin in a concentration- and light-dependent manner. However, tyrosine kinase of p60src, an enzyme not bound to a membrane, was not inhibited either in the light or in the dark. Oxygen uptake of neutrophils by photosensitization with hypericin resulted in the formation of singlet oxygen (1O2), O2.-, and hydroxyl radical (.OH) and enhanced lipid peroxidation. The formation of 1O2 was inhibited by azide, a quencher of 1O2, but not by desferrioxamine (DSF), a ferric ion chelator. By contrast, both generation of .OH and lipid peroxidation were inhibited by DSF but not by azide. Furthermore, PMA-induced O2.- generation inhibited by hypericin partially recovered in the presence of azide but not DSF. These results suggested that the light-dependent inhibition of O2.- generation by hypericin might be due to inhibition of tyrosine kinase, PKC, and NADPH oxidase via an oxygen-dependent mechanism, possibly through both Type I and II photosensitization mechanisms.
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PMID:Inhibition of neutrophil superoxide generation by hypericin, an antiretroviral agent. 748 96

The results presented in this paper demonstrate that the potentiation of phagocytosis of erythrocyte (E) IgG by TNF-alpha or PMA is not due to an oxygen-dependent mechanism. In fact, the potentiation of phagocytosis occurs normally in human neutrophils 1) when the respiratory burst is inhibited by diphenyleneiodonium, 2) in conditions where the reactive oxygen metabolites produced by the activation of NADPH oxidase, that accompanies the phagocytosis, were removed by catalase or superoxide dismutase, 3) of a patient lacking NADPH oxidase activity due to a genetic defect of p67-phox, 4) treated with staurosporine which allowed PMA to potentiate the ingestion of E-IgG at concentrations which inhibited the activation of the respiratory burst. Evidence is also presented that staurosporine not only did not inhibit, but amplified the potentiation of phagocytosis by PMA and TNF-alpha. This last finding suggests that the activation of protein kinase C plays a modulatory rather than a positive role in the mechanism of potentiation of phagocytosis.
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PMID:The potentiation by TNF-alpha and PMA of Fc receptor-mediated phagocytosis in neutrophils is independent of reactive oxygen metabolites produced by NADPH oxidase and of protein kinase C. 839 10

The purpose of these studies was to examine the sensitivity of the PIP 2-PLC-transducing pathway (GPLC) and its relationship to the respiratory burst in human polymorphonuclear leukocytes (PMN) stimulated by IL-8, TNF-alpha, or IL-1 beta during sequential changes in buffer oxygen tension from normoxia (pO2 = 180-200 mm Hg), to hypoxia (pO2 < 30 mm Hg) and then reoxygenation (pO2 > 140 mm Hg). Our specific hypothesis was that altered oxygen tensions would regulate the G PLC pathway in human PMN. G PLC activity was assayed by investigating phospholipase C activity by measuring inositol phosphates and diacylglycerol (DAG) formation. Respiratory burst activity was assayed as O 2 production and NADPH oxidase activation in intact PMN and in a cell-free system, respectively, and correlated separately to both early and late DAG production. At 1 min, DAG formation during normoxia was decreased by IL-8 plus fibronectin while hypoxia had no regulatory effect on control of DAG formation by any of the cytokines. In contrast to early DAG formation, hypoxia significantly downregulated late DAG formation induced by buffer without fibronectin, IL-8 plus fibronectin, and IL-1 beta with or without fibronectin. Hypoxia/reoxygenation in and of itself significantly increased DAG formation vs levels seen in the presence or absence of IL-8, TNF-alpha, or IL-1 beta with or without fibronectin. Changes in early DAG production during the alterations in oxygen tension correlated best with corresponding changes in O 2 production in intact cells, whereas late DAG production correlated best with NADPH oxidase activation assayed in the cell-free system. Thus, changes in oxygen tension can directly modulate the extent of the PMN response to stimulation by IL-8, TNF-alpha, or IL-1 beta and the G PLC-receptor pathway is particularly regulated by physiologically relevant periods of hypoxia/reoxygenation.
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PMID:Altered oxygen tension modulates cytokine-induced signal transduction in polymorphonuclear leukocytes: regulation of the G PLC pathway. 860 6

New selenium-containing compounds behave as GPx mimics and protect endothelial cells (HUVEC) from damage upon exposure to 55 microM linoleic acid hydroperoxide or to 200 microM hydrogen peroxide. The simultaneous presence of the GPx mimic and the hydroperoxyde is not necessary, since a pre-treatment of endothelial monolayers with 1 to 10 microM of such compounds, preserves their morphology, their cell density and their longer-term viability. The compounds which are most efficient in this model of oxidative stress also protect endothelial monolayers which have been incubated with an excess (10:1) of polymorphonuclear neutrophils (PMN) and with 1 ng/ml of TNF-alpha, if such monolayers are pre- and co-treated (10 microM). They inhibit the adhesion of activated neutrophils which show-up as polymorphous and very dense particles, in the vicinity of which endothelial alterations can be seen. The inhibition of leucocyte adhesion and that of endothelial activation/alteration have been quantified by means of immunoassays of myeloperoxidase and von Willebrand factor (vWf). The lead-compound BXT-51072 is not a direct inhibitor of the NADPH oxidase of PMN. TNF-alpha alone induces the endothelial release of Interleukin-8 (Il-8) as well as the expression of P- and E-selectin. The extent and the kinetics of inhibition of such processes by compound BXT-51072 would explain several of the effects observed in the presence of PMN. The GPx mimics also inhibit the endothelial production of Il-8 which is induced by Interleukin-1 alpha. Finally, compound BXT-51072 inhibits the endothelial expression of the adhesion factor VCAM-1 which is more slowly induced by TNF-alpha. Such antioxidant catalysts therefore protect endothelial cells from the toxic effects of TNF-alpha through mechanisms which include a down-regulation of cytokines and cell-adhesion factors.
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PMID:[Antioxidant and anti-inflammatory protection of vascular endothelial cells by new synthetic mimics of glutathione peroxidase]. 867 32

We investigated the effect of alterations in buffer oxygen tensions from normoxia (PO2 = 180-200 mm/Hg) to hypoxia (PO2 < 30 mm/HG) and then reoxygenation (PO2 > 140 mmHg) on the GPLD-pathway by measuring phosphatidylethanol formation in the presence of ethanol and subsequent NADPH oxidase activation and O2-production in polymorphonuclear leukocytes (PMN). Experiments were performed with PMN stimulated with either interleukin (IL)-8, tumor necrosis factor (TNF)-alpha, or IL-1 beta in the presence or absence of fibronectin. Hypoxia exerted a downregulating effect on this pathway and reoxygenation restored GPLD activation to levels seen during normoxia; however, supraphysiological concentrations of cytokines were able to reverse this pattern. Changes in GPLD activation correlated best with changes in O2-production during the hypoxia to hypoxia/reoxygenation transition induced by TNF-alpha-Fn and IL-1 beta +/- Fn. Thus, changes in oxygen tension can directly modulate the extent of the PMN response to stimulation by IL-8, TNF-alpha, or IL-1 beta, and activation of the GPLD-pathway appears to be highly sensitive to hypoxia and hypoxia/reoxygenation.
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PMID:Altered oxygen tension modulates cytokine-induced signal transduction in polymorphonuclear leukocytes: regulation of the GPLD pathway. 870 96

The present study investigates synergistic effects of the TNF-alpha inhibitor thalidomide and the poly(ADP-ribose) polymerase (PARP)-inhibitor nicotinic acid amide (NAA) in male DBA/1 hybird mice suffering from type II collagen-induced arthritis. Parameters including the arthritis index, chemiluminescence and anti-collagen antibody titers were used for the assessment of disease activity: The disease courses demonstrated clearly an inhibitory effect of thalidomide. NAA inhibited established collagen arthritis in a dose-dependent manner. The combined application of thalidomide and NAA caused a powerful synergistic inhibition of arthritis. Furthermore, thalidomide and NAA were tested ex vivo for their inhibition of the NADPH oxidase-dependent generation of reactive oxygen species by activated neutrophils and monocytes in unseparated human blood. Our data show that type II collagen-induced arthritis can be suppressed by the simultaneous inhibition of TNF-alpha, PARP, and NADPH oxidase.
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PMID:Synergistic effects of thalidomide and poly (ADP-ribose) polymerase inhibition on type II collagen-induced arthritis in mice. 872 22

Oxidative damage caused by oxygen free radicals from activated phagocytes contributes to the pathology of arthritis. The present study evaluates the activity of NADPH oxidase of neutrophils and monocytes from patients suffering from various inflammatory and autoimmune rheumatic disease. Production rates of reactive oxygen species [ROS] of neutrophils and monocytes from rheumatic patients are compared to those of healthy controls and non rheumatic disease controls and correlated with the plasma levels of tumor necrosis factor alpha, C-reactive protein and the sedimentation rates of erythrocytes. There was a two- to eightfold increase in phagocytic superoxide production in rheumatic patients, when compared to healthy subjects or patients with non-rheumatic internal diseases [p < 0.005]. The enhanced NADPH oxidase-dependent superoxide generation correlated well with elevated levels of tumor necrosis factor alpha [TNF-alpha] in plasma [p = 0.005], suggesting a causal relation. There was no correlation with the plasma levels of C-reactive protein and a weak though significant correlation with the sedimentation rates of erythrocytes [p = 0.043]. Removal of circulating TNF-alpha by dialysis of patients blood and inhibition of NADPH oxidase by prednisolone treatment normalized elevated ROS production to the levels of healthy controls and correlated with the clinical improvements. Our data support the hypothesis of a central role for TNF-alpha during the development of arthritis. The chemiluminescence assay described here may be useful as a convenient screen and as a potential follow up procedure for individual patients with rheumatic diseases.
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PMID:Priming of NADPH oxidase by tumor necrosis factor alpha in patients with inflammatory and autoimmune rheumatic diseases. 887 5

This study concerns the controversial problem of whether the TNF-alpha (TNF) induces a respiratory burst in human neutrophils in suspension. The results have shown that in these cells TNF induces a classical respiratory burst. In fact, the production of oxygen free radicals 1) is linked to the translocation of NADPH oxidase components from cytosol to the plasma membrane, 2) does not take place in neutrophils from a patient lacking the cytochrome b558, and 3) does not involve other sources such as mitochondrial respiratory chain or xanthine oxidase. Signal transduction studies have demonstrated that this respiratory burst 1) is not accompanied by calcium transients, stimulation of phosphoinositide turnover, and phospholipase D activity (moreover, this burst is associated with the stimulation of the activity of phospholipase A2, but not of sphingomyelinase); 2) is strictly dependent on activation of tyrosine kinases, which is functional to the translocation to the plasma membrane of the cytosolic NADPH oxidase component rac; and 3) is dependent on the integrity of the cytoskeleton because it is completely suppressed by cytochalasin B. The integrity of the cytoskeleton is required for a full translocation of all the NADPH oxidase components and for an optimal activation of tyrosine kinases, but not for phospholipase A2 activation. Taken together, these findings demonstrate that TNF activates the NADPH oxidase through stimulation of tyrosine kinases, whose function is cytoskeleton-dependent, and raise the problem of whether the activation of this respiratory burst involves signals arising from TNF-activated beta2 integrins.
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PMID:Mechanisms of stimulation of the respiratory burst by TNF in nonadherent neutrophils: its independence of lipidic transmembrane signaling and dependence on protein tyrosine phosphorylation and cytoskeleton. 890 41

The aim of this study was to determine the role of reactive oxygen species (ROS) in checking the growth of intracellular mycobacteria within human phagocytes. Peripheral blood-derived neutrophils and monocyte-derived macrophages were isolated from Chronic Granulomatous Disease (CGD) patients and normal healthy human volunteers. CGD patients are known to have a defect in the NADPH oxidase pathway, resulting in their neutrophils and monocyte-derived macrophages being unable to generate oxygen radicals which are required to kill intracellular bacteria. The cells were then infected with Bacille Calmette Guerin (BCG) or Mycobacterium avium, and the bacterial growth in each cell type determined by Colony Forming Units (CFU) estimate. The results obtained indicate that there was no demonstrable inhibition in the intracellular mycobacterial growth within neutrophils or macrophages derived from either Chronic Granulomatous Disease (CGD:deficient in NADPH oxidase pathway) or normal healthy volunteers. Macrophage treatment with either IFN-gamma or TNF-alpha had no effect.
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PMID:The role of reactive oxygen species (ROS) in the effector mechanisms of human antimycobacterial immunity. 935 Mar 48

Inflamed synovium is characterized by high concentrations of cytokines [interleukin (IL)-6, IL-1beta and tumour necrosis factor (TNF)-alpha] and the abundant presence of infiltrated monocytes, many of which are found adjacent to the resident fibroblast-like synoviocytes. We have used a co-culture of fibroblast-like synoviocytes and differentiated U937 cells to study IL-6, IL-1beta and TNF-alpha release. After a 3 day co-culture, 35% of the U937 cells had adhered and were fully differentiated towards monocytes, as determined by expression of p47phox, CD14, MSE-1, Mac-1, collagenase and NADPH oxidase activity. IL-6 release from fibroblast-like synoviocytes was induced 4-fold by co-culture with differentiated U937 cells. However, co-culture of differentiated U937 cells with fibroblast-like synoviocytes failed to release detectable levels of IL-1beta and TNF-alpha from the U937 cells. Addition of synovial fluid further increased IL-6 release, but again had no effect on IL-1beta or TNF-alpha, although U937 cells differentiated by phorbol ester were able to release these two cytokines and, in the case of the co-culture, mRNAs for both cytokines were highly expressed in the U937 cells. We postulate that the influx of monocytes into the synovium is instrumental in the elevation of IL-6 levels, but this is not sufficient to explain high levels of IL-1beta or TNF-alpha.
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PMID:Co-culture of synovial fibroblasts and differentiated U937 cells is sufficient for high interleukin-6 but not interleukin-1beta or tumour necrosis factor-alpha release. 956 69


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