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)

The effect of auranofin (AF) was examined on human neutrophil superoxide production and protein phosphorylation stimulated by phorbol esters. Low concentrations of auranofin (less than or equal to 0.5 microM) enhanced while higher concentrations (0.5-10 microM) inhibited superoxide release stimulated by a suboptimal concentration (0.005 microM) of phorbol myristate acetate (PMA). The enhancing but not the inhibitory effect of AF was lost if a maximal stimulating dose (0.05 microM) of PMA was used. In contrast AF had a biphasic effect on protein phosphorylation regardless of the stimulating concentration of PMA. Comparison of the dose-response curves for these effects of AF suggest that although changes in protein phosphorylation may be partly responsible for altered activity of the NADPH oxidase responsible for superoxide production, it is unlikely that they are mediated by a direct effect of AF on protein kinase C. Also, measurement of 3H-PDBu-binding to neutrophils showed that these actions of AF could not be attributed to altered binding of phorbol esters to their cellular receptor (protein kinase C).
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PMID:Auranofin modulates human neutrophil superoxide production and protein phosphorylation. 254 53

Superoxide anion production by polymorphonuclear leukocytes stimulated with phorbol 12-myristate 13-acetate is known to be inhibited by a number of inhibitors and substrates of serine proteases, in particular by tosylphenylalanylchloromethane (TosPheCH2Cl) and to a lesser extent by tosyllysylchloromethane (TosLysCH2Cl). We have reinvestigated the characteristics of this inhibition, in view of the fact that other serine protease inhibitors with similar specificities, phenylmethanesulfonyl fluoride and leupeptin, were without effect. We found that the inhibition of phorbol-ester-induced superoxide production after cell preincubation with the chloromethanes followed saturation kinetics, with Kinact and kinact values of 100 microM and 31 min-1 for TosPheCH2Cl and 2 mM and 18 min-1 for TosLysCh2Cl. We also showed that the two compounds, which can inhibit protein kinase C in vitro, inhibited neither its activity in vivo, nor its translocation induced by phorbol myristate acetate. Furthermore the intracellular non-protein sulfhydryl group content was not affected by the treatment with the chloromethanes. Finally, addition of the inhibitors to stimulated cells also led to a time-dependent, concentration-dependent inhibition of superoxide production. Altogether, our results suggest that the chloromethane target is neither a protease nor protein kinase C and is not involved in NADPH oxidase activation, but rather in maintenance of its activity. The possible identity of this protein is discussed.
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PMID:Inhibition of NADPH oxidase by aminoacyl chloromethane protease inhibitors in phorbol-ester-stimulated human neutrophils: a reinvestigation. Are proteases really involved in the activation process? 254 67

It has not been clarified whether dietary restriction alters macrophage functions, although the augmentation of T cell functions by dietary restriction is well known. Forty percent dietary restriction on 9-week-old male C3H/He mice caused a decrease of body weight. However, one of the major macrophage functions, the generation of superoxide anion (O2), was augmented in proteose peptone-elicited peritoneal macrophages (MPs) from diet-restricted mice. This increase was more striking when the cells were stimulated by 12-o-tetradecanoylphorbol-13-acetate (TPA), which directly activated protein kinase C, than by opsonized zymosan which binded to receptors on the cells. These results strongly suggest that the augmentation of O2- generation in MPs by dietary restriction is due to the increased activity of protein kinase C which phosphorylate and activate O2-generating enzyme system NADPH oxidase. It is thought that one of the major factors for the reduced incidence of tumor and infection in diet-restricted animals is the augmentation of O2-generation in MPs.
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PMID:Dietary restriction augments superoxide generation in mouse peritoneal macrophages: an investigation using a chemiluminescence probe specific for superoxide anion. 255 95

The mechanism of neutrophil activation by chemotactic receptor agonists was studied by monitoring stimulus-induced changes in the cytosolic free calcium concentration and hydrogen peroxide formation during the respiratory burst. Two receptor-dependent signal transduction sequences were identified. One sequence depends on calcium, phospholipase C and protein kinase C, and is rate limiting, while the other is comparatively fast and appears to be calcium-independent. The present studies indicate that both sequences must act in concert to transduce receptor-mediated signals and to activate the NADPH oxidase.
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PMID:[Properties and activation mechanism of neutrophilic leukocytes]. 265 18

A factor in medium conditioned by mouse tumor cells was shown previously to suppress the capacity of mouse peritoneal macrophages to undergo a respiratory burst and to kill protozoal pathogens (macrophage deactivation factor, MDF). Recently, pure transforming growth factor-beta (TGF-beta) proved to be a potent macrophage deactivator as well. Two lines of evidence suggest that MDF is not identical with TGF-beta. First, rabbit anti-TGF-beta IgG neutralized the respiratory burst-suppressing activity of TGF-beta without affecting the bioactivity of MDF, even when the latter was treated with acid to activate potentially latent TGF-beta. Second, in contrast to MDF, which decreases the affinity of the NADPH oxidase for NADPH, permeabilized macrophages that had been deactivated with TGF-beta displayed the same Km and Vmax of the oxidase as activated macrophages. As with MDF, TGF-beta had no effect on two other potential control points over the secretion of respiratory burst products, namely, hydrogen peroxide catabolism or glucose uptake. Finally, neither MDF nor TGF-beta affected the extent or affinity of binding of phorbol diesters to macrophages, the activity or cofactor requirements for protein kinase C, or the ability of protein kinase C to translocate quantitatively from cytosol to membrane fractions in response to phorbol diesters. Thus, 1) MDF is not identical with TGF-beta, and 2) in contrast to the activation or deactivation of macrophages by numerous other agents, TGF-beta regulates macrophage respiratory burst capacity at a level other than the apparent affinity of the oxidase for its substrate.
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PMID:Comparison of transforming growth factor-beta and a macrophage- deactivating polypeptide from tumor cells. Differences in antigenicity and mechanism of action. 271 32

The NADPH-dependent superoxide production induced by sodium dodecyl sulfate (SDS) in the sonicates of unstimulated pig neutrophils required both membrane fraction and two components of cytosol fraction. The potency of the cytosol fraction in the activation of the superoxide production could be reconstituted dose dependently by mixing two protein components with relative molecular masses of 300 kDa and 50 kDa. Another low-molecular-mass component (1.3 kDa) could substitute the 50-kDa component. In the cell-free system consisting of the 300- and 50-kDa components and the membrane fraction, the superoxide production was markedly enhanced by FAD with a required concentration for half-maximal effect of 0.16 microM and inhibited by divalent cations such as Ca2+, Ba2+, Co2+, Zn2+ and Mn2+ and not Mg2+. ATP was not necessary for the activation, indicating that protein kinases such as protein kinase C are not involved in the SDS-dependent activation of NADPH oxidase. The NADPH oxidase activated by SDS in the cell-free system was recovered in the membrane fraction, and the superoxide formation by the SDS-activated membrane exhibited a Km value for NADPH of 46 microM and optimum pH at 7.0. The formation did not require the addition of SDS and FAD to the reaction mixture and was scarcely inhibited by the divalent cations.
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PMID:Characterization of the NADPH-dependent superoxide production activated by sodium dodecyl sulfate in a cell-free system of pig neutrophils. 282 May 10

In guinea pig peritoneal neutrophils NaF at a concentration of above 5 mM elicited a dose-dependent, delayed and sustained activation of NADPH oxidase. Unlike in human neutrophils, in guinea pig cells, this response was independent of extracellular calcium. Fura2 fluorescence measurements indicated also a fluoride-mediated moderate elevation in the level of cytosolic calcium concentration. Pretreatment of neutrophils with pertussis toxin, blocked fluoride-promoted activation of NADPH oxidase, indicating that NaF stimulation was mediated by a G protein which is a pertussis toxin substrate. NaF-elicited calcium elevation was insensitive to the toxin. Upon transfer of NaF-stimulated cells to a fluoride-free medium, superoxide release declined and calcium levels diminished. The response of the deactivated, fluoride-prestimulated guinea pig neutrophils to a secondary stimulation with phorbol myristate acetate (PMA) or fMet-Leu-Phe, was either unaffected by the previous challenge with NaF (PMA) or augmented by it (the chemotactic peptide). In parallel to the activation of NADPH oxidase, NaF also induced translocation of protein kinase C to cell membranes. This effect was also abolished by a pretreatment with pertussis toxin.
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PMID:Fluoride-mediated activation of guinea pig neutrophils. 282 9

Generation of reactive oxygen species is a critical event in successful host defense against invading organisms. Work spanning at least 25 years has demonstrated that both neutrophils and macrophages rely on a variety of oxidants to damage bacterial constitutents. The neutrophil is armed with two different oxygen-dependent defenses, while the macrophage relies solely on nonenzymatic oxidant generation. The primary granules of neutrophils contain the enzyme myeloperoxidase, which combines with H2O2 and ultimately leads to production of many toxic oxidant species: Halogens, hypochlorous acid, chloramines, aldehydes, and singlet oxygen. All of these molecules are involved in potentially toxic structural alterations in the pathogen. MPO-independent oxidant generation in neutrophils and macrophages involves the generation of highly toxic species derived from the interaction of O2- and H2O2, such as hydroxyl radical and singlet oxygen. Recent work has concentrated on determining how the interaction of a phagocyte with a foreign particle ultimately triggers the oxidant cascade. Exciting work in the past several years has focused on the proposal that protein kinase C and intracellular Ca2+ are two important focal points, and the activation of these two species leads to NADPH oxidase activation and subsequent conversion of O2 to O2-. The exact mechanism coupling stimulus binding to response promises to be an exciting area of research in the years to come.
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PMID:The role of the respiratory burst of phagocytes in host defense. 282 13

The antiinflammatory agent piroxicam caused dose dependent inhibition of N-formylmethionyl-leucyl-phenylalanine (FMLP) induced monocyte superoxide release in vitro, but had no effect on the response to serum treated zymosan, phorbol myristate acetate or the calcium ionophore A23187. The inhibitory effect on the superoxide response to FMLP correlated with inhibition of specific 3H-FMLP binding. Piroxicam did not inhibit production of leukotriene B4 stimulated either by A23187 or by FMLP with arachidonic acid. Piroxicam did not inhibit phospholipid methylation. Since piroxicam inhibited neither the superoxide response to zymosan, a membrane receptor mediated response, nor phospholipid methylation, the effect of this drug on FMLP receptor binding appears to be relatively selective. Our data also exclude a significant effect of piroxicam on activation of protein kinase C or the NADPH oxidase of mononuclear phagocytes.
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PMID:Effects of piroxicam on superoxide generation, phospholipid methylation and leukotriene production by human blood mononuclear cells. 282 16

Evidences have been provided in our laboratory that in neutrophils different signal transduction sequences for the activation of O2(-)-forming NADPH oxidase can be triggered by the same stimulus (Biochem. Biophys. Res. Commun. 1986, 135, 556-565; 1986, 135, 785-794; 1986, 140, 1-11). The results presented here show that the transduction sequence triggered by fluoride via dissociation of G-proteins and involving messengers produced by stimulation of phosphoinositide turnover, Ca2+ changes and translocation of protein kinase C from the cytosol to the plasmamembrane, can be bypassed when a primed state of neutrophils is previously induced. In fact: i) fluoride causes a pertussis toxin insensitive and H-7 sensitive respiratory burst in human neutrophils, which is linked to the activation of hydrolysis of PIP2, rise in [Ca2+]1 and translocation of PKC. In Ca2+-depleted neutrophils these responses to fluoride do not occur and are restored by addition of CaCl2. ii) The pretreatment of Ca2+-depleted unresponsive neutrophils with non stimulatory doses of PMA restores the activation of the NADPH oxidase by fluoride but not the turnover of phosphoinositides and PKC translocation. The nature of the alternative transduction sequence, the reactions different from phospholipase C activated by G-protein for the alternative sequence and the role of these discrete pathways for NADPH oxidase activation are discussed.
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PMID:Fluoride can activate the respiratory burst independently of Ca2+, stimulation of phosphoinositide turnover and protein kinase C translocation in primed human neutrophils. 282 1


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