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)

The disruption of the molecular organization of the plasma membrane of leukocytes by phagocytosable particles, or by agents such as surfactants, antibodies, phospholipase C, fatty acids and chemotactic factors, leads to a stimulation of the phagocyte oxidative metabolism. Concanavalin A (Con A) has been used as a tool to study the mechanism of this metabolic regulation. The binding of Con A to the surface of polymorphonuclear leukocytes (PMNL) or macrophages produces a rapid enhancement of oxygen uptake and glucose oxidation through the hexose monophosphate pathway (HMP). This is explained by an activation of the granular NADPH oxidase, the key enzyme in the metabolic stimulation. The effect of Con A is not due to endocytosed lectin, since Con A covalently coupled to large sepharose beads still acts as stimulant. The metabolic changes caused by Con A are reversible. If, after the onset of stimulation, sugars with high affinity for Con A are added to the leukocyte suspension, the activity of granular NADPH oxidase and the rate of respiration and glucose oxidation return to their resting values. The metabolic burst, while partially supressed by treatment of PMNL with iodoacetate, sodium flouride and cytochalasin B, is slightly increased by colchicine. Con A induces a selective release of granular enzymes (beta-glucuronidase, peroxidase, alkaline phosphatase) from PMNL, whereas no leakage of cytoplasmic enzymes is observed. The enzyme release is inhibited by iodoacetate and by drugs known to increase cell levels of cyclic AMP. Based on a current view of the mode of interaction between Con A and cell surfaces, a model of the metabolic disruption of leukocytes is presented.
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PMID:Concanavalin A as a probe for studying the mechanism of metabolic stimulation of leukocytes. 16 45

An assay method for the simultaneous evaluation of the oxidative metabolism and adherence of human neutrophils is described, together with certain specific applications. Incubations were performed in serum-coated microtiter plates, where oxidative metabolism was measured as O2- release and, after washing out the nonadherent cells, the adhesion was measured as activity of acid phosphatase. Three agonists tested in this system--opsonized zymosan, concanavalin A, and N-formyl-methionyl-leucyl-phenylalanine--induced both activation of O2- release and cell adhesion, but the two functions had time course and dose dependence patterns that varied depending on the stimulant. Particularly with concanavalin A, O2- release and adhesion response were markedly dissociated; this lectin at low doses increased neutrophil adherence without triggering any O2- production, whereas at high doses it increased both O2- production and adherence. Anti-integrin monoclonal antibodies did not affect adhesion induced by low-dose concanavalin A but inhibited the adhesion induced by the other tested agonists. Adhesion and O2- production were also found to be differentially affected by the NADPH oxidase inhibitor diphenylene iodonium, the sulfhydryl reagent N-ethylmaleimide and the A2 agonist adenosine, indicating that these neutrophil responses have various transductional pathways that also depend on the type of stimulus.
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PMID:Simultaneous assay for oxidative metabolism and adhesion of human neutrophils: evidence for correlations and dissociations of the two responses. 134 79

Electropermeabilized human neutrophils were used to investigate the possible role of G-proteins in the respiratory burst elicited by concanavalin A (Con A). The Con A-induced activation of the NADPH oxidase was not inhibited by either pertussis toxin or cholera toxin. However, the burst was inhibited by GDP and GDP beta S providing evidence for the involvement of a G-protein(s). O2 consumption in Con A-stimulated cells was dependent on both ATP and Mg2+. ATP could be substituted by ATP gamma S but not by the non-hydrolyzable analog AMP-PNP, suggesting involvement of phosphotransferase reactions. It is concluded that at least two distinct types of G-proteins are capable of inducing the respiratory burst in neutrophils and that accumulation of phosphorylated intermediates may be essential for activation of the respiratory burst by the lectin.
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PMID:Concanavalin A stimulation of O2 consumption in electropermeabilized neutrophils via a pertussis toxin-insensitive G protein. 250 97

Here we have investigated the ability of recombinant interferon-gamma (rIFN-gamma) to modulate human neutrophil (PMN) functions. PMN incubated in the presence of rIFN-gamma showed an enhanced hydrogen peroxide production in response to Con A, FMLP, PMA or immune complexes. The effect of rIFN-gamma was dose dependent, being half maximal at 2 U/ml, and required between 90 min and 240 min of incubation to reach optimal response. The enhancing effect of rIFN-gamma on the respiratory response of PMN was not blocked by polymixin B sulphate, but an anti-rIFN-gamma monoclonal antibody and cycloheximide and actinomycin D were effective inhibitors. The enhancement of the response to Con A was not accompanied by an enhanced binding of the lectin. Neither the kinetic properties of the Con A-stimulated NADPH oxidase nor the expression of cytochrome b-245 were altered in rIFN-gamma-treated PMN. rIFN-gamma also enhanced granule secretion in response to Con A, FMLP and PMA. Initial studies on the possible alterations of transmembrane signalling in rIFN-gamma-treated PMN showed that neither inositol phosphates formation nor cytoplasmic calcium transients were altered.
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PMID:Interferon-gamma activates human neutrophil oxygen metabolism and exocytosis. 283 15

Complement receptor type 3 (CR3) was initially described as an opsonic receptor. Subsequently, CR3-mediated lectin-sugar recognition mechanisms have been shown to play a major role in the nonopsonic phagocytosis of several pathogens, among them Mycobacterium tuberculosis. Little is known about the binding and signal transduction mechanisms operating during nonopsonic ingestion through CR3 of different microorganisms. In the present study, we used CHO cells stably transfected with CR3 to show that CR3 was able to mediate internalization of zymosan and pathogenic mycobacteria (Mycobacterium kansasii and Mycobacterium avium) but not that of nonpathogenic species (Mycobacterium smegmatis and Mycobacterium phlei). A combination of mannan and beta-glucan inhibited the phagocytosis of zymosan but had no effect on M. kansasii ingestion. Among six monoclonal antibodies (MAbs) directed against the CD11b subunit of CR3 that decreased zymosan ingestion, only three inhibited M. kansasii phagocytosis. In particular, MAbs known to block the CR3 lectin site affected only internalization of zymosan. Using U937 macrophages, we observed that zymosan ingestion through CR3 induced superoxide production measured by cytochrome c reduction and by translocation of the NADPH oxidase cytosolic component p47phox to the phagosomal membrane, whereas phagocytosis of viable or heat-killed M. kansasii did not. Furthermore, lack of superoxide anion production during phagocytosis of M. kansasii was not due to inhibition of NADPH oxidase per se or superoxide anion scavenging. Together, our results indicate that (i) nonopsonic phagocytosis of zymosan and M. kansasii by CR3 implicates different molecular mechanisms involving multiple and distinct epitopes of CD11b and (ii) CR3 may transduce different cellular responses depending on the sites mediating nonopsonic phagocytosis.
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PMID:Nonopsonic phagocytosis of zymosan and Mycobacterium kansasii by CR3 (CD11b/CD18) involves distinct molecular determinants and is or is not coupled with NADPH oxidase activation. 1089 80

We have earlier shown that galectin-3, a lactose-binding mammalian lectin that is secreted from activated macrophages, basophils, and mast cells, induces activation of the NADPH oxidase in exudated but not in peripheral blood neutrophils (A. Karlsson, P. Follin, H. Leffler, and C. Dahlgren, Blood 91:3430-3438, 1998). The alteration in responsiveness occurring during extravasation correlated with mobilization of the gelatinase and/or specific granules to the cell surface, indicating a role for mobilizable galectin-3 receptors. In this study we have investigated galectin-3-induced NADPH oxidase activation, measured as superoxide production, in lipopolysaccharide (LPS)-primed neutrophils. Upon galectin-3 challenge, the LPS-primed cells produced superoxide, both extracellularly and intracellularly. A primed extracellular response to formylmethionyl-Leu-Phe (fMLF) was also achieved. The exposure of complement receptors 1 and 3 as well as the formyl peptide receptor on the cell surface was markedly increased after LPS treatment, indicating that granule fusion with the plasma membrane had occurred. Further assessment of specific markers for neutrophil granules showed that the LPS treatment had mobilized the gelatinase granules but only a minor fraction of the specific granules. We thus suggest that the mechanism behind LPS priming lies at the level of granule (receptor) mobilization for galectin-3 as well as for fMLF.
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PMID:Lipopolysaccharide-induced gelatinase granule mobilization primes neutrophils for activation by galectin-3 and formylmethionyl-Leu-Phe. 1115 75

Oxidized low-density lipoprotein (oxLDL) is an important risk factor for vascular injury. Its role on coronary vasoconstriction remains speculative. Endothelial monooxygenases (cytochrome P450s [CYPs]) are regulators of vascular tonus through production of epoxy fatty acids. We investigated the effects of oxLDL on CYP monooxygenases in human arterial coronary endothelial cells and explanted healthy and atherosclerotic aortae. We found oxLDL to induce radical oxygen species production via the action of NADPH oxidase NOX4. Intracellular radical oxygen species production prompted reduced protein expression of the transcriptional regulator nuclear factor 1 (NF-1). We identified novel DNA binding sites for NF-1 in promoter regions of CYPs. DNA binding of NF-1 was confirmed by electromobility shift assays. OxLDL repressed DNA binding of NF-1 and diminished transcript level of CYP genes targeted by this factor. The production of endothelial-derived hyperpolarization factor, a key regulator of vascular tonus, was also reduced. Repression of CYP monooxygenases was reversed, and production of endothelial-derived hyperpolarization factor was normalized after treatment of endothelium with the lectin-like oxLDL receptor antagonist kappa-carrageenan or blocking of LOX-1 with a specific antibody. This suggests a mechanistic role of CYP monooxygenases in oxLDL-induced vascular injury. Therapy of endothelial dysfunction through LOX-1 receptor antagonism will be an interesting avenue to explore. The full text of this article is available online at http://www.circresaha.org.
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PMID:Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury: therapy through LOX-1 receptor antagonism? 1465 32

Surfactant protein-D (SP-D) is a member of the collectin family of collagenous proteins with lectin activity. SP-D is expressed in numerous tissues, primarily in type II alveolar cells in the periphery of the lung. SP-D plays an important role in host defense of the lung. To evaluate the importance of SP-D in vivo, transgenic mice lacking SP-D (SP-D-/- mice) have been generated. Lipid accumulation and airspace enlargement were observed in the lungs of SP-D-/- mice within 3 weeks after birth, and progressed with advancing age. Airspace enlargement and abnormalities in elastin fibers supported the concept that SP-D was required to inhibit destruction of the alveoli. Alveolar macrophages from SP-D-/- mice produced more H2O2 and matrix metalloproteinases (MMP)-2, -9, and -12 compared with wild-type mice. In vitro studies demonstrated that oxidants derived in part from NADPH oxidase enhanced NF-kappaB activation and MMP production in alveolar macrophages from SP-D-/- mice. A specific inhibitor of NF-kappaB reduced MMP production by alveolar macrophages from SP-D-/- mice. Taken together, these data demonstrated oxidant-dependent activation of NF-kappaB and enhanced MMP expression by alveolar macrophages from SP-D-/- mice, a process likely to mediate airspace remodeling caused by SP-D deficiency. SP-D plays a critical role in regulating alveolar macrophage activation, oxidant production, and MMP activity that may influence the pathogenesis of various pulmonary disorders.
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PMID:Alveolar macrophages and emphysema in surfactant protein-D-deficient mice. 1642 69

Calcium channel blockers have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events. To investigate vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (10(-6) mol/) and manidipine (10(-6) mol/l) were used to pretreat angiotensin (Ang) II-stimulated rat cultured aortic endothelial cells. A 3-h period of Ang II treatment enhanced superoxide generation and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein, as detected by dihydroethidium staining and Western blotting, respectively. Pretreatment with amlodipine or manidipine attenuated the increased production of superoxide and the overexpression of NADPH oxidase. The enhanced expression of heme oxygenase-1 (HO-1) mRNA induced by Ang II was further increased by amlodipine, whereas pretreatment with manidipine led to a reduction in the expression of HO-1. Furthermore, Ang II increased vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Pretreatment with either amlodipine or manidipine decreased the overexpression of VCAM-1, ICAM-1, and MCP-1. We also demonstrated that amlodipine or manidipine prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor1 (LOX-1) content, thereby restoring control levels. These observations showed that amlodipine and manidipine reduced superoxide generation by the inhibition of the overexpression of NADPH oxidase in Ang II-stimulated endothelial cells. Such antioxidant effects of these agents might in turn have led to a decrease in the expression of VCAM-1, ICAM-1 and MCP-1. The salutary effects of calcium channel blockers in atherogenesis include the inhibition of the expression of LOX-1.
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PMID:Calcium [corrected] channel blockers reduce angiotensin II-induced superoxide generation and inhibit lectin-like oxidized low-density lipoprotein receptor-1 expression in endothelial cells. 1675 44

Studies have shown that oxidized low density lipoprotein (ox-LDL) elicits both necrotic and apoptotic cell death and several mechanisms have been proposed. Ox-LDL induces reactive oxygen species (ROS), a second messenger that might be involved in apoptosis, formation in different types of cells including endothelial cells (ECs) and smooth muscle cells (SMCs). As lectin-like ox-LDL receptor-1 (LOX-1) was the main receptor for ox-LDL, this study was designed to determine whether the apoptosis induced by ox-LDL was mediated by LOX-1 in cultured human umbilical vein endothelial cells (HUVECs) and whether there is an association between LOX-1 mediated apoptosis and the production of ROS. After exposure to ox-LDL (50,100, and 150 microg/ml for 18 h), HUVECs exhibit typical apoptotic characteristics as determined by transmission electron microscopy and flow cytometry analysis in a dose-dependent pattern. Ox-LDL increases intracellular ROS formation including superoxide anion (O2-) and hydrogen peroxide (H2O2) in a dose-dependent and time-dependent manner. Pretreatment with anti-LOX-1 mAb, Vitamin C, apocynin or catalase significantly reduced ROS production and prevented ox-LDL-induced apoptosis, while indomethacin or allopurinol had no effect. These results suggest that LOX-1 mediates ox-LDL-induced apoptosis in endothelial cells and that ROS production and NADPH oxidase might play an important role in ox-LDL-induced apoptosis.
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PMID:Oxidized low density lipoprotein receptor-1 mediates oxidized low density lipoprotein-induced apoptosis in human umbilical vein endothelial cells: role of reactive oxygen species. 1743 86


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