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 magnitude and duration of the abruptly occurring increases in cytosolic Ca2+ in human neutrophils following activation with PAF (20 and 200 nM) and FMLP (1 microM), have been compared and related to alterations in NADPH oxidase activity, membrane potential and intracellular cyclic AMP. Cytosolic Ca2+ and membrane potential were measured by spectrofluorimetry, transmembrane fluxes of Ca2+ by radiometric procedures, and NADPH oxidase activity and cyclic AMP by chemiluminescence and radioimmunoassay respectively. Activation of neutrophils with both PAF (200 nM) and FMLP (1 microM) was accompanied by an abrupt increase in cytosolic Ca2+, which was of similar magnitude for each activator (393+/-9 and 378+/-17 nM respectively). Unlike FMLP-activated cells in which Ca2+ was rapidly removed from the cytosol, peak levels of cytosolic Ca2+ were sustained for longer (0.14+/-0.02 vs 1.16+/-0.04 min, P<or=0.0001) and declined at a slower rate in PAF-treated neutrophils. The prolonged elevation of cytosolic Ca2+ in PAF-treated cells was due to accelerated store-operated influx of extracellular cation and was attenuated by dibutyryl cyclic AMP (4 mM), the Ca2+-chelator, EGTA (5 mM), and SKF 96365 (10 microM). In contrast to FMLP, basal levels of superoxide production and cyclic AMP were unaltered in PAF-activated neutrophils, while only moderate membrane depolarization was detected. These observations demonstrate that mechanisms which restore Ca2+ homeostasis to FMLP-activated neutrophils, viz. activation of NADPH oxidase and adenylate cyclase, are not operative in PAF-treated cells, presenting the potential hazard of Ca2+ overload and hyperactivity.
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PMID:Dissociation of the PAF-receptor from NADPH oxidase and adenylate cyclase in human neutrophils results in accelerated influx and delayed clearance of cytosolic calcium. 1197 71

The inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O2(.-)) generation by 2-benzyloxybenzaldehyde (CCY1a) was investigated in rat neutrophils, and the underlying mechanism of this inhibition was assessed. CCY1a concentration-dependently inhibited O2(.-) generation (IC(50)=18.5+/-4.3 microM). In cell-free systems, CCY1a failed to alter O2(.-) generation during dihydroxyfumaric acid autoxidation, in phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparations, or during arachidonic acid-induced NADPH oxidase activation. CCY1a increased cellular cyclic AMP (cAMP) levels in a time- and concentration-dependent manner, and this cAMP-elevating effect was inhibited by the adenylyl cyclase inhibitor 9-(tetrahydro-2'-furyl)adenine (SQ22536), adenosine deaminase (ADA), and the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline. In neutrophils, inhibition of O2(.-) generation by CCY1a was partially reversed by the protein kinase A inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). CCY1a did not affect fMLP-induced p38 mitogen-activated protein kinase phosphorylation, but concentration-dependently attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt (IC(50) about 31.3 and 19.4 microM, respectively). The plateau phase, but not the initial spike, of fMLP-induced [Ca2+](i) changes was inhibited by CCY1a in a concentration-dependent manner. CCY1a inhibition of Ca2+ entry, ERK, and Akt phosphorylation was not prevented by SQ22536 or ADA. fMLP-induced phospholipase D (PLD) activation was inhibited by CCY1a (IC(50)=13.9+/-2.0 microM). ADA and KT5720 did not prevent the inhibition of PLD activation by CCY1a. Collectively, these results indicate that the inhibition by CCY1a of fMLP-induced O2(.-) generation in rat neutrophils can probably be attributed to the increase in cAMP levels, and to the blockade of Ca2+ entry, suppression of Akt, and PLD activation via cAMP-independent mechanisms.
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PMID:Investigation of the cellular mechanism of inhibition of formyl-methionyl-leucyl-phenylalanine-induced superoxide anion generation in rat neutrophils by 2-benzyloxybenzaldehyde. 1266 40

The NADPH oxidase complex of phagocytes comprises a membrane-associated flavocytochrome b559, and 4 cytosolic components: p47phox, p67phox, p40phox, and the small GTPase Rac. Activation of the oxidase in vivo is the result of assembly of the cytosolic components with cytochrome b559 and is mimicked in vitro by a cell-free system consisting of membranes, p47phox, p67phox, nonprenylated or prenylated Rac, and an anionic amphiphile as activator (defined as "p47phox and amphiphile-dependent" or canonical pathway). We reported that prenylated Rac1 is capable of activating the NADPH oxidase in vitro in the absence of p47phox and amphiphile (defined as "p47phox and amphiphile-independent" pathway). We now demonstrate that the 2 pathways exhibit distinctive susceptibilities to inhibitors: 1) The anionic amphiphile lithium dodecyl sulfate, an activator of the canonical pathway, has the opposite effect (inhibition) on oxidase activation by prenylated Rac and p67phox; 2) GDP and, paradoxically, GTP (but not GMP, ATP, ADP, and AMP) prevent oxidase activation by the p47phox and amphiphile-independent pathway but do not affect activation by the canonical pathway; 3) The Rac-binding domain of p21-activated kinase is a potent inhibitor of activation by the p47phox and amphiphile-independent pathway while exerting a milder inhibitory effect on the canonical pathway; 4) The C-terminal polybasic Rac1 peptide 177-191 and the cationic antibiotic neomycin sulfate inhibit activation by the canonical pathway but do not affect activation by the p47phox and amphiphile-independent pathway; 5) Binding of prenylated Rac1 to membrane-mimicking phospholipid vesicles is, nevertheless, enhanced when these contain negatively charged lipids. It is proposed that preferential inhibition of oxidase activation, via the p47phox and amphiphile-independent pathway, is a reflection of interference by the inhibitors with Rac-dependent recruitment of p67phox to the membrane.
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PMID:Two pathways of activation of the superoxide-generating NADPH oxidase of phagocytes in vitro--distinctive effects of inhibitors. 1287 68

Cyclic AMP affects microvascular smooth muscle contraction and growth. Therefore, it is important to elucidate mechanisms regulating cyclic AMP production in microvascular smooth muscle. In this study, we determined whether several signal transduction pathways regulate receptor-induced cyclic AMP in isolated preglomerular microvessels and microvascular smooth muscle cells. Preglomerular microvessels were incubated with isoproterenol (beta-adrenoceptor agonist) and with and without U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), 1-butanol (phospholipase D inhibitor), CGP77675 (c-src inhibitor), HA1077 (Rho kinase inhibitor), Y27632 (Rho kinase inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), dipenyleneiodonium (NADPH oxidase inhibitor), or Tempol (superoxide dismutase mimetic). Cultured preglomerular microvascular smooth muscle cells were incubated with isoproterenol or forskolin (direct activator of adenylyl cyclase) and with or without U73122, C(2)-ceramide (phospholipase D inhibitor), or PP1 [src family inhibitor, 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine]. All studies were conducted with 3-isobutyl-1-methylxanthine (broad-spectrum phosphodiesterase inhibitor) to eliminate changes in cyclic AMP degradation. In microvessels isoproterenol-induced cyclic AMP was not affected by Y27632, HA1007, LY294002, dipenylene-iodonium, or Tempol; was increased by U73122 and GF109203X; and was decreased by 1-butanol and CGP77675. In cells, U73122 increased and C(2)-ceramide and PP1 decreased isoproterenol-induced cyclic AMP. Forskolin-induced cyclic AMP was not altered. These results indicate that receptor-mediated activation of adenylyl cyclase is 1) not modulated by Rho kinase, phosphatidylinositol-3-kinase, NADPH oxidase, or superoxide; 2) is attenuated by phospholipase C and protein kinase C; and 3) is augmented by phospholipase D and src. Phospholipase C, phospholipase D, and src modulate receptor-induced cyclic AMP by affecting beta-adrenoreceptor/G protein/adenylyl cyclase coupling rather than by directly affecting adenylyl cyclase activity.
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PMID:Modulation of cyclic AMP production by signal transduction pathways in preglomerular microvessels and microvascular smooth muscle cells. 1508 74

Cultured human THP-1 monocytes were exposed to serial concentrations of gemifloxacin over 4 h after pre-stimulation with zymogen A for 1 h or Staphylococcus aureus for 2 h. The following parameters were assessed: pH, phagocytosis, c-AMP, NO, TNFalpha, IL-1, IL-6, IL-8 and H2O2 levels, enzyme activities of protein kinase C, NADPH oxidase, SOD, gluthathion reductase, NAG and cathepsin D as well as lipid peroxidation. The reversiblity of these changes was determined in the presence of known blockers of the phagocytic process. The effects of gemifloxacin on DNA synthesis and killing of S. aureus was assessed in bacteria alone and in those bacteria phagocytosed by THP-1 monocytes over 24 h. Gemifloxacin in stimulated THP-1 monocytes over the first 30 min caused an increase in c-AMP, NO, H2O2 and TNFalpha levels and protein kinase C, NADPH oxidase, glutathione reductase, NAG and cathepsin D activities. The pH became more acidic and phagocytosis was stimulated. These parameters were reversed at 1 h and continued to decline until 4 h. Lipid peroxidation was at the highest levels at 1 h and IL-8 levels at 2 h. DNA synthesis and bacterial growth were suppressed at 2 h in both S. aureus alone and bacteria phagocytosed by THP-1 monocytes. These effects were at a higher magnitude at 24 h. Gemifloxacin initiates a phagocyticidal effect of THP-1 monocytes at an early time of 30 min which plays a role in killing bacteria but a higher magnitude of killing of bacteria occurs later by a standard static mechanism. This early action of gemifloxacin should decrease the spread of infection and the inflammatory response since the tissue destruction process was attenuated at 4 h.
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PMID:In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes. 1549 55

Extracellular ATP can serve as a signaling agent in animal cells, and, as suggested by recent reports, may also do so in plant cells. In animal cells it induces the production of reactive oxygen species through the mediation of NADPH oxidase. Similarly, here we report that in leaves of Arabidopsis (Arabidopsis thaliana), applied ATP, but not AMP or phosphate, induces the accumulation of superoxide (O2-) in a biphasic, dose-dependent manner, with a threshold at 500 nm ATP. This effect did not require ATP hydrolysis for it was mimicked by ATPgammaS. ATP also induced increased levels of Arabidopsis respiratory burst oxidase homolog D (AtrbohD) mRNA, but ATP-treated plants that had disrupted AtrbohD and AtrbohF genes did not accumulate O2-, indicating that NADPH oxidases are responsible for the induced O2- accumulation. Inhibitors of mammalian P2-type ATP receptors abolished ATP-induced O2- production, suggesting that the ATP effects may be mediated through P2-like receptors in plants. Cytosolic Ca2+ and calmodulin are likely to help transduce the ATP responses, as they do in animal cells, because a Ca2+ channel blocker, a Ca2+ chelator, and calmodulin antagonist all reduced ATP-induced O2- accumulation. Furthermore, ATP treatment enhanced the expression of genes that are induced by wounds and other stresses. The ATP measured at wound sites averaged 40 microm, well above the level needed to induce O2- accumulation and gene expression changes. Transgenic plants overexpressing an apyrase gene had reduced O2- production in response to applied ATP and wounding. Together, these data suggest a possible role for extracellular ATP as a signal potentially in wound and stress responses.
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PMID:Extracellular ATP induces the accumulation of superoxide via NADPH oxidases in Arabidopsis. 1642 98

The phagocyte NADPH oxidase consists of multiple protein subunits that interact with each other to form a functional superoxide-generating complex. Although the essential components for superoxide production have been well characterized, other proteins potentially involved in the regulation of NADPH oxidase activation remain to be identified. We report here that the Galphai subunit of heterotrimeric G proteins is a novel binding partner for p67phox in transfected HEK293T cells and peripheral blood polymorphonuclear leukocytes. p67phox preferably interacted with inactive Galphai. Expression of p67phox caused a dose-dependent decrease in intracellular cyclic AMP concentration, suggesting altered function of Galphai. We identified a fragment of p67phox, consisting of the PB1 domain and the C-terminal SH3 domain, to be critical for the interaction with Galphai. Because these domains are involved in the interaction with p47phox and p40phox, the relationship between the respective binding events was investigated. Wild-type Galphai, but not its QL mutant, could promote the interaction between p67phox and p47phox. However, the interaction between p67phox and p40phox was not affected by either Galphai form. These results provide the first evidence for an interaction between p67phox and an alpha subunit of heterotrimeric G proteins, suggesting a potential role for Galphai in the regulation or activation of NADPH oxidase.
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PMID:Activation state-dependent interaction between Galphai and p67phox. 1678 2

The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K(+)], there is evidence for a feedforward mechanism: Dietary K(+) intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K(+) excretion. This pathway may explain renal and extrarenal responses to altered K(+) intake that occur independently of changes in ECF [K(+)]. Mechanisms for conserving ECF K(+) during fasting or K(+) deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K(+) channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K(+) uptake. How these mechanisms are triggered by K(+) deprivation remains unclear. Cellular AMP kinase-dependent protein kinase activity provokes the acute transfer of K(+) from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K(+) diet for the cardiovascular system.
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PMID:Recent advances in understanding integrative control of potassium homeostasis. 1875 36

Short chain fatty acids (SCFAs) are metabolic by products of anaerobic bacteria fermentation. These fatty acids, despite being an important fuel for colonocytes, are also modulators of leukocyte function. The aim of this study was to evaluate the effects of SCFAs (acetate, propionate, and butyrate) on function of neutrophils, and the possible mechanisms involved. Neutrophils obtained from rats by intraperitoneal lavage 4 h after injection of oyster glycogen solution (1%) were treated with non toxic concentrations of the fatty acids. After that, the following measurements were performed: phagocytosis and destruction of Candida albicans, production of ROS (O(2)(*-), H(2)O(2), and HOCl) and degranulation. Gene expression (p47(phox) and p22(phox)) and protein phosphorylation (p47(phox)) were analyzed by real time reverse transcriptase chain reaction (RT-PCR) and Western blotting, respectively. Butyrate inhibited phagocytosis and killing of C. albicans. This SCFA also had an inhibitory effect on production of O(2)(*-), H(2)O(2), and HOCl by neutrophils stimulated with PMA or fMLP. This effect of butyrate was not caused by modulation of expression of NADPH oxidase subunits (p47(phox) and p22(phox)) but it was in part due to reduced levels of p47(phox) phosphorylation and an increase in the concentration of cyclic AMP. Acetate increased the production of O(2)(*-) and H(2)O(2) in the absence of stimuli but had no effect on phagocytosis and killing of C. albicans. Propionate had no effect on the parameters studied. These results suggest that butyrate can modulate neutrophil function and thus could be important in inflammatory neutrophil-associated diseases.
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PMID:Effects of short chain fatty acids on effector mechanisms of neutrophils. 1910 72

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.
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PMID:Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. 1924 71


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