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 a specific stimulation of polymorphonuclear leukocyte (PMN) tubulin tyrosinolation as induced by the peptide chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fmet-leu-phe) and the Ca2+ ionophore A23187 that is coupled to the NADPH oxidase-mediated stimulation of the PMN respiratory burst. The present study demonstrates that the presence of extracellular Ca2+ is necessary for fmet-leu-phe- and A23187-induced stimulation of PMN tubulin tyrosinolation, as indicated by the complete inhibition of the response by the addition of 1 mM EGTA to the extracellular medium. Methoxyverapamil (10(-5) M), a putative calcium channel blocker, completely inhibited the fmet-leu-phe-induced stimulation of tubulin tyrosinolation in PMN, but did not inhibit the A23187-induced response. Moreover, the calmodulin-binding drugs, trifluoperazine, fluphenazine, or chlorpromazine, at concentrations of 1 to 10 microM, caused significant inhibition of fmet-leu-phe- or A23187-induced stimulation of tubulin tyrosinolation. In related studies, enzymatic [14C]-tyrosinolation in isolated subcellular fractions of PMN revealed the presence of native tubulin in PMN fractions that were enriched in plasma membranes, the specific granules, or the azurophil granules. Most interestingly, tubulin tyrosine ligase (ligase), primarily a cytoplasmic enzyme, was detected in association with the PMN azurophil granule-rich fraction. Immunoautoradiography with the alpha-tubulin antibody YL 1/2 of isolated PMN subcellular fractions demonstrated a preferential stimulation of tyrosinolation of tubulin associated with the plasma membrane-rich fraction of fmet-leu-phe-stimulated cells. A significant stimulation was also observed in the cytoplasmic tubulin fraction. Consistent with the findings of in vitro tyrosinolation studies with PMN subcellular fractions, tyrosinolated tubulin was detected in the azurophil granule-enriched fractions isolated from both resting and fmet-leu-phe-stimulated cells. The antibody YL 1/2, which reacts with tyrosinolated alpha-tubulin and not with the detyrosinolated form, showed significant cross-reaction with several nontubulin PMN proteins.
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PMID:Ionic requirements and subcellular localization of tubulin tyrosinolation in human polymorphonuclear leukocytes. 241 18

Poly-L-histidine (PHSTD) of molecular weight 26,000 induced the generation of large amounts of superoxide (O2-) and hydrogen peroxide (H2O2) in human neutrophils (PMNs). Despite its low solubility at neutral pH, PHSTD was bound very rapidly to the PMN surfaces. Maximal generation of O2- took place with 4-5 X 10(-6) M of PHSTD, starting after a lag of about 25 sec and proceeding for 15-17 min at a rate of 150 nmol/10(7) PMNs/min, suggesting that this polycation is one of the most potent stimulators of O2- generation known, PHSTD was found to be non-toxic for PMNs even at millimolar concentrations. Generation of O2- by PHSTD depended on extracellular calcium; it was inhibited by calcium channel blockers and by trifluoperazine, and it triggered a sharp rise in intracellular calcium as determined by the Quin 2 fluorescence technique. The generation of both O2- and H2O2 by PHSTD was partially inhibited by cytochalasin B or (CYB, CYE). On the other hand, CYB markedly enhanced the generation of both O2- and H2O2 following stimulation of PMNs either by PHSTD, polyarginine, histone, or by antibody-opsonized group A streptococci. Electron microscopic analysis and NBT reduction tests revealed that both PHSTD and PHSTD-opsonized streptococci were avidly phagocytosed by PMNs. Since CYB totally inhibited internalization of both PHSTD and the PHSTD-opsonized streptococci, it was suggested that these agents stimulated oxygen radical generation mainly on the leukocyte surfaces. Complexes (CX) formed between PHSTD and polyanethole sulfonate (a strong polyanion) or between histone and the polyanion mimicked immune CX in their ability to trigger the generation of large amounts of O2- which were inhibited by CYB. Generation of O2- and chemiluminescence either by PHSTD or by PHSTD-opsonized streptococci were markedly inhibited by poly-L-glutamate, suggesting that PHSTD acted as a cationic agent which interacted via electrostatic forces with some negatively charged sites in the leukocyte membrane. Generation of H2O2 by PHSTD was also markedly inhibited by deoxyglucose, KCN, DASA, as well as by the lipoxygenase inhibitors nordihydroguaiaretic acid, phenidone, and propylgallate. On the other hand, cyclooxygenase inhibitors such as aspirin, indomethacin, and piroxicam were inactive, suggesting that arachidonic acid metabolism via lipoxygenase pathway might have been involved in the activation by PHSTD of the NADPH oxidase in PMNs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Poly L-histidine. A potent stimulator of superoxide generation in human blood leukocytes. 282 Aug 76

Three calcium channel antagonists, verapamil, diltiazem and nisoldipine, inhibited superoxide production in human neutrophils that were stimulated by phorbol 12-myristate 13-acetate (PMA) in a buffered saline lacking calcium. Concentrations of these drugs giving 50% control activity (IC50) were 0.3, 0.45 and 0.01 mM respectively. This inhibition was also observed in the presence of ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) and was not reversed by the addition of calcium. This suggests that calcium channel antagonists inhibited superoxide production independently of extracellular calcium. These calcium channel antagonists inhibited the mobilization of membrane-associated calcium, and protein phosphorylation probably catalyzed by C-kinase, both of which are thought to be involved in the signal transmission for the induction of superoxide production. Calcium channel antagonists also inhibited NADPH oxidase, responsible for superoxide production, with IC50 = 0.5, 3 and more than 0.08 mM, respectively, for verapamil, diltiazem and nisoldipine. The results indicate that calcium channel antagonists inhibit superoxide production by affecting not only the catalytic activity by also the activation of NADPH oxidase. Inhibition of superoxide production by calcium channel antagonists suggests that these antagonists do not affect cell functions merely by affecting calcium influx.
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PMID:Calcium channel antagonist induced inhibition of superoxide production in human neutrophils. Mechanisms independent of antagonizing calcium influx. 302 Nov 72

Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7) M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin, an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which active phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.
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PMID:Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins. 766 79

In our previous study, we demonstrated that reactive oxygen metabolites (ROM) generation from phagocytic cells may be involved in the carcinogenic mechanism of crocidolite asbestos. In the present study, the mechanism of human polymorphonuclear leukocytes (PMN) to generate ROM by crocidolite was investigated using verapamil, a calcium channel inhibitor; staurosporine, a NADPH oxidase inhibitor; and cytochalasin B (CB), an inhibitor of phagocytosis. The results indicate that whereas verapamil and staurosporine inhibited the crocidolite-induced ROM generation from PMN dose-dependently, CB caused an enhancement. We conclude that crocidolite-induced ROM generation involves a cell surface reaction due to influx of extracellular calcium through calcium channels and the activation of NADPH oxidase on the PMN cell membrane. This hypothesis was indirectly supported by dose-dependent enhancement of the ROM generation by CB, as CB increases calcium ion permeability in PMN. However, as in our previous studies, the time course of the ROM generation and the cell type difference suggested that ROM were also generated intracellularly from PMN due to phagocytosis of crocidolite. In conclusion, our evidence indicates that ROM generation from PMN by crocidolite involves cellular mechanisms related both to direct cell surface membrane interactions, together with an apparent phagocytic-dependent process.
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PMID:Cellular mechanisms of reactive oxygen metabolite generation from human polymorphonuclear leukocytes induced by crocidolite asbestos. 941 44

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

HarpinPss can induce hypersensitive reaction (HR) in tobacco leaves. As superoxide dismutase can inhibit but catalase can not inhibit the development of HR induced by harpinPss, superoxide anion is required for this response. HarpinPss can also induce the release of active oxygen and extracellular alkalinization, two early defence responses in tobacco suspension culture. Diphenylene iodoium, can completely inhibit the induction of HR in tobacco leaves, and the release of active oxygen in the suspension culture system, superoxide anion in these system may be produced by the activation of NADPH oxidase. Ethyleneglycol-bis (beta-aminoethyl) N, N, N'N'-tetraacetic acid (EGTA) can inhibit the development of harpinPss-induced HR and these two early defence responses in suspension culture system. Adding Ca2+ into the medium again, these responses can return to normal level in a short time. Lanthanum chloride, verapamil, neomycin, U-73122, and LiCl can also inhibit these harpinPss-induced responses. Therefore, the influx of Ca2+ mediated by calcium channel and the release of Ca2+ from internal Ca2+ pool may be involved in the two early defense responses induced by harpinPss. Cycloheximide and actinomycin D have no effect on the release of active oxygen but can inhibit harpinPss-induced HR even added them in the intermediate process for inducing HR. It indicates superoxide is just a trigger for HR, and HR is a more complex process that needs the sustained expression of some genes.
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PMID:[HarpinPss elicited early defense responses of tobacco cells and involvement of calcium]. 1254 98

VCAM-1 (vascular cell adhesion molecule-1) plays an important role in the regulation of inflammation in atherosclerosis, asthma, inflammatory bowel disease and transplantation. VCAM-1 activates endothelial cell NADPH oxidase, and this oxidase activity is required for VCAM-1-dependent lymphocyte migration. We reported previously that a mouse microvascular endothelial cell line promotes lymphocyte migration that is dependent on VCAM-1, but not on other known adhesion molecules. Here we have investigated the signalling mechanisms underlying VCAM-1 function. Lymphocyte binding to VCAM-1 on the endothelial cell surface activated an endothelial cell calcium flux that could be inhibited with anti-alpha4-integrin and mimicked by anti-VCAM-1-coated beads. VCAM-1 stimulation of calcium responses could be blocked by an inhibitor of intracellular calcium mobilization, a calcium channel inhibitor or a calcium chelator, resulting in the inhibition of NADPH oxidase activity. Addition of ionomycin overcame the calcium channel blocker suppression of VCAM-1-stimulated NADPH oxidase activity, but could not reverse the inhibitory effect imposed by intracellular calcium blockage, indicating that both intracellular and extracellular calcium mobilization are required for VCAM-1-mediated activation of NADPH oxidase. Furthermore, VCAM-1 specifically activated the Rho-family GTPase Rac1, and VCAM-1 activation of NADPH oxidase was blocked by a dominant negative Rac1. Thus VCAM-1 stimulates the mobilization of intracellular and extracellular calcium and Rac1 activity that are required for the activation of NADPH oxidase.
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PMID:Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. 1459 51

The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1 receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.
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PMID:Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. 1470 52


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