Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Multiple enzymes may stimulate ROS production in VSMC and endothelial cells. These include NADH/NADPH oxidase, xanthine oxidase, lipoxygenases, cyclooxygenase, P-450 monooxygenases, and the enzymes of mitochondrial oxidative phosphorylation. In addition to generation of intracellular O2- by these enzymes, extracellular stimuli including lipophilic substrates, membrane permeant oxidants (e.g., H2O2), cytokines, and growth factors may modulate cellular redox state. Both intracellular and extracellular ROS act as second-messengers to activate tyrosine and serine-threonine kinases, such as the MAP kinase family. As discussed in the previous sections, regulation of the MAP kinases is one example of the complexity of ROS-dependent signal transduction. Although the complexity of ROS-mediated signal transduction is daunting, the diversity offers multiple therapeutic targets for pharmacologic intervention.
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PMID:Redox signals that regulate the vascular response to injury. 1060 87

Serotonin (5-HT) stimulates mitogenesis in rat renal mesangial cells through a G protein-coupled 5-HT(2A) receptor. We tested the hypothesis that oxidants might be involved in the signal transduction pathway linking the receptor to extracellular signal-regulated protein kinase (ERK). 5-HT rapidly increased the activity and phosphorylation of ERK. These effects were blocked by the 5-HT(2A) receptor antagonist ketanserin. The peak effect was noted at 5-10 min, and half-maximal stimulation was achieved at 10-30 nM 5-HT. Chemical inhibitor and activator studies supported the involvement of phospholipase C, protein kinase C (PKC), and reactive oxygen species (ROS, i.e., H(2)O(2) and superoxide) generated by an NAD(P)H oxidase-like enzyme in the ERK activation cascade. Mapping studies supported a location for the NAD(P)H oxidase enzyme and the ROS downstream from PKC. Our studies are most consistent with an ERK activation pathway as follows: 5-HT(2A) receptor --> G(q) protein --> phospholipase C --> diacylglycerol --> classical PKC --> NAD(P)H oxidase --> superoxide --> superoxide dismutase --> H(2)O(2) --> mitogen-activated extracellular signal-regulated kinase --> ERK. These studies demonstrate a role for the 5-HT(2A) receptor in rapid, potent, and efficacious activation of ERK in rat renal mesangial cells. They support a role for oxidants in conveying the stimulatory signal from 5-HT, because 1) chemical antioxidants attenuate the 5-HT signal, 2) oxidants and 5-HT selectively activate ERK to a similar degree, 3) 5-HT produces superoxide and H(2)O(2) in these cells, and 4) a specific enzyme [NAD(P)H oxidase] has been implicated as the source of the ROS, which react selectively downstream of classical PKC.
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PMID:5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O(2) generation in rat renal mesangial cells. 1075 Dec 27

Hypoxia elicits a variety of adaptive responses at the tissue level, at the cellular level, and at the molecular level. A physiological response to hypoxia requires the existence of an O(2) sensor coupled to a signal transduction system, which in turn activates the functional response. Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O(2) sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O(2) binding or release at different PO(2) levels. Other studies suggest that ion channels may change conductance as a function of PO(2), allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O(2) species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O(2) sensors by increasing their generation of ROS during hypoxia. These oxidant signals appear to act as second messengers in the adaptive responses to hypoxia in a variety of cell types. Such observations contribute to a growing awareness that mitochondria do more than just generate ATP, in that they initiate signaling cascades involved in adaptive responses to hypoxia and that they participate in the control of cell death pathways.
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PMID:Cellular oxygen sensing by mitochondria: old questions, new insight. 1079 53

Diabetes mellitus is associated with increased ROS generation, oxidative injury and obesity. To elucidate the relationship between nutrition and ROS generation, we have investigated the effect of glucose challenge on ROS generation by leucocytes, p47phox protein, a key protein in the enzyme NADPH oxidase and alpha-tocopherol levels. Blood samples were drawn from 14 normal subjects prior to, at 1, 2 and 3 h following ingestion of 75 g glucose. ROS generation by polymorphonuclear leucocytes (PMNL) and mononuclear cells (MNC) increased to a peak of 244 +/- 42% and 233 +/- 34% of the basal respectively at 2h. The levels of p47phox in MNC homogenates increased significantly at 2 h and 3 h after glucose intake. alpha-Tocopherol levels decreased significantly at 1 h, 2 h and 3 h. We conclude that glucose intake stimulates ROS generation and p417phox of NADPH oxidase; increases oxidative load and causes a fall in alpha-tocopherol concentration.
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PMID:Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. 1094 14

An NADPH oxidase complex composed of a membrane-bound flavocytochrome b558 consisting of two subunits (p22phox and gp91phox) and cytosolic activating factors (p47phox and p67phox) generates superoxide anions from oxygen in the respiratory burst of phagocytic cells. Inconsistent results have been previously obtained concerning its additional occurrence in pulmonary artery endothelial cells (PAEC), and this issue was addressed in the present study. PAEC isolated from porcine pulmonary trunk contained mRNA for p22phox and gp91phox as demonstrated by reverse transcription-polymerase chain reaction. Immunohistochemistry demonstrated cytochrome subunits, p22phox, gp91phox, p47phox, and p67phox, both in vitro in isolated PAEC and in situ in endothelial cells in tissue sections of the pulmonary trunk. Isolated PAEC generated reactive oxygen species (ROS; measured by lucigenin-induced chemiluminescence and conversion of dihydrorhodamine 123 into rhodamine 123) in response to stimulation with phorbol 12-myristate 13-acetate. This stimulated ROS production was sensitive to the flavoprotein inhibitor diphenylene-iodonium, and reduced when the superoxide scavenger superoxide dismutase was added. Chemiluminescence measurements of superoxide generation by stimulated PAEC accounted for approximately 1% of that generated by stimulated peritoneal macrophages. The data demonstrate a low-output NADPH oxidase system in porcine PAEC sharing several components with that identified in phagocytic cells.
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PMID:NADPH oxidase subunits and superoxide production in porcine pulmonary artery endothelial cells. 1095 20

Matrix metalloproteinases (MMPs) play a pivotal role in angiogenesis, atherogenesis, vascular remodeling after vascular injury, and instability of atherosclerotic plaque. The present study was undertaken to investigate the effect of lysophosphatidylcholine, a major component of oxidized low density lipoprotein (LDL), on the regulation of MMPs in cultured bovine aortic endothelial cells (BAECs). Furthermore, we explored the potential role of oxidative stress in the regulation of MMP. LPC increased the secretion of gelatinolytic activity, as well as, protein of MMP-2 from BAECs. The stimulation of BAEC with superoxide increased the production of MMP-2 and it also induced its activation. Electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap agent demonstrated that lysophosphatidycholine (LPC) induced generation of reactive oxygen (ROS) species from BAECs. The inhibition of NADH/NADPH oxidase, one of the potential sources of superoxide in endothelial cells, attenuated the effect of LPC. Our findings suggest that LPC might activate the endothelial NADH/NADPH oxidase to enhance superoxide production, and it might, in turn, enhance MMP-2 induction.
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PMID:Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. 1122 25

Endogenously produced reactive oxygen species are important for intracellular signaling mechanisms leading to vascular smooth muscle cell (VSMC) growth. It is therefore critical to define the potential enzymatic sources of ROS and their regulation by agonists in VSMCs. Previous studies have investigated O2*- production using lucigenin-enhanced chemiluminescence. However, lucigenin has been recently criticized for its ability to redox cycle and its propensity to measure cellular reductase activity independent from O2*-. To perform a definitive characterization of VSMC oxidase activity, we used electron spin resonance trapping of O2*- with DEPMPO. We confirmed that the main source of O2*- from VSMC membranes is an NAD(P)H oxidase and that the O2*- formation from mitochondria, xanthine oxidase, arachidonate-derived enzymes, and nitric oxide synthases in VSMC membranes was minor. The VSMC NAD(P)H oxidase(s) are able to produce more O2*- when NADPH is used as the substrate compared to NADH (the maximal NADPH signal is 2.4- +/- 0.4-fold higher than the NADH signal). The two substrates had similar EC(50)'s ( approximately 10-50 microM). Stimulation with angiotensin II and platelet-derived growth factor also predominantly increased the NADPH-driven signal (101 +/- 8% and 83 +/- 1% increase above control, respectively), with less of an effect on NADH-dependent O2*- (17 +/- 3% and 36 +/- 5% increase, respectively). Moreover, incubation of the cells with diphenylene iodonium inhibited predominantly NADPH-stimulated O2*-. In conclusion, electron spin resonance characterization of VSMC oxidase activity supports a major role for an NAD(P)H oxidase in O2*- production in VSMCs, and provides new evidence concerning the substrate dependency and agonist-stimulated activity of this key enzyme.
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PMID:Electron spin resonance characterization of the NAD(P)H oxidase in vascular smooth muscle cells. 1129 58

Vascular endothelial growth factor (VEGF) is a potent vascular endothelial cell-specific mitogen that modulates endothelial cell function. In the present study, we show that VEGF induces manganese-superoxide dismutase (MnSOD) mRNA and protein in human coronary artery endothelial cells (HCAEC) and pulmonary artery endothelial cells. VEGF-mediated induction of MnSOD mRNA was inhibited by pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI), and 4-(2-aminoethyl)-benzenesulfonyl fluoride, but not with the nitric oxide synthase inhibitor L-NAME (N-monomethyl-L-arginine) or the xanthine oxidase inhibitor allopurinol. VEGF stimulation of MnSOD was also inhibited by adenoviral-mediated overexpression of catalase Cu, Zn-SOD and a dominant-negative form of the small GTPase component of NADPH oxidase Rac1 (Rac1N17). Treatment of HCAEC with VEGF resulted in a transient increase in ROS production at 20 min, as measured by 2,7-dichlorodihydrofluorescein oxidation. This effect was abrogated by expression of Rac1N17. Taken together, these findings suggest that VEGF induces MnSOD by an NADPH oxidase-dependent mechanism and that VEGF signaling in the endothelium is coupled to the redox state of the cell.
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PMID:Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. 1164 Dec 65

Activation and deactivation of macrophages are of considerable importance during the development of various disease states, atherosclerosis among others. Macrophage activation is achieved by oxidized lipoproteins (oxLDL) and is determined by oxygen radical (ROS) formation. The oxidative burst was measured by flow cytometry and quantitated by oxidation of the redox-sensitive dye dichlorodihydrofluorescein diacetate. Short-time stimulation dose-dependently elicited ROS formation. Diphenylene iodonium prevented ROS formation, thus pointing to the involvement of a NAD(P)H oxidase in producing reduced oxygen species. In contrast, preincubation of macrophages with oxLDL for 16 h showed an attenuated oxidative burst upon a second contact with oxLDL. Taking into account that oxLDL is an established peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist and considering the anti-inflammatory properties of PPARgamma, we went on and showed that a PPARgamma agonist such as ciglitazone attenuated ROS formation. Along that line, major lipid peroxidation products of oxLDL, such as 9- and 13-hydroxyoctadecadienoic acid, shared that performance. Supporting evidence that PPARgamma activation accounted for reduced ROS generation came from studies in which proliferator-activated receptor response element decoy oligonucleotides, but not a mutated oligonucleotide, supplied in front of oxLDL delivery regained a complete oxidative burst upon cell activation. We conclude that oxLDL not only elicits an oxidative burst upon first contact, but also promotes desensitization of macrophages via activation of PPARgamma. Desensitization of macrophages may have important consequences for the behavior of macrophages/foam cells in atherosclerotic lesions.
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PMID:Dualism of oxidized lipoproteins in provoking and attenuating the oxidative burst in macrophages: role of peroxisome proliferator-activated receptor-gamma. 1188 52


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