Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.6 (NADPH oxidase)
 10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we have demonstrated that leptin increases blood pressure (BP) in the rats through two oxidative stress-dependent mechanisms: stimulation of extracellular signal-regulated kinases (ERK) by H(2)O(2) and scavenging of nitric oxide (NO) by superoxide (O(2-.)). Herein, we examined if renal glutathione system and antioxidant enzymes determine the mechanism of prohypertensive effect of leptin. Leptin administered at 0.5 mg/kg/day for 4 or 8 days increased BP and renal Na(+),K(+)-ATPase activity and reduced fractional sodium excretion; these effects were prevented by NADPH oxidase inhibitor, apocynin. Superoxide scavenger, tempol, abolished the effect of leptin on BP and renal Na(+) pump in rats receiving leptin for 8 days, whereas ERK inhibitor, PD98059, was effective in animals treated with leptin for 4 days. Leptin administered for 4 days decreased glutathione (GSH) and increased glutathione disulfide (GSSG) in the kidney. In animals receiving leptin for 8 days GSH returned to normal level, which was accompanied by up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of the GSH biosynthetic pathway. In addition, superoxide dismutase (SOD) activity was decreased, whereas glutathione peroxidase (GPx) was increased in rats receiving leptin for 8 days. Cotreatment with gamma-GCS inhibitor, buthionine sulfoximine (BSO), accelerated, whereas GSH precursor, N-acetylcysteine (NAC), attenuated leptin-induced changes in gamma-GCS, SOD, and GPx. In addition, coadministration of BSO changed the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent in animals receiving leptin for 4 days, whereas NAC had the opposite effect in rats treated with leptin for 8 days. These results suggest that initial change in GSH redox status induces decrease in SOD/GPx ratio, which results in greater amount of (O)2-.)) versus H(2)O(2) in later phase of leptin treatment, thus shifting the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent.
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PMID:Renal antioxidant enzymes and glutathione redox status in leptin-induced hypertension. 1869 Apr 14

Oxidative stress is one of the hypotheses involved in the etiology of Alzheimer's disease (AD). Considerable attention has been focused on increasing the intracellular glutathione (GSH) levels in many neurodegenerative diseases, including AD. Pycnogenol (PYC) has antioxidant properties and stabilizes intracellular antioxidant defense systems including glutathione levels. The present study investigated the protective effects of PYC on acrolein-induced oxidative cell toxicity in cultured SH-SY5Y neuroblastoma cells. Decreased cell survival in SH-SY5Y cultures treated with acrolein correlated with oxidative stress, increased NADPH oxidase activity, free radical production, protein oxidation/nitration (protein carbonyl, 3-nitrotyrosine), and lipid peroxidation (4-hydroxy-2-nonenal). Pretreatment with PYC significantly attenuated acrolein-induced cytotoxicity, protein damage, lipid peroxidation, and cell death. A dose-response study suggested that PYC showed protective effects against acrolein toxicity by modulating oxidative stress and increasing GSH. These findings provide support that PYC may provide a promising approach for the treatment of oxidative stress-related neurodegenerative diseases such as AD.
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PMID:Protective effect of Pycnogenol in human neuroblastoma SH-SY5Y cells following acrolein-induced cytotoxicity. 1882 68

Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, through a mechanism mediated by reactive oxygen species (ROS) production. Numerous tumoral cells develop mechanisms to escape from the TGF-beta-induced tumor suppressor effects. In this work we show that in FaO rat hepatoma cells inhibition of the epidermal growth factor receptor (EGFR) with the tyrphostin AG1478 enhances TGF-beta-induced cell death, coincident with an elevated increase in ROS production and GSH depletion. These events correlate with down-regulation of genes involved in the maintenance of redox homeostasis, such as gamma-GCS and MnSOD, and elevated mitochondrial ROS. Nonetheless, not all the ROS proceed from the mitochondria. Emerging evidences indicate that ROS production by TGF-beta is also mediated by the NADPH oxidase (NOX) system. TGF-beta-treated FaO cells induce nox1 expression. However, the treatment with TGF-beta and AG1478 greatly enhanced the expression of another family member: nox4. NOX1 and NOX4 targeted knock-down by siRNA experiments suggest that they play opposite roles, because NOX1 knockdown increases caspase-3 activity and cell death, whilst NOX4 knock-down attenuates the apoptotic process. This attenuation correlates with maintenance of GSH and antioxidant enzymes levels. In summary, EGFR inhibition enhances apoptosis induced by TGF-beta in FaO rat hepatoma cells through an increased oxidative stress coincident with a change in the expression pattern of NOX enzymes.
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PMID:The inhibition of the epidermal growth factor (EGF) pathway enhances TGF-beta-induced apoptosis in rat hepatoma cells through inducing oxidative stress coincident with a change in the expression pattern of the NADPH oxidases (NOX) isoforms. 1884 61

The goal of this study was to test the hypothesis that NADPH oxidase contributes importantly to renal cortical oxidative stress and inflammation, as well as renal damage and dysfunction, and increases in arterial pressure. Fifty-four 7- to 8-wk-old Dahl salt-sensitive (S) or R/Rapp strain rats were maintained for 5 wk on a high sodium (8%) or high sodium + apocynin (1.5 mmol/l in drinking water). Arterial and venous catheters were implanted on day 21. By day 35 in the high-Na S rats, mRNA expression of renal cortical gp91phox, p22phox, p47phox, and p67phox NADPH subunits in S rats increased markedly, and treatment of high-Na S rats with the NADPH oxidase inhibitor apocynin resulted in significant decreases in mRNA expression of these NADPH oxidase subunits. At the same time, in apocynin-treated S rats 1) renal cortical GSH/GSSG ratio increased, 2) renal cortical O2(.-) release and NADPH oxidase activity decreased, and 3) renal glomerular and interstitial damage markedly fell. Apocynin also decreased renal cortical monocyte/macrophage infiltration, and apocynin, but not the xanthine oxidase inhibitor allopurinol, attenuated decreases in renal hemodynamics and lowered arterial pressure. These data suggest that NADPH oxidase plays an important role in causing renal cortical oxidative stress and inflammation, which lead to decreases in renal hemodynamics, renal cortical damage, and increases in arterial pressure.
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PMID:NADPH oxidase contributes to renal damage and dysfunction in Dahl salt-sensitive hypertension. 1892 60

We have previously demonstrated that the induction of haem oxygenase-1 (EC 1.14.99.3) plays a protective role for soybean plants against cadmium and UV-B stress. Here, we have investigated the possible signal transduction pathways involved in haem oxygenase-1 induction in leaves of soybean plants subjected to salt stress. Treatment with 100 mM NaCl during 48 h increased thiobarbituric acid reactive substances by 30%, whereas GSH decreased by 50%, with respect to controls. These effects were prevented by pre-incubation with diphenyleneiodonium (DPI; an NADPH oxidase inhibitor), [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; a guanylate cyclase inhibitor) or LaCl3 (calcium channel blocker). NaCl at 100 mM produced in situ accumulation of H2O2 and O2*-, which were also prevented by DPI, ODQ or LaCl3. Moreover, salt-induced haem oxygenase-1 activity was also totally abolished by pretreatment with the different inhibitors. These results clearly demonstrated that the signal transduction pathways involved in oxidative stress triggered by salt stress were similar to those implicated in haem oxygenase-1 induction, and provide additional information suggesting that haem oxygenase might play a key role in the antioxidative protection machinery of higher plants.
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PMID:Signal transduction pathways and haem oxygenase induction in soybean leaves subjected to salt stress. 1901 65

The ubiquitous tripeptide glutathione (GSH) is an essential factor in many biological processes, thus its depletion has a major impact on cell function and survival. In this study, we examined regulation of GSH in cardiomyocytes under chronic oxidative stress elicited by myocardial infarction (MI). Cardiac dysfunction was induced in rats by coronary artery ligation, and experiments were conducted in myocytes isolated from non-infarcted left ventricle and septum after 6-8 weeks. Fluorescence microscopy studies using the probe monochlorobimane showed that [GSH] in myocytes from post-MI hearts was 42% less than in sham control hearts (P < 0.05). However, depleted GSH levels were normalized after 5-6 h by an insulin mimetic (bis-peroxovanadium-1,10-phenanthroline, bpV(phen); 10 micromol l(-1)) or by exogenous pyruvate (5 mmol l(-1)). The increase in [GSH] by bpV(phen) was partly inhibited by buthionine sulphoximine (BSO; 50 micromol l(-1)), a blocker of GSH synthesis, and by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU; 100 micromol l(-1)), an inhibitor of glutathione disulphide reductase. By comparison, the effect of pyruvate was not altered by BSO but was completely blocked by BCNU. Studies using inhibitors of signalling cascades indicated that upregulation of [GSH] by bpV(phen) in myocytes from post-MI hearts was mediated by mitogen activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and p38 mitogen-activated protein kinase but not by phosphatidylinositol 3-kinase. The effect of pyruvate was not altered by any kinase inhibitor tested. In cells loaded with the probe TEMPO-9-AC to monitor superoxide anion, baseline fluorescence was 2.3-fold greater in post-MI myocytes than in sham control myocytes (P < 0.05) and was markedly decreased by diphenyleneiodonium (30 micromol l(-1)), an inhibitor of NADPH oxidase, exogenous GSH (10 mmol l(-1)) or bpV(phen). In parallel studies, [GSH] in post-MI myocytes was also normalized by diphenyleneiodonium or exogenous GSH. These data show that GSH is differentially regulated by receptor tyrosine kinase-dependent and -independent agonists that maintain functional GSH levels necessary to neutralize excess generation of reactive oxygen species in the failing heart.
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PMID:Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction. 1939 62

Hyperoxaluria and crystal deposition induce oxidative stress (OS) and renal epithelial cells injury, both mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are considered as the main sources of reactive oxygen species (ROS). Taurine is known to have antioxidant activity and shows renoprotective effect. We investigate the effect of taurine treatment on renal protection, and the putative source of ROS, in a rat model of calcium oxalate nephrolithiasis. Rats were administered with 2.5% (V/V) ethylene glycol + 2.5% (W/V) ammonium chloride (4 ml/day), with restriction on intake of drinking water (20 ml/day) for 4 weeks. Simultaneous treatment with taurine (2% W/W, mixed with the chow) was performed. At the end of the study, indexes of OS and renal injury were assessed. Renal tubular ultrastructure changes were analyzed under transmission electron microscopy. Crystal deposition in kidney was scored under light microscopy. Angiotensin II in kidney homogenates was determined by radioimmunoassay. Expression of NADPH oxidase subunits p47phox and Nox-4 mRNAs in kidney was evaluated by real time-polymerase chain reaction. The data showed that oxidative injury of the kidney occurred in nephrolithiasis-induced rats. Hyperplasia of mitochondria developed in renal tubular epithelium. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mitochondria decreased and the mitochondrial membrane showed oxidative injury. Taurine treatment alleviated the oxidative injury of the kidney, improved SOD and GSH-Px activities, as well as the mitochondrial membrane injury, with lesser crystal depositions in the kidney. We could not detect statistical changes in the renal angiotensin II level, and the renal p47phox and Nox-4 mRNAs expression in those rats. The results suggest that mitochondria but not NADPH oxidase may account for the OS and taurine protected kidney from oxidative injury through mitochondrial-linked pathway in this rat model.
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PMID:Taurine protected kidney from oxidative injury through mitochondrial-linked pathway in a rat model of nephrolithiasis. 1951 7

We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoK(ATP)). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H(2)O(2) production, which were reversed by mitoK(ATP) antagonists. In vivo antioxidant treatment with N-acetylcysteine decreased both mitoK(ATP) activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoK(ATP) activation. The mild uncoupling mediated by mitoK(ATP) increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoK(ATP) as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess.
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PMID:Mitochondrial ATP-sensitive K(+) channels as redox signals to liver mitochondria in response to hypertriglyceridemia. 1970 50

Cellular redox homeostasis is essential for plant growth, development as well as for the resistance to biotic and abiotic stresses, which is governed by the complex network of prooxidant and antioxidant systems. Recently, new evidence has been published that NADPH, produced by glucose-6-phosephate dehydrogenase enzyme (G6PDH), not only acted as the reducing potential for the output of reduced glutathione (GSH), but was involved in the activity of plasma membrane (PM) NADPH oxidase under salt stress, which resulted in hydrogen peroxide (H(2)O(2)) accumulation. H(2)O(2) acts as a signal in regulating G6PDH activity and expression, and the activities of the enzymes in the glutathione cycle as well, through which the ability of GSH regeneration was increased under salt stress. Thus, G6PDH plays a critical role in maintaining cellular GSH levels under long-term salt stress. In this addendum, a hypothetical model for the roles of G6PDH in modulating the intracellular redox homeostasis under salt stress is presented.
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PMID:Involvement of glucose-6-phosphate dehydrogenase in reduced glutathione maintenance and hydrogen peroxide signal under salt stress. 1970 76

Etiolated Arabidopsis thaliana seedlings germinated in the presence of reducing buffers such as reduced gluthathione (GSH) and dithiothreitol (DTT) have altered morphology. GSH and DTT inhibited hypocotyl elongation in a dose-dependent manner. The GSH-mediated effect was prevented by the simultaneous addition of extracellular ATP (eATP). NADPH oxidase (NOX) activity and endogenous nitric oxide (NO) generation were required to mediate eATP action on the hypocotyl elongation. A correlation was observed between hypocotyl length, eATP concentration and NO production. The action of eATP and NO on superoxide (O(2)(-)) accumulation and peroxidase activity was investigated. The O(2)(-) distribution was regulated by eATP and NO during hypocotyl elongation. Our data suggest that a finely tuned balance of redox status and optimal levels of ATP and NO are essential to regulate the hypocotyl elongation in the dark.
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PMID:Extracellular ATP, nitric oxide and superoxide act coordinately to regulate hypocotyl growth in etiolated Arabidopsis seedlings. 2040 65


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