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 aim of this study was to evaluate neutrophil function in patients suffering from the generalized form of early onset periodontitis (EOP). We investigated neutrophil migration in vivo and neutrophil superoxide production and adhesion in response to a variety of compounds; neutrophils were isolated both from blood and a skin experimental exudate of 15 patients with EOP and of 15 sex- and age-matched normal control subjects. No difference was found in neutrophil migration in vivo (71.2+/-16.4x10(6) and 68.8+/-10.7x10(6) PMN/cm2/24 h in patients affected by early onset periodontitis and normal subjects respectively) and in adhesion. The superoxide production in response to STZ and PMA was similar between the 2 groups, while superoxide production in response to fMLP was markedly lower in patients than in control subjects both in circulating neutrophils (5.6+/-2.2 versus 10.4+/-2.3 nmoles O2-/10(6) cells, p<0.0001) and in exudate neutrophils (16.3+/-4.3 versus 22.3+/-4.7 nmoles O2-/10(6) cells, p<0.005). In general, neutrophil function in patients suffering from early onset periodontitis does not differ from control subjects, suggesting that the overall defence function of these cells is normal. The only parameter that we have found to be different between the 2 groups is the low superoxide production after fMLP stimulation. The stimulus- and function-specificity of this defect in neutrophils from patients indicates the existence of a dysregulation of the signal transduction pathway distal to fMLP receptor and proximal to NADPH oxidase activation.
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PMID:Neutrophil migration, oxidative metabolism and adhesion in early onset periodontitis. 1048 5

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabetes was induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N:(G)-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N:-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N:-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.
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PMID:Mechanisms underlying endothelial dysfunction in diabetes mellitus. 1115 81

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress
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PMID:Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. 1240 19

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT(1)-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT(1)-R antagonist candesartan (0.5 mg.kg(-1).day(-1)) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats (n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91(phox) and p22(phox) mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91(phox) and p22(phox) mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91(phox) and p22(phox), decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT(1)-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.
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PMID:Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. 1514 62

Eosinophils are selectively primed and activated by the cytokine IL-5. The aim of this investigation was to study the effects of IL-5 treatment on stimulation-dependent protein phosphorylations, in human peripheral blood eosinophils. After IL-5 treatment, basal phosphorylation patterns showed increases in the phosphorylation of 67, 80 and 93 kDa proteins. Cell stimulations resulted in the following protein phosphorylation increases: 50, 60, 67, 80 and 93 kDa (PMA); 50, 67, 80 and 93 kDa (STZ); and 67, 80 and 93 kDa (IL-5). The phosphorylation of the 50 and 60 kDa proteins was shown to be MEK-independent and dependent on some PKC isoform/s, whereas that of the 67, 80 and 93 kDa proteins was both MEK- and PKC-alpha, beta, delta, gamma, tau and zeta-independent. A phosphoprotein of 50 kDa was identified as p47(phox) and another of 67 kDa protein as the tyrosine phosphatase SHPTP-1. Incubation with IL-5 followed by cell stimulation increased the total phosphorylation of p47(phox). Bidimensional (IEF-SDS/PAGE) analysis showed that the combination of IL-5 treatment followed by stimulation with either PMA or STZ induced the formation of an additional, hyperphosphorylated form of p47(phox). The presence of this form would explain the higher NADPH oxidase activity normally observed after IL-5 priming.
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PMID:The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. 1547 55

Endothelin-1 (ET-1) and JAK2 are both implicated in diabetic complications. Therefore, we investigated whether ET-1 differentially activates JAK2 under conditions of normal (5 mM) and high (25 mM) glucose. We tested the hypothesis that reactive oxygen species mediate the activation of JAK2 in response to ET-1. In rat aortic vascular smooth muscle cells (VSMC), ET-1 (10 (- 7) M, 5 min) stimulated the activation of JAK2, which was further enhanced under high glucose conditions. Allopurinol (xanthine oxidase inhibitor, 1 microM) and l-NAME (nitric oxide synthase inhibitor, 1 mM) had no effect on ET-1-induced JAK2 activation, while apocynin (NAD(P)H oxidase inhibitor 100 microM) resulted in a significant inhibition of ET-1-induced JAK2 and MAPK activation. Overexpression of SOD did not inhibit ET-1-induced activation of JAK2, but catalase (50 units/mL) treatment resulted in complete inhibition. In vivo administration of apocynin (1.5 mM) resulted in a significant decrease ( 50%), while the ETA receptor antagonist ABT-627 completely inhibited phosphorylation of JAK2 in aortae from STZ-induced diabetic rats. Additionally, DHE staining of aortic sections was significantly reduced in diabetic rats treated with ABT-627. These data suggest that in VSMC, ET-1 via the ETA receptor, utilizes NAD(P)H oxidase to activate JAK2.
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PMID:Endothelin-1 activation of JAK2 in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species. 1629 54

Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.
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PMID:The direct antioxidative and anti-inflammatory effects of peroxisome proliferator-activated receptors ligands are associated with the inhibition of angiotensin converting enzyme expression in streptozotocin-induced diabetic rat aorta. 1697 61

Oxidative stress plays an important role in the pathogenesis of diabetic complications, and we investigated the effect of superoxide dismutase (SOD) mimetic, tempol, in diabetic nephropathy. Streptozotocin-induced diabetic rats were treated with tempol from 2 weeks until 8 weeks. The expression of NADPH oxidase, catalase, and myeloperoxidase (MPO), superoxide dismutase activity, and production of peroxide and hypochlorite were evaluated. Tempol treatment prevented the increase in NADPH oxidase and peroxide production in the glomeruli of diabetic rat. Catalase was decreased without change in SOD activity, and MPO was enhanced in the kidney of diabetic rats. Tempol treatment stimulated SOD activity and increased the conversion of superoxide to hydrogen peroxide, and hydrogen peroxide on its hand was converted to hypochlorite by the increased MPO. The reduction of peroxide by tempol was followed by the decrease in TGF-beta and mesangial matrix expansion. However, tempol did not reduce hypochlorite or urinary protein excretion. In conclusion, tempol inhibited glomerular matrix expansion via suppression of peroxide production and TGF-beta, but it failed to reduce proteinuria, probably due to the increased hypochlorite production in diabetic nephropathy.
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PMID:Double-edged action of SOD mimetic in diabetic nephropathy. 1726 58

The role of glomerular SREBP-1c in diabetic nephropathy was investigated. PEPCK-promoter transgenic mice overexpressing nuclear SREBP-1c exhibited enhancement of proteinuria with mesangial proliferation and matrix accumulation, mimicking diabetic nephropathy, despite the absence of hyperglycemia or hyperlipidemia. Isolated transgenic glomeruli had higher expression of TGFbeta-1, fibronectin, and SPARC in the absence of marked lipid accumulation. Gene expression of P47phox, p67phox, and PU.1 were also activated, accompanying increased 8-OHdG in urine and kidney, demonstrating that glomerular SREBP-1c could directly cause oxidative stress through induced NADPH oxidase. Similar changes were observed in STZ-treated diabetic mice with activation of endogenous SREBP-1c. Finally, diabetic proteinuria and oxidative stress were ameliorated in SREBP-1-null mice. Adenoviral overexpression of active and dominant-negative SREBP-1c caused consistent reciprocal changes in expression of both profibrotic and oxidative stress genes in MES13 mesangial cells. These data suggest that activation of glomerular SREBP-1c could contribute to emergence and/or progression of diabetic nephropathy.
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PMID:Involvement of glomerular SREBP-1c in diabetic nephropathy. 1796 14

The involvement of inflammatory processes has been recognized in development and/or progression of diabetic nephropathy. However, the mechanisms involved in the pathogenesis of renal inflammation have not been completely understood. In this study, we tested the hypothesis that accumulation of advanced oxidation protein products (AOPPs), which occurs in diabetes, may promote inflammatory responses in diabetic kidney. Streptozotocin-induced diabetic rats were randomized to iv injection of vehicle, native rat serum albumin (RSA), and AOPPs-modified RSA (AOPPs-RSA) in the presence or absence of oral administration of apocynin. A control group was followed concurrently. Compared with RSA- or vehicle-treated diabetic rats, AOPPs-RSA-treated animals displayed significant increase in renal macrophage infiltration and overexpression of monocyte chemoattractant protein-1 and TGF-beta1. This was associated with deteriorated structural and functional abnormalities of diabetic kidney, such as glomerular hypertrophy, fibronectin accumulation, and albuminuria. AOPP challenge significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide generation in renal homogenates and up-regulated membrane expression of renal NADPH oxidase subunits p47(phox) and gp91(phox). All these AOPPs-induced perturbations in diabetic kidney could be prevented by the NADPH oxidase inhibitor apocynin. These data suggest that chronic accumulation of AOPPs may promote renal inflammation in diabetes probably through activation of renal NADPH oxidase.
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PMID:Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. 1817 76


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