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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain edema is the most life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. We have recently found that administration of pigment epithelium-derived factor (PEDF) inhibits retinal hyperpermeability in rats by counteracting biological effects of vascular endothelial growth factor (VEGF). In this study, we investigated whether PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a pre-cooled metal probe on the parietal skull. VEGF and its receptor Flk-1 gene and/or protein expressions were up-regulated in the cold-injured brain. Cold injury induced brain edema, which was reduced by intraperitoneal injection of VEGF antibodies (Abs) or apocynin, an inhibitor of NADPH oxidase. PEDF mRNA and protein levels were up-regulated in response to cold injury. PEDF dose-dependently inhibited the brain edema, whose effect was neutralized by simultaneous treatments with anti-PEDF Abs. Although VEGF and Flk-1 gene and/or protein expressions were not suppressed by PEDF, PEDF or anti-VEGF Abs inhibited the cold injury-induced NADPH oxidase activity in the brain. Further, PEDF treatment inhibited activation of Rac-1, an essential component of NADPH oxidase in the cold-injured brain, while it did not affect mRNA levels of gp91phox, p22phox, or Rac-1. These results demonstrate that PEDF could inhibit the cold injury-induced brain edema by blocking the VEGF signaling to hyperpermeability through the suppression of NADPH oxidase via inhibition of Rac-1 activation. Our present study suggests that PEDF may be a novel therapeutic agent for the treatment of brain edema.
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PMID:Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury-induced brain edema in mice. 1769 94

The link between chronic alcohol consumption and cardiovascular injury including hypertension is well known. However, molecular mediators implicated with alcohol-induced elevation in blood pressure (BP) remain elusive. The aim of this study was to investigate the relationship of chronic ethanol-induced endothelial injury and elevation in BP with angiotensin II levels in rats. Male Fisher rats were divided into two groups of seven animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks and (2) ethanol (4 g kg(-1), orally) daily for 12 weeks. The BP (systolic, diastolic, and mean) was recorded every week. The animals were anesthetized with pentobarbital after 12 weeks; blood and thoracic aorta were isolated and analyzed for aortic reactivity response, angiotensin II levels, and oxidative endothelial injury. The results show that the systolic, diastolic, and mean BP were significantly elevated 12 weeks after ethanol ingestion. The increased BP was related to elevated angiotensin II levels in the plasma and aorta of alcohol treated group compared to control. The aortic NADPH oxidase activity, ratio of oxidized to reduced glutathione (GSSG/GSH) and lipid peroxidation significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), and vascular endothelial growth factor (VEGF) protein expressions were depressed in alcohol group compared to control. The phenylephrine-mediated vasoconstriction response was not altered, while acetylcholine-mediated vasorelaxation response was depressed in the aorta of ethanol treated rats compared to control. It is concluded that chronic ethanol ingestion induces hypertension which is correlated with elevated tissue angiotensin II levels, activation of NADPH oxidase activity causing endothelial injury, depletion of endothelial NO generating system, and impaired vascular relaxation in rats.
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PMID:Chronic alcohol-induced oxidative endothelial injury relates to angiotensin II levels in the rat. 1772 10

Reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. However, the direct roles of endogenous ROS production still remain to be elucidated. In this study, we found that high levels of ROS were spontaneously produced by ovarian and prostate cancer cells. This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in the cells. To further analyze the source of ROS production, we found that ovarian cancer cells have much higher expression of NOX4 NADPH oxidase, and that specific inhibition of NADPH oxidase subunit p47(phox) diminished ROS production. To analyze the functional relevance of ROS production, we showed that ROS regulated hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. Elevated levels of endogenous ROS were required for inducing angiogenesis and tumor growth. NOX4 knockdown in ovarian cancer cells decreased the levels of VEGF and HIF-1 alpha and tumor angiogenesis. This study suggests a new mechanism of higher ROS production in ovarian cancer cells and provides strong evidence that endogenous ROS play an important role for cancer cells to induce angiogenesis and tumor growth. This information may be useful to understand the new mechanism of cancer cells in inducing tumorigenesis and to develop new therapeutic strategy by targeting ROS signaling in human cancer in the future.
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PMID:Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. 1800 27

Vascularization, under physiological or pathophysiological conditions, typically takes place by one or more of the following processes: angiogenesis, vasculogenesis, arteriogenesis, and lymphangiogenesis. Although all of these mechanisms of vascularization have sufficient contrasting features to warrant consideration under separate cover, one common feature shared by all is their sensitivity to the VEGF signaling pathway. Conditions such as wound healing and physical exercise result in increased production of reactive oxygen species such as H(2)O(2), and both are associated with increased tissue vascularization. Understanding these two scenarios of adult tissue vascularization in tandem offers the potential to unlock the significance of redox regulation of the VEGF signaling pathway. Does H(2)O(2) support tissue vascularization? H(2)O(2) induces the expression of the most angiogenic form of VEGF, VEGF-A, by a HIF-independent and Sp1-dependent mechanism. Ligation of VEGF-A to VEGFR2 results in signal transduction leading to tissue vascularization. Such ligation generates H(2)O(2) via an NADPH oxidase-dependent mechanism. Disruption of VEGF-VEGFR2 ligation-dependent H(2)O(2) production or decomposition of such H(2)O(2) stalls VEGFR2 signaling. Numerous antioxidants exhibit antiangiogenic properties. Current evidence lends firm credence to the hypothesis that low-level endogenous H(2)O(2) supports vascular growth.
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PMID:Redox regulation of the VEGF signaling path and tissue vascularization: Hydrogen peroxide, the common link between physical exercise and cutaneous wound healing. 1819 54

Initially viewed as dangerous byproducts of aerobic life, reactive oxygen species (ROS) nowadays appear to be essential secondary messengers of many signaling cascades and cellular functions. The establishment of ROS as important signaling molecules has been confirmed by the existence of specialized ROS producing complexes expressed in nonphagocytic cells, the NADPH oxidase complex (NOX). Because of the diversity of their proteic targets (besides lipids and DNA), ROS have multiple and sometimes contradictory functions. In the present review, we focus on several different signaling pathways influenced by ROS and NOX in tumorigenesis, focusing on proliferation and angiogenesis. We review the ROS targets regulating proliferation, including cellular signaling (phosphatases, AP1, and nuclear factor-kappa B [NF-kappaB]) and cell cycle targets (CDC25, cyclin D, and forkhead proteins), and the role of NOX during proliferation. Finally, we review the direct and indirect involvement of ROS and NOX in (tumor) angiogenesis through the regulation of different biologic systems such as vascular endothelial growth factor, angiotensin II, hypoxia-inducible factor, AP1, and inflammation.
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PMID:The ROS-NOX connection in cancer and angiogenesis. 1819 84

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT(1) receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT(1) receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT(1) receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT(1) receptor enhances the activation of nuclear factor NF-kappaB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT(1) receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT(1) receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.
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PMID:The role of angiotensin type 1 receptor in inflammation and endothelial dysfunction. 1822 Oct 99

Diabetic nephropathy is the most serious complication in diabetes mellitus. Oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and vascular endothelial growth factor (VEGF) pathway play critical roles in the development of diabetic nephropathy. We evaluated the effects of apocynin, NADPH oxidase inhibitor on diabetic nephropathy in a type 2 diabetic rat model. Sixteen Otsuka Long Evans Tokushima Fatty (OLETF) rats and 9 Long Evans Tokushima Otsuka (LETO) were divided into the following three groups: LETO rats (n=9), control OLETF rats (n=7) and apocynin-treated OLETF rats (n=9). We examined body weights, plasma glucose levels, urinary albumin-creatinine ratio (ACR) and protein-creatinine ratio (PCR). At 50 weeks, experimental rats were sacrificed and their kidneys were extracted for hematoxylin eosin stain, immunohistochemical VEGF stain and VEGF mRNA real-time RT-PCR. To examine oxidative stress, we checked 24h urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and MDA (malondialdehyde). Urinary protein and albumin excretions were reduced after apocynin treatment, though apocynin could not significantly decrease serum glucose levels. There were improvements of glomerular and mesangial expansion in the apocynin-treated OLETF rats. Apocynin significantly decreased optical density of glomerular VEGF expression in immunohistochemical stain and reduced the concentration of 24h urinary 8-OHdG and MDA. From these results, it was suggested that apocynin may have the potential to protect against diabetic nephropathy via amelioration of oxidative stress.
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PMID:Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property. 1911 63

Studies in both animals and humans indicate that angiogenesis is implicated in the development of atherosclerotic lesions. Thus, inhibition of angiogenesis may provide a novel therapeutic approach for the treatment of atherosclerosis. Because epidemiological studies have indicated an inverse relation between red wine intake and coronary disease, we determined the antiangiogenic potential of red wine polyphenols (RWPs) in the ischemic hindlimb model. Neovascularization was accelerated by the chronic infusion of angiotensin II (Ang II; 0.1 mg/kg/day). RWPs (25 mg/kg/day) or vehicle were administrated in the drinking water 7 days before the ligation. After 21 days, Ang II potentiated the ischemia-induced neovascularization in the hindlimb, as assessed by microangiography and measurement of microvessel density. This effect was associated with an increased formation of reactive oxygen species (ROS) and increased expression of hypoxia-inducible factor (HIF)-2alpha, endothelial nitric-oxide synthase (eNOS), and vascular endothelial growth factor (VEGF). RWPs intake significantly prevented the angiogenic process, the formation of ROS and nitrated proteins, and the expression HIF-2alpha, eNOS, and VEGF induced by Ang II. Similar preventive effects were observed with the antioxidant and NADPH oxidase inhibitor apocynin. These findings indicate that RWPs have potent antiangiogenic properties in vivo by preventing the expression of proangiogenic factors, including VEGF and eNOS most likely by inhibiting oxidative stress. Thus, the antiangiogenic properties of red wine polyphenols might contribute to their protective effect against coronary disease.
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PMID:Red wine polyphenols prevent acceleration of neovascularization by angiotensin II in the ischemic rat hindlimb. 1919 29

The objective of this study is to determine growth factor expression and activation of signaling pathways associated with intravitreous neovascularization and peripheral avascular retina using a model of retinopathy of prematurity (ROP) relevant to today with oxygen monitoring in neonatal units. Studies using 50/10 oxygen-induced retinopathy (OIR) and 50/10 OIR+SO models were reviewed. Repeated fluctuations in oxygen increased retinal vascular endothelial growth factor (VEGF) even while peripheral avascular retina persisted and prior to the development of intravitreous neovascularization. Repeated fluctuations in oxygen increased VEGF(164) expression but not VEGF(120). Neutralizing VEGF bioactivity significantly reduced intravitreous neovascularization and arteriolar tortuosity without interfering with ongoing retinal vascularization. Repeated oxygen fluctuations led to retinal hypoxia and increased reactive oxygen species (ROS). Inhibiting ROS with NADPH oxidase inhibitor, apocynin, reduced avascular retina by interfering with apoptosis. Supplemental oxygen reduced retinal VEGF concentration and exacerbated NADPH oxidase activation to contribute to intravitreous neovascularization through activation of the JAK/STAT pathway. Oxygen stresses relevant to those experienced by preterm infants today trigger signaling of different pathways to cause avascular retina and intravitreous neovascularization. Increased signaling of VEGF appears important to the development of both avascular retina and intravitreous neovascularization.
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PMID:The effects of oxygen stresses on the development of features of severe retinopathy of prematurity: knowledge from the 50/10 OIR model. 1963 55

Thiazolidinediones, peroxisome proliferators-activated receptor gamma (PPARgamma) ligands, have been recognized as a potential therapeutic agents for the treatment of pathological neovascularization. In the present study, we examined the molecular mechanism by which troglitazone (TROG), a PPARgamma agonist, exerts its inhibitory action in vascular endothelial growth factor (VEGF)-induced angiogenesis signaling. In an in vitro angiogenesis model using human umbilical vein endothelial cells, TROG (20 muM) significantly suppressed VEGF-induced cell proliferation and invasion of the cells into the Matrigel basement membrane, which was not reversed by treatment with PPAR antagonists, GW9662 (10 muM) and bisphenol A diglycidyl ether (10 muM). TROG also blocked VEGF-induced reactive oxygen species (ROS) production and its downstream extracellular signal-regulated kinase (ERK) phosphorylation, and this inhibitory effect was not reversed by GW9662 (10 muM). The antiangiogenic activity of TROG correlated with suppression of VEGF-induced matrix metalloproteinase (MMP)-2 and membrane type 1 (MT1)-MMP expression. In addition, the effects of TROG on VEGF-induced MMP-2 and MT1-MMP expression were comparable to those of the NADPH oxidase inhibitor diphenylene iodium (10 muM) and ERK inhibitor PD98056 (10 muM). Furthermore, in an in vivo angiogenesis system using a chick chorioallantoic membrane model, TROG dose-dependently inhibited VEGF-induced angiogenesis, which was similar to the inhibitory effect of N-acetylcysteine on VEGF-induced angiogenesis. The results suggest that the inhibitory effects of TROG on VEGF-induced angiogenesis were mediated through the suppression of VEGF-induced ROS production and ERK phosphorylation.
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PMID:Troglitazone inhibits vascular endothelial growth factor-induced angiogenic signaling via suppression of reactive oxygen species production and extracellular signal-regulated kinase phosphorylation in endothelial cells. 1976 43


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