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)

Insulin stimulation of target cells elicits a burst of H(2)O(2) that enhances tyrosine phosphorylation of the insulin receptor and its cellular substrate proteins as well as distal signaling events in the insulin action cascade. The molecular mechanism coupling the insulin receptor with the cellular oxidant-generating apparatus has not been elucidated. Using reverse transcription-PCR and Northern blot analyses, we found that Nox4, a homolog of gp91phox, the phagocytic NAD(P)H oxidase catalytic subunit, is prominently expressed in insulin-sensitive adipose cells. Adenovirus-mediated expression of Nox4 deletion constructs lacking NAD(P)H or FAD/NAD(P)H cofactor binding domains acted in a dominant-negative fashion in differentiated 3T3-L1 adipocytes and attenuated insulin-stimulated H(2)O(2) generation, insulin receptor (IR) and IRS-1 tyrosine phosphorylation, activation of downstream serine kinases, and glucose uptake. Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated IR tyrosine phosphorylation induced by coexpression of PTP1B by inhibiting PTP1B catalytic activity. These data suggest that Nox4 provides a novel link between the IR and the generation of cellular reactive oxygen species that enhance insulin signal transduction, at least in part via the oxidative inhibition of cellular protein-tyrosine phosphatases (PTPases), including PTP1B, a PTPase that has been previously implicated in the regulation of insulin action.
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PMID:The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. 1496 67

The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-kappaB (NF-kappaB), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-kappaB superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-kappaB and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.
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PMID:Molecular mechanisms of high glucose-induced cyclooxygenase-2 expression in monocytes. 1498 66

Activated astrocytes produce a large amount of bioactive molecules, including reactive oxygen and nitrogen species. Astrocytes are in general resistant to those reactive species. However, we previously reported that immunostimulated astrocytes became highly vulnerable to metabolic insults, such as glucose deprivation. In this study, we investigated whether H(2)O(2) production was associated with the increased vulnerability. Glucose deprivation for up to 8 hr did not change the intracellular level of H(2)O(2) in astrocytes. Treatment with lipopolysaccharide plus interferon-gamma for 48 hr evoked astroglial H(2)O(2) production; however, no apparent death or injury was observed in immunostimulated astrocytes. Glucose deprivation after 48 hr of immunostimulation markedly increased H(2)O(2) level, depleted adenosine triphosphate (ATP), and enhanced lactate dehydrogenase (LDH) release. The ATP depletion and LDH release were in part prevented by catalase, mannitol, and N-acetyl-L-cysteine. The enhanced level of H(2)O(2) in glucose-deprived immunostimulated astrocytes appeared to be secondary to the depletion of reduced glutathione. 4-(2-Aminoethyl)bebzenesulfonyl fluoride (AEBSF), an inhibitor of NADPH oxidase, reduced H(2)O(2) level and LDH release in glucose-deprived immunostimulated astrocytes. H(2)O(2), either endogenously produced or exogenously added, depolarized mitochondrial transmembrane potential in glucose-deprived astrocytes, leading to their ATP depletion and death. The present results strongly indicate that glucose deprivation causes deterioration of immunostimulated astrocytes by increasing the intracellular concentration of H(2)O(2).
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PMID:Glucose deprivation increases hydrogen peroxide level in immunostimulated rat primary astrocytes. 1499 48

Under anaerobiosis, the mitochondrion of Saccharomyces cerevisiae is restricted to unstructured promitochondria. These promitochondria provide unknown metabolic functions that are required for growth. Since high glucose concentrations are mainly fermented by S. cerevisiae during stationary phase (due to nitrogen starvation), an optimized promitochondria isolation procedure was investigated. Firstly, the unusual promitochondria ultrastructure was checked in intact cells by electron microscopy using a cryo-fixation and freeze-substitution method. The rapid response of anaerobic cells toward oxygen justified the adoption of several critical steps, especially during spheroplasting. Control of spheroplasting was accompanied by a systematic analysis of spheroplast integrity, which greatly influence the final quality of promitochondria. Despite the presence of remnant respiratory chain components under anaerobiosis, characterization of isolated promitochondria by high-resolution respirometry did not reveal any antimycin A- and myxothiazol-sensitive NADH and NADPH oxidase activities. Moreover, the existence of a cyanide-sensitive and non-phosphorylating NADH-dependent oxygen consumption in promitochondria was demonstrated. Nevertheless, promitochondria only slightly contribute to the overall oxygen consumption capacity observed in highly glucose-repressed anaerobic cells.
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PMID:Isolation and properties of promitochondria from anaerobic stationary-phase yeast cells. 1503 59

Neutrophils from pregnant women display reduced neutrophil-mediated effector functions, such as reactive oxygen metabolite (ROM) release. Because the NADPH oxidase and NO synthase produce ROMs and NO, the availability of their substrate NADPH is a potential regulatory factor. NADPH is produced by glucose-6-phosphate dehydrogenase (G-6-PDase) and 6-phosphogluconate dehydrogenase (6-PGDase), which are the first two steps of the hexose monophosphate shunt (HMS). Using immunofluorescence microscopy, we show that 6-PGDase, like G-6-PDase, undergoes retrograde transport to the microtubule-organizing centers in neutrophils from pregnant women. In contrast, 6-PGDase is found in an anterograde distribution in cells from nonpregnant women. However, lactate dehydrogenase distribution is unaffected by pregnancy. Cytochemical studies demonstrated that the distribution of 6-PGDase enzymatic activity is coincident with 6-PGDase Ag. The accumulation of 6-PGDase at the microtubule-organizing centers could be blocked by colchicine, suggesting that microtubules are important in this enzyme's intracellular distribution. In situ kinetic studies reveal that the rates of 6-gluconate turnover are indistinguishable in samples from nonpregnant and pregnant women, suggesting that the enzyme is functionally intact. Resonance energy transfer experiments showed that 6-PGDase and G-6-PDase are in close physical proximity within cells, suggesting the presence of supramolecular enzyme complexes. We suggest that the retrograde trafficking of HMS enzyme complexes during pregnancy influences the dynamics of NADPH production by separating HMS enzymes from glucose-6-phosphate generation at the plasma membrane and, in parallel, reducing ROM and NO production in comparison with fully activated neutrophils from nonpregnant women.
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PMID:6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase form a supramolecular complex in human neutrophils that undergoes retrograde trafficking during pregnancy. 1512 28

Neutrophil functions are impaired in patients with diabetes mellitus. Bacterial phagocytosis and oxidative burst activity are reduced at high glucose concentrations in diabetic patients. Defects in neutrophil oxidative burst capacity are of multifactorial origin in diabetes mellitus and correlate with glucose levels. It has been reported that neutrophil NADPH oxidase activity is impaired and superoxide production is reduced in diabetic patients with or without any infections. Nicotinamide is a vitamin B3 derivative and a NAD precursor with immunomodulatory effects. In vitro studies demonstrated that nicotinamide increases NAD and NADH content of beta cells. The authors hypothesized that nicotinamide may restore the impaired oxidative burst capacity of neutrophils in diabetic patients by increasing the NADH content as an electron donor and possibly through NADPH oxidase activity of the cell. In order to test the hypothesis, this placebo-controlled and open study was designed to evaluate neutrophil functions in infection-free poorly controlled type 2 diabetic patients as compared to healthy subjects and assess the effects of nicotinamide on neutrophil phagocytosis as well as oxidative burst activity. Thirty patients with type 2 diabetes mellitus were enrolled in the study. Sixteen were females and 14 were males, with a mean age 58 +/- 10. All patients were on sulphonylurea treatment and their hemoglobin A(1c) (HbA(1c)) levels were above 7.5%. The control group consisted of 10 voluntary healthy subjects. Diabetic and control subjects were not significantly different in terms of age, body mass index (BMI), leucocyte and neutrophil counts, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR), but HbA(1c) and fasting glucose levels were significantly higher in patients with diabetes mellitus. Phagocytic activity and respiratory burst indexes were measured by flow cytometric analyses as previously described by Rothe and Valet (Methods Enzyml., 233, 539-548, 1994) and compared in diabetic subjects and healthy controls. Diabetic patients were grouped to receive either 50 mg/kg oral nicotinamide (n = 15) or placebo (n = 15) for a period of 1 month. The 2 groups did not differ in terms of treatment, frequency of hypertension, BMI, diabetes duration, age, fasting plasma glucose (FPG), HbA(1c), CRP, ESR, polymorphonuclear leukocyte (PNL) and neutrophil counts. Neutrophil functions were reassessed after the treatment period. Phagocytic activity represented as indexes were lower in diabetic patients when compared to healthy subjects, but the differences were not statistically significant (P >.05). Patients with diabetes mellitus had significantly lower oxidative burst indexes when compared to healthy controls (P values <.05). In diabetic patients, a negative correlation between neutrophil functions and HbA(1c) was found which was not statistically significant (P values >.05). Phagocytic indexes were similar in nicotinamide and placebo groups after treatment period (P >.05). But oxidative burst activity in patients receiving nicotinamide was greater when compared with placebo and the difference was statistically significant at 30 and 45 minutes (P values.04 and.03). This effect of nicotinamide may be due to increased NADH content and NADPH oxidase activity of the cell, which needs to be further studied. Impaired neutrophil functions may aggravate various infections in patients with diabetes mellitus and blood glucose regulation is an important target of treatment to improve neutrophil functions. But nicotinamide treatment may help to improve prognosis in diabetic patients with severe infections.
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PMID:Nicotinamide effects oxidative burst activity of neutrophils in patients with poorly controlled type 2 diabetes mellitus. 1520 86

In hemorrhagic shock, local hypoxia is present and followed by reoxygenation during the therapeutic process. In endothelium, reactive oxygen species (ROS) have been identified as a cause of inflammatory reactions and tissular lesions in ischemic territory during reoxygenation. This study was designed to identify the enzymatic mechanisms of ROS formation during reoxygenation after hypoxia. Because severe shock, in vivo, can affect both O2 and nutriments, we combined hypoxia at a level close to that found in terminal vessels during shock, with glucose depletion, which induces a relevant additional stress. Human umbilical vein endothelial cells (HUVEC) underwent 2 h of hypoxia (Po2 approximately 20 mmHg) without glucose and 1 h of reoxygenation (Po2 approximately 120 mmHg) with glucose. ROS production was measured by the fluorescent marker 2',7'-dichlorodihydrofluorescein diacetate, and cell death by propidium iodide. After 1 h of reoxygenation, fluorescence had risen by 143 +/- 17%. Cell death was equal to 8.6 +/- 2.4%. Antimycin A and stigmatellin, which inhibits the type III mitochondrial respiratory chain complex, reduced ROS production to values of 61 +/- 10 and 59 +/- 7%, respectively, but inhibitors of other chain complexes did not affect it. In addition, the increase in fluorescence was not affected by inhibition of NADPH oxidase, xanthine oxidase, NOS, cyclooxygenase, cytochrome P-450 monooxygenase, or monoamine oxidase. We did not observe any increase in cell death. These results show that, in HUVEC, mitochondria are responsible for ROS production after hypoxia and reoxygenation and suggest that a ROS release site is activated in the cytochrome b of the type III respiratory chain complex.
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PMID:Reoxygenation after hypoxia and glucose depletion causes reactive oxygen species production by mitochondria in HUVEC. 1520 81

Recent studies demonstrating a close relationship between postprandial hyperglycemia and the incidence of atherosclerotic cardiovascular disease prompted us to investigate the generation and source of reactive oxygen species (ROS) in endothelial cells stimulated by short-term exposure to a high glucose concentration. In addition, we investigated the effect of insulin on ROS production induced by high glucose concentration. Cultured bovine aortic endothelial cells demonstrated a significant increase in intracellular ROS generation after a 3-h exposure to 25 mM glucose (131.4% versus 5 mM glucose). This increased generation of ROS was suppressed by an inhibitor of NAD(P)H oxidase. Intracellular ROS production in cells exposed to 3 h of high glucose concentration was increased significantly by the presence of a physiological concentration of insulin. However, after a 1-h exposure to high glucose levels, ROS generation in cells incubated with insulin was only about 80% of that measured in cells incubated without insulin. The generation of intracellular nitric oxide (NO) resulting from an acute insulin effect may account for this difference. In conclusion, acute hyperglycemia itself may possibly cause endothelial oxidative stress in patients with postprandial hyperglycemia. Endothelial oxidative stress may be determined by the interaction between NO and superoxide generation.
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PMID:Short-term exposure of high glucose concentration induces generation of reactive oxygen species in endothelial cells: implication for the oxidative stress associated with postprandial hyperglycemia. 1523 Oct 66

Chronic hyperglycemia in diabetes mellitus is an oxidative stress created by an imbalance of prooxidants over antioxidant defenses. The pathogenesis would involve several mechanisms including glucose autoxidation, protein glycation, the polyol pathway, and overproduction of superoxide radicals in mitochondria and via NAD(P)H oxidase. Glycemic equilibrium plays a very important role in the prooxidant/antioxidant balance. Macromolecules such as found in the extracellular matrix, lipoproteins, and deoxyribonucleic acid also constitute targets for free radicals in diabetes mellitus. This oxidative tress is involved in the pathophysiology of diabetes complications. The chronic hyperglycemic status also favors glycation reactions (irreversible glucose binding on protein amino groups), thereby leading to advanced glycation endproducts. Via their recognition by cell receptors, advanced glycation endproducts also participate in the development of oxidative stress and the inflammatory status. Involvement of oxidative stress and advanced glycation endproducts in diabetes complications is the basis of the development of adjunct therapies with antioxidant and/or anti)advanced glycation endproducts molecules.
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PMID:[Diabetes mellitus, oxidative stress and advanced glycation endproducts]. 1524 48

Structural and functional integrity of brain function profoundly depends on a regular oxygen and glucose supply. Any disturbance of this supply becomes life threatening and may result in severe loss of brain function. In particular, reductions in oxygen availability (hypoxia) caused by systemic or local blood circulation irregularities cannot be tolerated for longer periods due to an insufficient energy supply to the brain by anaerobic glycolysis. Hypoxia has been implicated in central nervous system pathology in a number of disorders including stroke, head trauma, neoplasia and neurodegenerative disease. Complex cellular oxygen sensing systems have evolved for tight regulation of oxygen homeostasis in the brain. In response to variations in oxygen partial pressure (P(O(2))) these induce adaptive mechanisms to avoid or at least minimize brain damage. A significant advance in our understanding of the hypoxia response stems from the discovery of the hypoxia inducible factors (HIF), which act as key regulators of hypoxia-induced gene expression. Depending on the duration and severity of the oxygen deprivation, cellular oxygen-sensor responses activate a variety of short- and long-term energy saving and cellular protection mechanisms. Hypoxic adaptation encompasses an immediate depolarization block by changing potassium, sodium and chloride ion fluxes across the cellular membrane, a general inhibition of protein synthesis, and HIF-mediated upregulation of gene expression of enzymes or growth factors inducing angiogenesis, anaerobic glycolysis, cell survival or neural stem cell growth. However, sustained and prolonged activation of the HIF pathway may lead to a transition from neuroprotective to cell death responses. This is reflected by the dual features of the HIF system that include both anti- and proapoptotic components. These various responses might be based on a range of oxygen-sensing signal cascades, including an isoform of the neutrophil NADPH oxidase, different electron carrier units of the mitochondrial chain such as a specialized mitochondrial, low P(O(2)) affinity cytochrome c oxidase (aa(3)) and a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF prolyl-hydroxylase (PHD) and HIF asparaginyl hydroxylase, known as factor-inhibiting HIF (FIH-1). Thus specific oxygen-sensing cascades, by means of their different oxygen sensitivities, cell-specific and subcellular localization, may help to tailor various adaptive responses according to differences in tissue oxygen availability.
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PMID:Cellular oxygen sensing need in CNS function: physiological and pathological implications. 1529 39


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