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)

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

Vascular endothelial activation is an early step during leukocyte/endothelial adhesion and transendothelial leukocyte migration in inflammatory states. Leukocyte transmigration occurs through intercellular gaps between endothelial cells. Vascular endothelial cadherin (VE-cadherin) is a predominant component of endothelial adherens junctions that regulates intercellular gap formation. We found that tumor necrosis factor (TNF) caused tyrosine phosphorylation of VE-cadherin, separation of lateral cell-cell junctions, and intercellular gap formation in human umbilical vein endothelial cell (HUVEC) monolayers. These events appear to be regulated by intracellular oxidant production through endothelial NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase because antioxidants and expression of a transdominant inhibitor of the NADPH oxidase, p67(V204A), effectively blocked the effects of TNF on all 3 parameters of junctional integrity. Antioxidants and p67(V204A) also decreased TNF-induced JNK activation. Dominant-negative JNK abrogated VE-cadherin phosphorylation and junctional separation, suggesting a downstream role for JNK. Finally, adenoviral delivery of the kinase dead PAK1(K298A) decreased TNF-induced JNK activation, VE-cadherin phosphorylation, and lateral junctional separation, consistent with the proposed involvement of PAK1 upstream of the NADPH oxidase. Thus, PAK-1 acts in concert with oxidase during TNF-induced oxidant production and loss of endothelial cell junctional integrity.
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PMID:NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction. 1527 97

We previously showed that a systemic inhibitor of gp91(phox) (nox2)-based NAD(P)H oxidase abolishes angiotensin II (Ang II)-induced vascular hypertrophy. In the present study, we tested whether perivascular transfection with Ad-gp91ds-eGFP (an adenoviral bicistronic construct targeting NAD(P)H oxidase in fibroblasts) or controls Ad-CMV-eGFP and Ad-scrmb-eGFP would affect medial hypertrophy in response to Ang II. In C57BL/6J mice, we applied Ad-gp91ds-eGFP or controls to the left carotid adventitia, and 2 days later we implanted minipumps delivering vehicle or Ang II (750 microg/kg per day) for 7 days. None of the viral treatments affected Ang II-induced systolic blood pressure elevation. Immunohistochemical staining showed marker eGFP in adventitial fibroblasts and some macrophages, indicating expression of the gp91ds inhibitor. As expected, Ang II induced medial hypertrophy (medial cross-sectional area, 32.96+/-2.04 versus 20.57+/-1.00x10(3) microm2, Ang II versus control; P<0.001) that was significantly inhibited by Ad-gp91ds-eGFP (26.23+/-0.90x10(3) microm2; P<0.01) but not control viruses. Application of viruses alone did not change medial size under control conditions. Immunohistochemical staining and semiquantitative analysis showed a 70% increase in reactive oxygen species levels measured by the lipid peroxidation byproduct 4-hydroxynonenal (4-HNE) throughout the carotid wall in the Ang II group versus vehicle. After treatment with Ad-gp91ds-eGFP, 4-HNE generation was normalized. Thus NAD(P)H oxidases in adventitial fibroblasts and macrophages appear to modulate Ang II-induced medial hypertrophy.
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PMID:Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. 1530 82

Because systems controlled by basal NAD(P)H oxidase activity appear to contribute to differences in responses of endothelium-removed bovine coronary (BCA) and pulmonary (BPA) arteries to hypoxia, we characterized the Nox oxidases activities present in these vascular segments and how cytosolic NAD(P)H redox systems could be controlling oxidase activity. BPA generated approximately 60-80% more lucigenin (5 microM) chemiluminescence detectable superoxide than BCA. Apocynin (10 microM), a NAD(P)H oxidase inhibitor, and 6-aminonicotinamide (1 mM), a pentose phosphate inhibitor (PPP), both attenuated (approximately by 50-70%) superoxide detected in BPA and BCA. There was no significant difference in the expression of Nox2 or Nox4 mRNA or protein detected by Western blot analysis. NADPH and NADH increased superoxide in homogenates and isolated microsomal membrane fractions in a manner consistent with BPA and BCA having similar levels of oxidase activity. BPA had 4.2-fold higher levels of NADPH than BCA. The activity and protein levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting PPP enzyme generating cytosolic NADPH, were 1.5-fold higher in BPA than BCA. Thus BPA differ from BCA in that they have higher levels of G6PD activity, NADPH, and superoxide. Because both arteries have similar levels of Nox expression and activity, elevated levels of cytosolic NADPH may contribute to increased superoxide in BPA.
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PMID:Cytosolic NADPH may regulate differences in basal Nox oxidase-derived superoxide generation in bovine coronary and pulmonary arteries. 1534 89

Angiotensin II (AII) is a neurohormone and contractile agonist of vascular smooth muscle that has been shown to be involved in the pathogenesis of vascular disease, which may be partially caused by its effect on oxidant stress. Energy metabolism was examined in pig carotid arteries treated with AII, because the activity of pathways of intermediary metabolism of glucose determines the status of cytosolic NADH/NAD and NADPH/NADP redox, factors which are involved in oxidant stress. Contractile responses to AII were characterized by an increase in isometric force followed by a gradual decline to near-basal levels. Despite contractile activation, no change in glycolysis, lactate production, glucose oxidation, fatty acid oxidation, O2 consumption, glycogen content or high-energy phosphates was detected when compared to resting unstimulated arteries. Paradoxically, total uptake of glucose was inhibited by AII. Treatment with diphenylene iodinium, an inhibitor of NAD(P)H oxidase and superoxide production, reversed the inhibition of glucose uptake and revealed the expected increase in glucose uptake and oxidation upon contractile activation of smooth muscle by AII. The intracellular [lactate]/[pyruvate] ratio was increased, reflecting an increase in cytosolic NADH/NAD redox, whereas NADPH/NADP redox was decreased by AII. No change in NADPH/NADP redox was observed when membrane depolarization with K+ was used as the contractile agent. It is concluded that the pattern of force generation, metabolism and energetics of AII-stimulated contraction are significantly different from that of other contractile agonists. Most notably AII inhibited glucose uptake. NAD(P)H oxidase and/or attendant superoxide may play a role in modulating glucose metabolism. AII induces opposite changes in NADH/NAD redox and NADPH/NADP redox, which may have important consequences for oxidant stress.
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PMID:Effect of angiotensin II on energetics, glucose metabolism and cytosolic NADH/NAD and NADPH/NADP redox in vascular smooth muscle. 1553 13

Two-photon microscopy allows determination of UV-excitable fluorophores using long-wavelength light. We aimed to determine NAD(P)H autofluorescence as a measure for macrophage NADPH-oxidase activation. RAW264.7 macrophages were grown on glass coverslips and kept in HBSS for microscopic investigation. Cells were excited with 710 nm light and NAD(P)H autofluorescence was detected. Glucose as well as NaCN evoked an increase of NAD(P)H autofluorescence. Activators of NADPH oxidase lead to significantly decreased NAD(P)H autofluorescence. Therefore, this work shows the suitability of two-photon microscopy as a non-invasive method determining changes in phagocyte NAD(P)H upon activation.
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PMID:Non-invasive live-cell measurement of changes in macrophage NAD(P)H by two-photon microscopy. 1558 5

It is tempting to speculate that increased vasoconstriction and loss of endothelium-dependent vasodilation might be etiological factors of elevated blood pressure in the insulin-resistant state. Vascular contraction induced by angiotensin II and the expression of NAD(P)H oxidase were increased in the aorta of insulin-resistant mice. In addition, both angiotensin II type 1 receptor expression and superoxide anion production were up-regulated in these mice. Another mechanism for imparing endothelial function is the uncoupling of endothelial nitric oxide synthase (eNOS). It has become clear from studies on the aorta of insulin-resistant rat that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO (nitric oxide) due to an enhanced formation of superoxide anion (NO/superoxide anion imbalance), which are caused by relative deficiency of tetrahydrobiopterin, a cofactor of NOS, in vascular endothelial cells. Supplementation of tetrahydrobiopterin restored endothelial function and relieved oxidative tissue damage through activation of eNOS in those rats. These results indicate that generation of superoxide anion from NAD(P)H oxidases and an uncoupled eNOS may be pathogenic factors for impaired endothelial function and hypertension in the insulin-resistant state.
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PMID:Malfunction of vascular control in lifestyle-related diseases: mechanisms underlying endothelial dysfunction in the insulin-resistant state. 1559 93

The recent discovery of non-phagocytic NAD(P)H oxidases belonging to the Nox family of enzymes sharing extensive homology to the leukocyte NAD(P)H oxidase has revolutionized our understanding of oxidative signaling related to fundamental biological processes and disease states. One form of this enzyme, Nox1, is a growth factor-responsive enzyme that catalyzes formation of the reactive oxygen species superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)). Its expression is linked to a number of biological responses including cellular proliferation, angiogenesis, and activation of cellular signaling pathways. Whereas early published studies have described three distinct isoforms of Nox1, the current body of literature fails to adequately recognize this notion. Also, functional differences between isoforms remain relatively unexplored. Herein, we report that expression of human Nox1 is restricted to two distinct isoforms derived from a single gene; that is, the full-length gene product and a shorter spliced variant which lacks one of the NAD(P)H binding domains. We have developed PCR primer sets that distinguish between the two forms of Nox1 in several human cell lines. We could not find evidence for expression of the shortest reported form of Nox1 (NOH-1S), previously identified as a proton channel, and the absence of paired splice sites in the gene suggests that it represents a reverse transcriptase artifact. A survey of the scientific literature reveals that the majority of studies related to Nox1 do not utilize molecular strategies that would adequately discern between the two Nox1 variants. The current literature suggest the two identified isoforms of human Nox1 (which we have named Nox1-L and Nox1-S) may be functionally distinct. Future studies related to Nox1 will benefit from establishing the identity of the Nox1 isoform expressed and the functions attributed to each variant.
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PMID:A reappraisal of the genomic organization of human Nox1 and its splice variants. 1570 75

In vascular smooth muscle (VSM) of Squalus acanthias, endothelin-1 (ET-1) signals via the ET(B) receptor. In both shark and mammalian VSM, ET-1 induces a rise in cytosolic Ca(2+) concentration ([Ca(2+)](i)) via activation of the inositol trisphosphate (IP(3)) receptor (IP(3)R) and subsequent release of Ca(2+) from the sarcoplasmic reticulum (SR). IP(3)R-mediated release of SR Ca(2+) causes calcium-induced calcium release (CICR) via the ryanodine receptor (RyR), which can be sensitized by cyclic adeninediphosphate ribose (cADPR). cADPR is synthesized from NAD(+) by a membrane-bound bifunctional enzyme, ADPR cyclase. We have previously shown that the antagonists of the RyR, Ruthenium Red, high concentrations of ryanodine and 8-Br cADPR, diminish the [Ca(2+)](i) response to ET-1 in shark VSM. To investigate how ET-1 might influence the activity of the ADPR cyclase, we employed inhibitors of the cyclase. To explore the possibility that ET-1-induced production of superoxide (O(2)*-) might activate the cyclase, we used an inhibitor of NAD(P)H oxidase (NOX), DPI and a scavenger of O(2)*-, TEMPOL. Anterior mesenteric artery VSM was loaded with fura-2AM to measure [Ca(2+)](i). In Ca(2+)-free shark Ringers, ET-1 increased [Ca(2+)](i) by 104+/-8 nmol l(-1). The VSM ADPR cyclase inhibitors, nicotinamide and Zn(2+), diminished the response by 62% and 72%, respectively. Both DPI and TEMPOL reduced the response by 63%. The combination of the IP(3)R antagonists, 2-APB or TMB-8, with DPI or TEMPOL further reduced the response by 83%. We show for the first time that in shark VSM, inhibition of the ADPR cyclase reduces the [Ca(2+)](i) response to ET-1 and that superoxide may be involved in the activation of the cyclase.
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PMID:Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle. 1576 6

Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O2*-) and hydrogen peroxide (H2O2) appear most important in redox signaling. Whereas O2*- predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO*), H2O2 influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H2O2 in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase-derived H2O2 amplifies its own production. Recent studies have shown that H2O2 stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H2O2-dependent pathological signaling in vascular cells, thus contributing to vascular disease development. The latest progress on Nox functions in vascular cells is also discussed [Nox for NAD(P)H oxidases, representing a family of novel NAD(P)H oxidases].
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PMID:NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease. 1586 Jul 62


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