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)

Diphenyleneiodonium (DPI) inhibits activity of flavoenzymes like NADPH oxidase, the major source of superoxide anion in cardiovascular system, but affects also other oxidoreductases. Contradictory data have been published concerning the effect of diphenyleneiodonium on the production of reactive oxygen species in cells, both inhibitory and stimulatory action of DPI being reported. We have examined the effect of DPI on the cellular production of reactive oxygen and nitrogen species (ROS/RNS) and on the proliferation and apoptosis of human vascular endothelial cells. We found increased oxidation of ROS-sensitive probes (dihydrorhodamine 123 and 2',7'-dichlorodihydrofluorescein diacetate) when DPI (20 microM-100 microM) was present in the treated cells. However, oxidation of the fluorogenic probes was inhibited if DPI (20 microM-100 microM) was removed from the reaction medium after cell preincubation. These results suggest an artifactual oxidation of the fluorogenic probes by DPI or its metabolites. A similar pattern of influence of DPI on the production of NO (measured with 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate) was observed. Modulation of generation of reactive oxygen and nitrogen species in DPI-treated cells influenced the nitration of tyrosine residues of cellular proteins, estimated by Western blotting. Decreased level of nitration generally paralleled the lowered production of ROS. A decreased 3-(4,5-dimethylthiazolyl)-3-3(4-sulphophenyl) tetrazolium (MTT) reducing activity of cells for was observed immediately after 1h treatment of human endothelial cells with DPI (1 microM-100 microM), in spite of lack of changes in cell viability estimated by other methods. These results point to a next limitation of MTT in estimation of viability of cells treated with oxidoreductase inhibitors. DPI inhibited the proliferation of HUVECs as well as immortalized cell line HUVEC-ST, as assessed by acid phosphatase activity test and measurement of total nucleic acid content. Proapoptotic action of DPI was observed 12 h after incubation with this compound.
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PMID:Induction of apoptosis and modulation of production of reactive oxygen species in human endothelial cells by diphenyleneiodonium. 1579 48

Iron deficiency is associated with multiple health problems, including the cardiovascular system. However, the mechanism of action of iron-deficiency-induced cardiovascular damage is unclear. The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA. Male weanling rats were fed with either control or iron-deficient diets for 12 weeks. Cardiac ultrastructure was examined by transmission electron microscopy. Western blot analysis was used to evaluate cytochrome c, endothelial and inducible NOS, NADPH oxidase, caveolin-1 and RhoA. Protein nitrotyrosine formation was measured by ELISA. Rats fed an iron-deficient diet exhibited increased heart weight and size compared with the control group. Heart width, length and ventricular free wall thickness were similar between the two groups. However, the left ventricular dimension and chamber volume were significantly enhanced in the iron-deficient group compared with controls. Ultrastructural examination revealed mitochondrial swelling and abnormal sarcomere structure in iron-deficient ventricular tissues. Cytochrome c release was significantly enhanced in iron-deficient rats. Protein expression of eNOS (endothelial NOS) and iNOS (inducible NOS), and protein nitrotyrosine formation were significantly elevated in cardiac tissue or mitochondrial extraction from the iron-deficient group. Significantly up-regulated NADPH oxidase, caveolin-1 and RhoA expression were also detected in ventricular tissue of the iron-deficient group. Taken together, these results suggest that dietary iron deficiency may have induced cardiac hypertrophy characterized by aberrant mitochondrial and irregular sarcomere organization, which was accompanied by increased reactive nitrogen species and RhoA expression.
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PMID:Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration. 1587 45

Oxidative stress underlies many forms of vascular disease as well as tissue injury following ischemia and reperfusion. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex as expressed in vascular cells differs from that in phagocytic leucocytes both in biochemical structure and functions. The crucial flavin-containing catalytic subunits, Nox1 and Nox4, are not found in leucocytes, but are highly expressed in vascular cells and upregulated with vascular remodeling, such as that found in hypertension and atherosclerosis. The difference in catalytic subunits offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic functions carried out by reactive oxygen and nitrogen species. Nitric oxide and targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack, than are conventional antioxidants. The roles of Nox isoforms in other inflammatory conditions are yet to be explored.
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PMID:Mechanisms for suppressing NADPH oxidase in the vascular wall. 1596 5

The pathophysiological mechanism of Salmonella enterica subsp. enterica serovar Typhimurium (Salmonella typhimurium) induced gastroenteritis is controlled by interplay of various cell signaling events. Adherence of this organism through type-1 fimbriae is known to be a vital prerequisite for the establishment of infection. In the present investigation male albino Wistar rats were immunized with purified type-1 fimbriae and challenged intragastrically with S. typhimurium. Electrolyte transport and level of different second messengers were studied in four different groups of animals. Transepithelial fluxes of Na+ and Cl- revealed absorption in immunized-challenged group as observed in case of control and immunized group while secretion was observed in infected group. Ca2+ and 3-0-methyl-D-glucose fluxes did not show any change. Significant increase in the level of intracellular Ca2+, cAMP, membrane form of protein kinase C, prostaglandins, NADPH oxidase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, total oxygen free radicals, reactive nitrogen intermediates, citrulline and lipid peroxidation was found in the infected group. However, in the immunized-challenged group, the values of all the parameters were found to be same as that of control as well as immunized groups. Na+, K(+)-ATPase and calmodulin levels were found to be unaltered in all the groups of animals. Thus, the immunization with type-1 fimbriae has been found to be quite effective leading to the prevention of multiple physiologic derangements in isolated ileal cells suggesting the protective role of the fimbriae.
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PMID:The effect of type-1 fimbrial immunization on gut pathophysiological response in rats infected with Salmonella enterica subsp. enterica serovar Typhimurium. 1601 47

Phagocytes limit replication or kill ingested organisms by producing toxic reactive oxygen and nitrogen species via NADPH oxidase and inducible nitric oxide synthase (iNOS). The present experiments were to investigate the production and the possible roles of superoxide, hydrogen peroxide (H2O2) and nitric oxide (NO) in the MQ-NCSU chicken macrophage cell line infected with Salmonella in vitro. After infection, intracellular Salmonella viable counts remained constant until 24 h post infection (PI) and started to decline from 48 h PI. Infection of cells with S. Typhimurium, S. Enteritidis and S. Gallinarum, as well as exposure to S. Enteritidis LPS induced low, but significant concentrations of superoxide 1 to 2 h PI, as determined by reduction of ferricytochrome c. There was no difference in superoxide production in infected cells and control cells after 4 h. Increased H2O2 was observed from cells infected with all the different Salmonella species between 2 and 3 h of infection. Nitrite was always greater in infected cells compared to uninfected cells at all times. However, Salmonella was not completely eliminated from the cells though these cells are capable of eliciting a noticeable oxidative burst response and great nitrosative responses, indicating that a strong oxidative burst (and other mechanism/s) is essential for the elimination of intracellular Salmonella.
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PMID:Oxidative and nitrosative responses of the chicken macrophage cell line MQ-NCSU to experimental Salmonella infection. 1605 Jan 78

In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development and progression of diabetic retinopathy. Bisphosphonates are potent inhibitors of bone resorption and are widely used drugs for the treatment of osteoporosis and osteolytic bone metastasis. Recently, farnesyl pyrophosphate synthase has been shown as a molecular target of nitrogen-containing bisphosphonates, and inhibition of post-translational prenylation of small molecular weight G proteins is likely involved in their anti-resorptive activity on osteoclasts. NADPH oxidase-derived reactive oxygen species (ROS) generation is required for the AGE-RAGE signaling in vascular wall cells, and small G protein Rac is a critical component of vascular NADPH oxidase complex. These observations let us to speculate that minodronate, a newly developed nitrogen-containing bisphosphonate, might be a promising remedy for treating patients with diabetic retinopathy by inhibiting the AGE-RAGE signaling pathways through suppression of ROS generation via inhibition of Rac prenylation. In this paper, we like to propose the possible ways of testing our hypotheses: (1) Does treatment with minodronate decrease the risk for the development and progression of diabetic retinopathy in osteoporotic patients? (2) If the answer is yes, is this beneficial effect of minodronate superior to that of other nitrogen-noncontaining bisphosphonates with equihypolipidemic properties? (3) Does minodronate treatment suppress NADPH oxidase-mediated ROS generation in retinas of diabetic animals? (4) Does treatment with pyridoxamine, a post-Amadori inhibitor of AGE formation, attenuate these beneficial effects of minodronate on diabetic retinopathy? These clinical and animal studies could clarify whether the use of minodronate is of benefit in patients with AGE-RAGE-related disorders such as diabetic retinopathy, even in the absence of osteoporosis.
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PMID:Minodronate, a nitrogen-containing bisphosphonate, is a promising remedy for treating patients with diabetic retinopathy. 1621 33

Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of diabetic vascular complications. Indeed, AGEs elicit oxidative stress generation in vascular wall cells through an interaction with their receptor (RAGE), thus playing an important role in vascular inflammation and altered gene expression of growth factors and cytokines. We have previously shown that minodronate, a nitrogen-containing bisphosphonate, blocked the angiogenic signaling of vascular endothelial growth factor in ECs through its antioxidative properties. However, the effects of minodronate on AGE-exposed ECs remain to be elucidated. In this study, we investigated whether and how minodronate could inhibit AGE-induced reactive oxygen species (ROS) generation and subsequent vascular cell adhesion molecule-1 (VCAM-1) gene expression in human umbilical vein endothelial cells (HUVEC). Minodronate or an NADPH oxidase inhibitor, diphenylene iodonium, completely inhibited the AGE-induced ROS generation in HUVEC. Geranylgeranyl pyrophosphate reversed the antioxidative properties of minodronate in AGE-exposed ECs. Furthermore, minodronate was found to prevent AGE-induced nuclear factor--KB activation and subsequently suppress VCAM-1 gene expression in HUVEC. These results demonstrate that minodronate could inhibit VCAM- 1 expression in AGE-exposed ECs by suppressing NADPH oxidase-derived ROS generation, probably via inhibition of geranylgeranylation of Rac, a component of endothelial NADPH oxidase. Our present study suggests that minodronate may have a therapeutic potential in the treatment of patients with diabetic vascular complications.
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PMID:Minodronate, a nitrogen-containing bisphosphonate, inhibits advanced glycation end product-induced vascular cell adhesion molecule-1 expression in endothelial cells by suppressing reactive oxygen species generation. 1644 May 84

Because most studies addressing the regulatory mechanisms of intercellular adhesion molecule (ICAM)-1 expression have used cultured endothelial cells, we set out to develop an isolated mouse lung preparation to study gene and protein expression in its proper cellular context in the organ. Lungs from CD1 mice were isolated and perfused (2 ml/min, 37 degrees C) with a recirculating volume of RPMI 1640 solution supplemented with 3 g/100 ml albumin. Lungs maintained their isogravimetric state for 4 h. Tumor necrosis factor (TNF-alpha; 2,000 U/ml) was added to the perfusate for 0.5, 1, 2, or 3.5 h to induce ICAM-1 expression or lungs received no treatment (control). After quick-freezing the lungs using liquid nitrogen at different time points, the prepared tissue homogenates were analyzed for ICAM-1 protein expression by Western blotting and NF-kappaB activation by electrophoretic mobility shift assay. TNF-alpha caused a progressive increase in NF-kappaB activity after 0.5 h and ICAM-1 protein expression two- to threefold of basal after 2 h. Untreated lungs expressed a low and constant level of ICAM-1 between 0 and 3.5 h. TNF-alpha failed to induce NF-kappaB activation and ICAM-1 expression in lungs of NADPH oxidase-deficient mice lacking p47(phox). We disaggregated mouse lungs using collagenase and stained the cells for ICAM-1 and VE-cadherin (used as an endothelial marker) to assess the in situ endothelial-specific expression of ICAM-1. We observed that TNF-alpha challenge resulted in increased ICAM-1 expression in endothelial cells freshly isolated from lungs. These data show the role of NADPH oxidase-derived oxidant signaling in the mechanism of NF-kappaB activation and ICAM-1 expression in mouse lung endothelial cells. Moreover, the general method presented herein has potential value in assessing mechanisms of gene and protein expression in the isolated-perfused mouse lung model.
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PMID:De novo ICAM-1 synthesis in the mouse lung: model of assessment of protein expression in lungs. 1671 32

Sphingolipids including ceramide and its derivatives such as ceramide-1-phosphate, glycosyl-ceramide, and sphinogosine (-1-phosphate) are now recognized as novel intracellular signal mediators for regulation of inflammation, apoptosis, proliferation, and differentiation. One of the important and regulated steps in these events is the generation of these sphingolipids via hydrolysis of sphingomyelin through the action of sphingomyelinases (SMase). Several lines of evidence suggest that reactive oxygen species (ROS; O2-, H2O2, and OH-,) and reactive nitrogen species (RNS; NO, and ONOO-) and cellular redox potential, which is mainly regulated by cellular glutathione (GSH), are tightly linked to the regulation of SMase activation. On the other hand, sphingolipids are also known to play an important role in maintaining cellular redox homeostasis through regulation of NADPH oxidase, mitochondrial integrity, and antioxidant enzymes. Therefore, this paper reviews the relationship between cellular redox and sphingolipid metabolism and its biological significance.
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PMID:Sphingolipid signaling and redox regulation. 1671 89

Sepsis remains one of the leading causes of death in intensive care units, despite recent acquired knowledge on pathophysiology and treatment. Several mediators of inflammation and cellular damage have been implicated in the complex host-pathogen interaction underlying organ damage and multisystem organ failure , which are hallmarks of sepsis and common causes of death. Among such mediators, reactive oxygen/nitrogen species have been increasingly studied in the context of direct cytotoxicity as well as altered cell signaling. While the generation of reactive oxygen species by inflammatory cells in sepsis is well known, recent studies have shown that vascular cells are able to release reactive oxygen intermediates that may be associated with endothelial dysfunction of sepsis. These compounds can activate transcription factors such as NF-kappaB that sustain inflammatory process or enzymatic systems like poly(ADP-ribose) polymerase-1, which are involved in apoptosis and cytotoxicity of sepsis. Our laboratory recently showed that platelet-derived exosomes from septic patients carry components of a superoxide-producing NADPH oxidase and can, at least in vitro, induce apoptosis of endothelial and vascular smooth muscle cells by a ROS-dependent pathway. Taken together, these data show that reactive oxygen species are involved in cell signaling and organ injury in sepsis. Efforts must be made to identify the precise contribution of these factors in septic process, in order to clarify the mechanisms associated with the disease. This will certainly lead to discovery of therapeutic strategies that can help us to mitigate vascular dysfunction of sepsis.
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PMID:Redox mechanisms of vascular cell dysfunction in sepsis. 1678 90


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