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 highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.
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PMID:Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells. 819 1

PMN obtained from asthmatic subjects demonstrate a heightened respiratory burst with increased superoxide generation compared to normals. This enhanced superoxide anion generation could be secondary to increased activity of the respiratory burst NADPH oxidase or diminished metabolism of superoxide via superoxide dismutase (SOD). The two forms of SOD expressed in PMN, CuZnSOD expressed constitutively in the cytosol and inducible mitochondrial MnSOD, were investigated in asthmatics. Resting PMN from asthmatics (N = 9) contained significantly less MnSOD activity compared to controls (0.46 +/- 0.16 vs. 0.79 +/- 0.17 units/10(7) PMN, respectively; P = 0.0002). As several cytokines including interleukins (IL) -1, -4, and -6 as well as granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the PMN respiratory burst and are synthesized in the asthmatic lung, their effects on PMN MnSOD activity were assayed. In contrast to its effects on lymphocytes, both IL-1 and IL-6 significantly inhibited in a dose-dependent fashion the induction of MnSOD in PMN from normals (0.42 +/- 0.12 and 0.45 +/- 0.05 units/10(7) PMN, respectively, at 10 units/ml of each cytokine; P = 0.02 compared to resting cells) but failed to further modulate MnSOD production in asthmatic PMN. IL-4 and GM-CSF had no effect on MnSOD production, and TNF effects could not be studied because of its effects on cell viability. There were no differences in the activity of CuZnSOD (N = 9) or NADPH oxidase (N = 4) in the two groups. Inhibition of MnSOD activity in PMN secondary to cytokine exposure in the asthmatic lung could explain, at least in part, the increased generation of superoxide from PMN obtained from asthmatics. This would promote the presence and severity of inflammation in the asthmatic lung. These data further support a role for IL-1 and IL-6 in allergic inflammation.
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PMID:Activities of superoxide dismutases and NADPH oxidase in neutrophils obtained from asthmatic and normal donors. 839 94

Inflamed synovium is characterized by high concentrations of cytokines [interleukin (IL)-6, IL-1beta and tumour necrosis factor (TNF)-alpha] and the abundant presence of infiltrated monocytes, many of which are found adjacent to the resident fibroblast-like synoviocytes. We have used a co-culture of fibroblast-like synoviocytes and differentiated U937 cells to study IL-6, IL-1beta and TNF-alpha release. After a 3 day co-culture, 35% of the U937 cells had adhered and were fully differentiated towards monocytes, as determined by expression of p47phox, CD14, MSE-1, Mac-1, collagenase and NADPH oxidase activity. IL-6 release from fibroblast-like synoviocytes was induced 4-fold by co-culture with differentiated U937 cells. However, co-culture of differentiated U937 cells with fibroblast-like synoviocytes failed to release detectable levels of IL-1beta and TNF-alpha from the U937 cells. Addition of synovial fluid further increased IL-6 release, but again had no effect on IL-1beta or TNF-alpha, although U937 cells differentiated by phorbol ester were able to release these two cytokines and, in the case of the co-culture, mRNAs for both cytokines were highly expressed in the U937 cells. We postulate that the influx of monocytes into the synovium is instrumental in the elevation of IL-6 levels, but this is not sufficient to explain high levels of IL-1beta or TNF-alpha.
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PMID:Co-culture of synovial fibroblasts and differentiated U937 cells is sufficient for high interleukin-6 but not interleukin-1beta or tumour necrosis factor-alpha release. 956 69

We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II-induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II-induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II-induced IL-6 expression. Because we observed that exogenous H(2)O(2) also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H(2)O(2) were compared. Ang II, as well as exogenous H(2)O(2), activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous H(2)O(2), however, Ang II did not influence phosphorylation and degradation of IkappaB-alpha/beta or nuclear translocation of p65, nor did it increase NF-kappaB promoter activity. PD98059 and SB203580 inhibited Ang II-induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis-element in Ang II-induced IL-6 gene expression. NF-kappaB-binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-kappaB-dependent, pathway in cardiac fibroblasts.
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PMID:ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. 1159 88

Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells.
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PMID:Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. 1526 24

Pigment epithelium-derived factor (PEDF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. Atherosclerosis is an inflammatory-fibroproliferative disease as well. Oxidative stress plays a major role in retinopathy and atherosclerosis. Accordingly, we investigated effects of PEDF on reactive oxygen species (ROS) generation, NF-kappaB activation and interleukin (IL)-6 expression in TNF-alpha-exposed HUVEC. TNF-alpha significantly increased intracellular ROS generation, which was completely blocked by PEDF or diphenylene iodonium, an inhibitor of NADPH oxidase. Further, PEDF completely prevented the TNF-alpha-induced increase in NADPH oxidase activity. PEDF or an antioxidant, N-acetylcysteine, significantly inhibited the TNF-alpha-induced NF-kappaB activation. PEDF inhibited TNF-alpha-induced expression of IL-6 at both mRNA and protein levels. Moreover, TNF-alpha downregulated PEDF mRNA levels. Ligand blot analysis revealed that HUVEC possessed a membrane protein with binding affinity for PEDF. The results demonstrated that PEDF inhibited TNF-alpha-induced NF-kappaB activation and subsequent IL-6 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may play an important role in the development and progression of atherosclerosis.
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PMID:Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. 1527 19

Cardiopulmonary bypass (CPB) causes acute lung injury. Reactive oxygen species (ROS) from NADPH oxidase may contribute to this injury. To determine the role of NADPH oxidase, we pretreated pigs with structurally dissimilar NADPH oxidase inhibitors. Low-dose apocynin (4-hydroxy-3-methoxy-acetophenone; 200 mg/kg, n = 6), high-dose apocynin (400 mg/kg, n = 6), or diphenyleneiodonium (DPI; 8 mg/kg) was compared with diluent (n = 8). An additional group was treated with indomethacin (10 mg/kg, n = 3). CPB was performed for 2 h with deflated lungs, complete pulmonary artery occlusion, and bronchial artery ligation to maximize lung injury. Parameters of pulmonary function were evaluated for 25 min following CPB. Blood chemiluminescence indicated neutrophil ROS production. Electron paramagnetic resonance determined the effect of apocynin and DPI on in vitro pulmonary endothelial ROS production following hypoxia-reoxygenation. Both apocynin and DPI attenuated blood chemiluminescence and post-CPB hypoxemia. At 25 min post-CPB with Fi(O(2)) = 1, arterial Po(2) (Pa(o(2))) averaged 52 +/- 5, 162 +/- 54, 335 +/- 88, and 329 +/- 119 mmHg in control, low-dose apocynin, high-dose apocynin, and DPI-treated groups, respectively (P < 0.01). Indomethacin had no effect. Pa(O(2)) correlated with blood chemiluminescence measured after drug administration before CPB (R = -0.60, P < 0.005). Neither apocynin nor DPI prevented the increased tracheal pressure, plasma cytokine concentrations (tumor necrosis factor-alpha and IL-6), extravascular lung water, and pulmonary vascular protein permeability observed in control pigs. NADPH oxidase inhibition, but not xanthine oxidase inhibition, significantly blocked endothelial ROS generation following hypoxia-reoxygenation (P < 0.05). NADPH oxidase-derived ROS contribute to the severe hypoxemia but not to the increased cytokine generation and pulmonary vascular protein permeability, which occur following CPB.
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PMID:Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. 1527 7

Cultured human THP-1 monocytes were exposed to serial concentrations of gemifloxacin over 4 h after pre-stimulation with zymogen A for 1 h or Staphylococcus aureus for 2 h. The following parameters were assessed: pH, phagocytosis, c-AMP, NO, TNFalpha, IL-1, IL-6, IL-8 and H2O2 levels, enzyme activities of protein kinase C, NADPH oxidase, SOD, gluthathion reductase, NAG and cathepsin D as well as lipid peroxidation. The reversiblity of these changes was determined in the presence of known blockers of the phagocytic process. The effects of gemifloxacin on DNA synthesis and killing of S. aureus was assessed in bacteria alone and in those bacteria phagocytosed by THP-1 monocytes over 24 h. Gemifloxacin in stimulated THP-1 monocytes over the first 30 min caused an increase in c-AMP, NO, H2O2 and TNFalpha levels and protein kinase C, NADPH oxidase, glutathione reductase, NAG and cathepsin D activities. The pH became more acidic and phagocytosis was stimulated. These parameters were reversed at 1 h and continued to decline until 4 h. Lipid peroxidation was at the highest levels at 1 h and IL-8 levels at 2 h. DNA synthesis and bacterial growth were suppressed at 2 h in both S. aureus alone and bacteria phagocytosed by THP-1 monocytes. These effects were at a higher magnitude at 24 h. Gemifloxacin initiates a phagocyticidal effect of THP-1 monocytes at an early time of 30 min which plays a role in killing bacteria but a higher magnitude of killing of bacteria occurs later by a standard static mechanism. This early action of gemifloxacin should decrease the spread of infection and the inflammatory response since the tissue destruction process was attenuated at 4 h.
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PMID:In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes. 1549 55

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
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PMID:Increased oxidative stress in obesity and its impact on metabolic syndrome. 1559

The therapeutic efficacy in the treatment of metastatic cancer with high doses of interleukin-2 (IL-2) has been limited by the onset of vascular leak syndrome (VLS) and related toxicities. VLS is characterized by an increase in vascular permeability and severe hypotension resulting in interstitial edema and organ failure. This study explores the protective effects of histamine dihydrochloride (HDC) against IL-2-induced toxicities in mice. Treatment with HDC administered before or after IL-2 (1.25 x 10(6) IU, BID) was shown to protect mice from VLS-related toxicities and mortality in a dose-dependent manner. Survival rates when HDC was added were 56, 75 and 81% at doses of 0.47, 4.7 and 47.0 mg/kg, respectively, compared to 42% survival with IL-2 alone. HDC protected against IL-2-induced macroscopic pulmonary lesions, reduced edema (up to 62% reduction in lung wet/dry weight ratio) and reduced capillary leakage into the lungs as measured by a reduction in Evans Blue dye content. In addition, the systemic effect on serum cytokine levels showed that HDC only moderately lowered IL-2 induced IFN-gamma, IL-6, IL-10, IL-18 and TNF-alpha. Serum levels of IL-1beta, IL-4 and IL-12 were not measurably induced by IL-2 treatment. HDC modulates many cellular functions including regulating cytokines and blocking immune-suppression caused by reactive oxygen species (ROS) generated by the NADPH oxidase. However, the protective effect of HDC on alleviating IL-2-induced pulmonary edema was not related to ROS inhibition. Our data indicate that HDC treatment improves survival and protects against IL-2 induced VLS independent of ROS regulation in mice.
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PMID:Histamine improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice. 1582 Apr 45


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