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 aim of this study was to verify the hypothesis that beta-carotene may prevent 7-ketocholesterol (7-KC)-induced apoptosis in human macrophages. Therefore, THP-1 macrophages were exposed to 7-KC (5-50 microM) alone and in combination with beta-carotene (0.25-1 microM). 7-KC inhibited the growth of macrophages in a dose- and a time-dependent manner by inducing an arrest of cell cycle progression in the G0/G1 phase and apoptosis. Concomitantly, p53, p21, and Bax expressions were increased by 7-KC, whereas the levels of AKT, Bcl-2, and Bcl-xL were decreased. beta-Carotene prevented the growth-inhibitory effects of 7-KC in a dose- and time-dependent manner as well as the effects of 7-KC on the expression of cell cycle- and apoptosis-related proteins. 7-KC also enhanced reactive oxygen species (ROS) production through an increased expression of NAD(P)H oxidase (NOX-4). The effects of 7-KC were counteracted by the addition of the NAD(P)H oxidase inhibitor DPI or by cotransfection of siNOX-4 mRNA. beta-Carotene prevented 7-KC-induced increase in ROS production and in NOX-4 expression, as well as the phosphorylation of p38, JNK, and ERK1/2 induced by 7-KC. These data suggest a possible antiatherogenic role of beta-carotene through the prevention of 7-KC toxicity in human macrophages.
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PMID:Redox regulation of 7-ketocholesterol-induced apoptosis by beta-carotene in human macrophages. 2537 21

We investigated the effects of the 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) on the NADPH oxidase activity, gp91(phox) gene expression, cyclic guanosine-3',5'-monophosphate (cGMP) and cyclic adenosine-3',5'-monophosphate (cAMP) levels in the human myelomonocytic THP-1 cell line. THP-1 cells treated with BAY 41-2272 (0.3-10 microM) for 48 h significantly increased the superoxide anion (O(2)(*-)) release. This increase was not affected when cells were pre-treated with the specific cGMP-phosphodiesterase inhibitor zaprinast, the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (ODQ), the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl) adenine (SQ 22,536) or the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). In addition, BAY 41-2272 (3 and 10 microM; 48 h) was able to increase gp91(phox) gene expression on THP-1 cells. The pre-treatment with zaprinast, 3-isobutyl-l-methyl-xanthine (IBMX; 0.5 mM), ODQ, SQ 22,536 or l-NAME caused no additional effect on the expression of gp91(phox) evoked by BAY 41-2272. Treatment of THP-1 cells with BAY 41-2272 caused a significant increase in cGMP and cAMP levels. Our findings show that BAY 41-2272 caused a significant increase on the O(2)(*-) release and gp91(phox) gene expression by THP-1 cells, and an elevation of intracellular cGMP and cAMP levels. However, we could not detect a clear correlation between both O(2)(*-) release and gp91(phox) gene expression with activation of cGMP and cAMP signaling pathways.
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PMID:Effects of BAY 41-2272, an activator of nitric oxide-independent site of soluble guanylate cyclase, on human NADPH oxidase system from THP-1 cells. 1749 38

Clinical use of human immunodeficiency virus protease inhibitors such as ritonavir may be associated with cardiovascular disease. The objective of this study was to determine the effects and molecular mechanisms of ritonavir on cholesterol efflux from human macrophage-derived foam cells, which is a critical factor of atherogenesis. Human THP-1 monocytes and peripheral blood mononuclear cells were preincubated with acetylated low-density lipoprotein and [(3)H]cholesterol to form foam cells, which were then treated with apolipoprotein A-I for cholesterol efflux assay. A clinically relevant concentration of ritonavir (15 mumol/L) significantly reduced cholesterol efflux from THP-1 and peripheral blood mononuclear cells to apolipoprotein A-I by 30 and 29%, respectively, as compared with controls. In addition, ritonavir significantly decreased the expression of scavenger receptor B1 and caveolin-1, whereas it significantly increased superoxide anion production and activated extracellular signal-regulated kinase (ERK) 1/2 in macrophages. Mitochondrial membrane potential was significantly reduced, whereas NADPH oxidase subunits were increased in ritonavir-treated macrophages. Consequently, the antioxidant seleno-l-methionine, the specific ERK1/2 inhibitor PD98059, or infection of a recombinant adenovirus encoding the dominant-negative form of ERK2 effectively blocked ritonavir-induced decrease of cholesterol efflux. Therefore, human immunodeficiency virus protease inhibitor ritonavir significantly inhibits cholesterol efflux from macrophages, which may be mediated by mitochondrial dysfunction, oxidative stress, ERK1/2 activation, and down-regulation of scavenger receptor B1 and caveolin-1.
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PMID:Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. 1787 77

Toll-like receptor 4 (TLR4) is required for recognition of lipopolysaccharide (LPS) of Gram-negative bacteria and induction of the innate immune response to them. Nevertheless, the involvement of some crucial pathways in TLR4 signalling is poorly understood. Here, we report that LPS-induced TLR4 signalling triggers cross talk of HIF-1alpha and ASK1 in THP-1 human myeloid monocytic leukaemia cells. Both pathways are activated via redox-dependent mechanism associated with tyrosine kinase/phospholipase C-1gamma-mediated activation of protein kinase C alpha/beta, which are known to activate NADPH oxidase and the production of reactive oxygen species that activate both HIF-1alpha and ASK1. ASK1 contributes to the stabilisation of HIF-1alpha, most likely via activation of p38 MAP kinase.
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PMID:LPS-induced Toll-like receptor 4 signalling triggers cross-talk of apoptosis signal-regulating kinase 1 (ASK1) and HIF-1alpha protein. 1815 67

A prominent feature of various inflamed and diseased tissue is the presence of low oxygen tension (hypoxia). Effector cells of the innate immune system must maintain their viability and physiologic functions in a hypoxic microenvironment. Monocytes circulating in the bloodstream differentiate into macrophages. During this process, cells acquire the ability to exert effects at hypoxic sites of inflammation. The transcription factor hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability. In this study, we demonstrated that lipopolysaccharide (LPS) induces HIF-1 activation by enhancing both HIF-1alpha protein expression through a translation-dependent pathway and HIF-1alpha transcriptional activity in THP-1 human myeloid cells that have undergone macrophage differentiation but not in undifferentiated monocytic THP-1 cells. LPS-induced HIF-1 activation was blocked by treatment with antioxidant (N-acetylcysteine or thioredoxin-1), NADPH oxidase inhibitor (diphenyleneiodonium), indicating that reactive oxygen species generated in response to LPS are essential in this process. LPS-mediated activation of HIF-1 was independent of NF-kappaB activity. LPS-induced ROS generation and HIF-1 activation required the expression of Toll-like receptor 4 or myeloid differentiation factor (MyD) 88, thus providing a molecular basis for the selective activation of HIF-1 in differentiated THP-1 cells.
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PMID:LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner. 1819 3

Oxidative stress is commonly observed in the elderly and could be involved in age-related diseases. However, the determinants of superoxide anion overproduction are not clearly understood. Superoxide anion production was evaluated using a lucigenin-based chemiluminescence method in 478 elderly subjects (304 women, 174 men; 79.5+/-7.1 years). Homocysteine (HCy) metabolism (homocysteinemia, vitamin B12, plasma, and erythrocyte folates), inflammation (CRP, fibrinogen, alpha-1 acid glycoprotein), lipid parameters (total cholesterol, triglycerides, HDL and LDL cholesterol), and nutritional parameters (albumin, transthyretin) were determined. The results show that HCy levels (p<0.001) and superoxide anion production (p=0.04) increase with aging, but CRP does not. Highest HCy (>20 microM) (OR 1.83 (1.09-3.07), p=0.02) and CRP over 5 mg/L (adjusted OR 2.01 (1.15-3.51), p=0.01) are the main determinants in superoxide anion production in the elderly. These clinical data are confirmed in an in vitro study using THP-1 monocyte-like cells. Incubation with HCy thiolactone (HTL) (0-200 microM) and LPS (0-20 ng/ml) dramatically enhances NADPH oxidase expression and activation. Moreover, a synergic action was evidenced for low concentrations of HTL (20 microM) and LPS (5 ng). Taken together, the clinical data and in vitro experiments support the hypothesis that moderate homocysteinemia and low-grade inflammation synergically enhance NADPH oxidase activity in the elderly.
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PMID:Homocysteine and inflammation as main determinants of oxidative stress in the elderly. 1908 60

To determine whether macrophage differentiation involves increased uptake of vitamin C, or ascorbic acid, we assessed the expression and function of its transporter SVCT2 during phorbol ester-induced differentiation of human-derived THP-1 monocytes. Induction of THP-1 monocyte differentiation by phorbol 12-myristate 13-acetate (PMA) markedly increased SVCT2 mRNA, protein, and function. When ascorbate was present during PMA-induced differentiation, the increase in SVCT2 protein expression was inhibited, but differentiation was enhanced. PMA-induced SVCT2 protein expression was blocked by inhibitors of protein kinase C (PKC), with most of the affect due to the PKCbetaI and betaII isoforms. Activation of MEK/ERK was sustained up to 48 h after PMA treatment, and the inhibitors completely blocked PMA-stimulated SVCT2 protein expression, indicating an exclusive role for the classical MAP kinase pathway. However, inhibitors of NF-kappaB activation, NADPH oxidase inhibitors, and several antioxidants also partially prevented SVCT2 induction, suggesting diverse distal routes for control of SVCT2 transcription. Both known promoters for the SVCT2 were involved in these effects. In conclusion, PMA-induced monocyte-macrophage differentiation is enhanced by ascorbate and associated with increased expression and function of the SVCT2 protein through a pathway involving sustained activation of PKCbetaI/II, MAP kinase, NADPH oxidase, and NF-kappaB.
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PMID:Macrophage differentiation increases expression of the ascorbate transporter (SVCT2). 1923 38

Macrophage phagocytosis activates NADPH oxidase, an electron transport system in the plasma membrane. This study examined the feasibility of utilizing electrons transferred through the plasma membrane via NADPH oxidase to run a biofuel cell. THP-1 human monocytic cells were chemically stimulated to differentiate into macrophages. Further they were activated to induce a phagocytic response. During differentiation, cells became adherent to a plain gold electrode which was used as anode in a two-compartment fuel cell system. The current production in the fuel cell always corresponded to the NADPH oxidase activity, which was evaluated by the amount of superoxide anion produced upon stimulation in combination with the expression levels of the different NADPH oxidase subunits in cells. Moreover, our results of different inhibitory tests let us conclude that (i) the current observed in the fuel cell originates from NADPH oxidase in activated macrophages and (ii) there are multiple electron transport pathways from the cells to the electrode. One pathway involves superoxide anions produced upon stimulation, additional not yet identified electron transport occurs independently of superoxide anions.This type of novel biofuel cell driven by living human cells may eventually develop into a battery replacement for small medical devices.
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PMID:A novel biofuel cell harvesting energy from activated human macrophages. 1957 54

We previously reported that HIV protease inhibitor, ritonavir, could inhibit cholesterol efflux and induce endothelial dysfunction. In this study, we further determined the effects and molecular mechanisms of a clinically relevant combination of highly active antiretroviral therapy (HAART) drugs on in vitro cholesterol efflux from human macrophage-derived foam cells. Foam cells derived from human monocyte cell line (THP-1) and periphery blood mononuclear cells (PBMCs) treated with HAART drugs including stavudine, didanosine and indinavir individually or in combination of three drugs (3-plex), followed by the initiation of cholesterol efflux with apolipoprotein A-I (apoA-I). Clinically relevant concentrations of HAART 3-plex significantly reduced cholesterol efflux in foam cells derived from THP-1 and PBMCs. HAART 3-plex significantly reduced the intracellular cholesterol transport molecule caveolin-1, whereas it increased superoxide anion production in THP-1 foam cells as compared with controls. Furthermore, mitochondrial membrane potential was significantly reduced, whereas the expression of NADPH oxidase subunit p67(phox) was increased in HAART 3-plex-treated macrophages. Consequently, antioxidants including ginsenosides Rb1 and Rg1, S-allyl cysteine sulphoxide (SACS), simvastatin (SVT) and vitamin E significantly abolished HAART 3-plex-induced inhibition of cholesterol efflux. Therefore, HAART drugs significantly inhibit cholesterol efflux from human macrophage-derived foam cells through downregulation of caveolin-1 and increase of oxidative stress.
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PMID:Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells. 1977 Aug 38

Chronic alcohol consumption leads to inflammation and cirrhosis of the liver. In this study, we observed that liver sinusoidal endothelial cells (LSEC) derived from ethanol-fed rats showed several fold increases in the mRNA expression of endothelin-1 (ET-1), hypoxia-inducible factor-1alpha (HIF-1alpha), and inflammatory cytochemokines compared with control rat LSEC. We also observed the same results in acute ethanol-treated LSEC from control rats and human dermal microvascular endothelial cells. Ethanol-mediated ET-1 expression involved NADPH oxidase and HIF-1alpha activation. Furthermore, ethanol increased the expression of the ET-1 cognate receptor ET-BR in Kupffer cells and THP-1 monocytic cells, which also involved HIF-1alpha activation. Promoter analysis and chromatin immunoprecipitation showed that hypoxia response element sites in the proximal promoter of ET-1 and ET-BR were required for the binding of HIF-1alpha to up-regulate their expression. We showed that microRNAs, miR-199 among several microRNAs, attenuated HIF-1alpha and ET-1 expression, while anti-miR-199 reversed the effects, suggesting that ethanol-induced miR-199 down-regulation may contribute to augmented HIF-1alpha and ET-1 expression. Our studies, for the first time to our knowledge, show that ethanol-mediated ET-1 and ET-BR expression involve HIF-1alpha, independent of hypoxia. Additionally, ethanol-induced ET-1 expression in rat LSEC is regulated by miR-199, while in human endothelial cells, ET-1 expression is regulated by miR-199 and miR-155, indicating that these microRNAs may function as novel negative regulators to control ET-1 transcription and, thus, homeostatic levels of ET-1 to maintain microcirculatory tone.
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PMID:Ethanol-induced expression of ET-1 and ET-BR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199. 1978 78


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