Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several murine macrophage genes that exhibit transcriptional response to LPS (e.g., IP-10, D3) have IFN-stimulated response element (ISRE) sequences present in regions flanking the transcription start sites. In the present study, the ability of LPS to activate proteins in murine peritoneal macrophages capable of binding to the ISRE has been investigated. Nuclear extracts from both LPS-treated and untreated macrophages are capable of forming four distinct complexes with a radiolabeled oligonucleotide containing the ISRE sequence as detected by electrophoretic mobility shift assays. LPS-treated nuclei contained an additional ISRE binding activity (complex I) that was not found in unstimulated cells. The induction of the latter activity by LPS was sensitive to polymyxin B sulfate, a lipid A antagonist, demonstrating that LPS was the primary inducing activity. All five retarded protein-DNA complexes formed were specific for the ISRE sequence as shown by competition with a series of oligonucleotides containing either ISRE-related or -unrelated sequences. Complex I binding activity was dependent upon the concentration of LPS and the time of LPS treatment. Furthermore, complex I was similar to that induced in response to treatment with IFN-beta in terms of electrophoretic mobility and specificity for the ISRE. LPS-induced complex I formation was partially independent of protein synthesis and could not be blocked by including neutralizing antibody to IFN-alpha/beta in the culture medium. Thus, even though LPS is a potent inducer of IFN-beta in murine macrophages, class I IFN expression may not be an obligatory intermediate event in the LPS-driven activation of ISRE binding activity. These results suggest that induction of ISRE binding activity may be an important part of the signaling process initiated by LPS.
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PMID:Lipopolysaccharide induces DNA binding activity specific for the IFN-stimulated response element in murine peritoneal macrophages. 152 82

In an analysis of nitric oxide (.NO) production and toxicity, chicken macrophage-generated .NO inhibited mitochondrial activity in both .NO-producing macrophages themselves and lymphoid tumor targets. However, differences in targeting of mitochondrial toxicity were observed among these cells. Two chicken macrophage cell lines, HD11 and MQ-NCSU, produced .NO (measured as nitrite) dependent upon concentrations of L-arginine and bacterial endotoxin (lipopolysaccharide). Mitochondrial activity was negatively correlated with the amount of .NO produced. Using a modified MTT assay, .NO induced suppression in two mitochondrial complexes. Mitochondrial activity was significantly suppressed among HD11 cells receiving LPS alone (complex I, 63.0 +/- 5.5% suppression; complex II, 27.9 +/- 5.2%). In contrast, mitochondrial activities in samples receiving LPS plus inhibitor, NG-nitro-L-arginine methyl ester (NAME; 5 mM) or 2,4-diamino-6-hydroxypyrimidine (DAHP; 5 mM), were not significantly different from control values. When HD11 macrophages were cocultured with lymphoblastoid tumor targets, RECC-CU60 (T cell) or LSCC-RP9 (B cell), adding LPS (1 microgram/ml), tumor cell mitochondrial activity was significantly suppressed. In the generator macrophages, complex I was more suppressed than complex II, whereas in lymphoid targets no such difference was observed. These results indicate that .NO inhibits complex I and II mitochondrial activity but that differential targeting can occur among chicken leukocyte populations.
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PMID:Nitric oxide (.NO)-induced mitochondrial injury among chicken .NO-generating and target leukocytes. 802 70

The human TNF promoter contains four potential nuclear factor-kappa B (NF-kappa B)-binding sites, with the strongest binding seen for the -605 motif. Nuclear extracts from unstimulated cells of the human monocytic cell line, Mono Mac 6, contain one specific binding protein (complex II), consistent with a constitutive p50 homodimer. Stimulation of Mono Mac 6 cells with LPS will increase complex II and will strongly induce a second specific complex (complex I), which represents the p50/65 heterodimer. Treatment of Mono Mac 6 cells with pyrrolidine-dithiocarbamate (PDTC) at 300 microM will block the LPS-induced complex I almost completely and will reduce complex II to the constitutive level. Binding activity of other nuclear factors that recognize the SP-1 and c/EBP motifs of the human TNF promoter is not affected by such treatment. Northern blot analysis demonstrates that PDTC treatment will strongly reduce LPS-induced TNF transcripts. Secreted TNF protein as detected in the Wehi 164S/ActD bioassay and in a sandwich immunoassay was similarly reduced by PDTC. Kinetic analyses show that after LPS stimulation, NF-kappa B will peak at 1 h, TNF transcript prevalence at 2 h, and TNF protein at 4 h. PDTC did not shift this response to LPS to a later time, but suppressed NF-kappa B mobilization, TNF transcripts, and TNF protein over the entire 8-h observation period. Analysis of freshly isolated, LPS-stimulated blood monocytes showed a similar blockade of NF-kappa B. Furthermore, in these primary cells, induction of TNF transcripts, as determined by Northern blot analysis and by quantitative polymerase chain reaction, was prevented by PDTC as was TNF protein production. These data show that dithiocarbamates can profoundly affect cytokine expression and suggest that NF-kappa B is involved in LPS-induced TNF gene expression in human monocytes.
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PMID:Pyrrolidine dithiocarbamate inhibits NF-kappa B mobilization and TNF production in human monocytes. 825 5

The transcription factor NF-kappa B stimulates the transcription of proinflammatory cytokines including TNF-alpha. LPS (endotoxin) and hypoxia both induce NF-kappa B activation and TNF-alpha gene transcription. Furthermore, hypoxia augments LPS induction of TNF-alpha mRNA. Previous reports have indicated that antioxidants abolish NF-kappa B activation in response to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation. This study tested whether mitochondrial ROS are required for both NF-kappaB activation and the increase in TNF-alpha mRNA levels during hypoxia and LPS. Our results indicate that hypoxia (1.5% O2) stimulates NF-kappa B and TNF-alpha gene transcription and increases ROS generation as measured by the oxidant sensitive dye 2',7'-dichlorofluorescein diacetate in murine macrophage J774.1 cells. The antioxidants N-acetylcysteine and pyrrolidinedithiocarbamic acid abolished the hypoxic activation of NF-kappa B, TNF-alpha gene transcription, and increases in ROS levels. Rotenone, an inhibitor of mitochondrial complex I, abolished the increase in ROS signal, the activation of NF-kappa B, and TNF-alpha gene transcription during hypoxia. LPS stimulated NF-kappa B and TNF-alpha gene transcription but not ROS generation in J774.1 cells. Rotenone, pyrrolidinedithiocarbamic acid, and N-acetylcysteine had no effect on the LPS stimulation of NF-kappa B and TNF-alpha gene transcription, indicating that LPS activates NF-kappa B and TNF-alpha gene transcription through a ROS-independent mechanism. These results indicate that mitochondrial ROS are required for the hypoxic activation of NF-kappa B and TNF-alpha gene transcription, but not for the LPS activation of NF-kappa B.
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PMID:Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. 1087 78

The involvement of mitochondrial dysfunction in septic disturbances of tissues is controversial. The aim of this study was to investigate the effects of endotoxin-induced sepsis on the function of heart and skeletal muscle mitochondria. Rabbits were made septic by subcutaneous injection of endotoxin (lipopolysaccharide, LPS) from Escherichia coli at concentrations of 100 or 150 microg LPS.kg(-1) 24 h prior to the experiments. Mitochondrial respiration was measured in saponin-skinned muscle fibers and compared with photometrically detected activities of respiratory chain enzymes as well as with function of perfused hearts. In heart fibers a dosage of 100 microg LPS.kg(-1) caused a significant decrease of state 3-respiration for the substrates pyruvate (-38%), octanoyl-carnitine (-38%) and succinate (-30%) with correspondingly decreased respiratory control indexes (RCI). In addition, endotoxin caused a decreased temporal stability of the rate of state 3-respiration. At least in part these changes can be attributed to a reduced activity of complex I + III (-50%) of the respiratory chain. State 4-respiration rates were not significantly altered. The lowered state 3-respiration in heart mitochondria seems to contribute to the impairment of heart muscle function as detected by an increase of coronary vascular resistance (CVR) in endotoxin-treated hearts. Functional properties of mitochondria from M. Vastus lasteralis were not affected by 100 microg LPS.kg(-1) but a higher dosage of 150 microg LPS.kg(-1) caused decreased RCI for the substrates pyruvate (-29%) and octanoyl-carnitine (-32%). Also the activity of complex I + III was not significantly affected at lower dose of endotoxin but decreased (-42%) after treatment with 150 microg LPS.kg(-1). Results demonstrate the involvement of impaired mitochondria in the pathophysiology of septic organ failure and a tissue specificity of endotoxaemia.
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PMID:Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function. 1123 Dec 95

In LPS-mediated states of sepsis, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production inhibit cellular respiration and mitochondrial electron transport. NO has been demonstrated to inhibit mitochondrial respiration by nitrosylation of the iron-sulfur centers of aconitase, complex I (NADH-ubiquinone oxidoreductase), complex II (succinate-ubiquinone oxidoreductase), and complex IV (cytochrome c oxidase). However, little is known of the effect of NO on expression of critical proteins in the electron transport chain. In ANA-1 murine macrophages, LPS-mediated NO synthesis decreases Cyt b protein expression and steady-state mRNA levels. Mitochondrial run-on analysis demonstrates unaltered Cyt b mitochondrial gene transcription. In this study utilizing LPS-stimulated ANA-1 murine macrophages, we demonstrate that expression of the mitochondrial protein, Cyt b, is significantly decreased as the result of a unique and previously unknown, NO-dependent posttranscriptional regulatory mechanism. (c)2001 Elsevier Science.
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PMID:Nitric oxide inhibits expression of cytochrome B in endotoxin-stimulated murine macrophages. 1174 Dec 89

It is known that nitric oxide (NO) is produced in response to a septic insult such as bacterial invasion and that overproduction of NO can have serious debilitating consequences. The mechanism by which NO causes damage at the cellular level is less clear. We have therefore studied the response to a septic insult in an anaesthetised spontaneously breathing Sprague-Dawley rat model. Six rats were given either an intravenous infusion of bacterial cell wall lipopolysaccharide (LPS, 5 mg/kg) or saline control over 1 hour. For electron paramagnetic resonance (EPR) studies, blood samples were collected every hour for a further two hours and liver tissue samples were collected postmortem. Measurement was also made of PaO2, blood pressure, base deficit, aortic and renal blood flow and hepatic microvascular pO2 (using porphyrin phosphoresence). Tissue samples were also collected for mitochondrial complex activity analysis. After the administration of LPS blood pressure, blood flow and microvascular PO2 were diminished and the base deficit increased. In addition a clear difference was observed by EPR between control and insulted blood and tissue samples. A large heam-nitrosyl signal is observed as well as an increase in the signal at g = 1.94, corresponding to the iron-sulphur centres of complex I becoming more reduced. However, no significant difference was observed for any of the mitochondrial complex activities. The effect of the NO produced was to depress the circulatory variables and increase base deficit, combined with a reduced oxygen consumption this implies an impairment of normal aerobic respiration. This was supported by increased iron-sulphur signals observed by EPR indicating a blockage in the mitochondrial redox chain with the subsequent accumulation of electrons. As no effect was observed in the mitochondrial complex activities this indicates that this inhibition is reversible in early stage sepsis. We conclude that nitric oxide produced in response to a septic insult can inhibit mitochondria causing an impairment of oxygen utilisation by aerobic respiration.
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PMID:Inhibition of mitochondrial respiration during early stage sepsis. 1456 71

We have identified a novel signaling pathway that leads to expression of matrix metalloproteinase-9 (MMP-9) in murine macrophages in response to the bacterial endotoxin, LPS. We showed that p38 kinase was essential for this induction and observed that LPS-induced MMP-9 expression was sensitive to rottlerin, a putative protein kinase Cdelta (PKCdelta) inhibitor. However neither infection with a retrovirus expressing a dominant negative mutant of PKCdelta nor down-regulation of PKCdelta by prolonged PMA treatment affected MMP-9 expression, thus excluding involvement of PKCdelta. Interestingly, LPS-induced MMP-9 expression and p38 kinase phosphorylation were shown to be suppressed by the antioxidant N-acetylcysteine and the flavoenzyme inhibitor diphenyleneiodonium chloride, but not by pyrrolidine dithiocarbamate, an NF-kappaB inhibitor. In addition, LPS was found to induce the production of mitochondrial reactive oxygen species (ROS) and this effect was rottlerin-sensitive, suggesting an inhibitory effect of rottlerin on mitochondrial ROS. LPS-induced MMP-9 expression and p38 kinase phosphorylation were also inhibited by rotenone, a specific inhibitor of mitochondrial complex I, supporting the role of mitochondrial ROS in LPS signaling to MMP-9. Finally, we showed that the ROS-p38 kinase cascade targets the transcription factor AP-1. Taken together, our findings identify a ROS-p38 kinase-AP-1 cascade as a novel pathway mediating LPS signaling to MMP-9 expression in macrophages.
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PMID:Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. 1555 94

Altered cerebral energy metabolism and mitochondrial dysfunction in periphery and in brain are implicated in the pathophysiology of schizophrenia. This study investigated whether cerebral glucose metabolism (rCGM) abnormalities are linked to altered mitochondrial complex I activity in the periphery, in schizophrenia. Sixteen schizophrenic patients, 8 with total positive PANSS score >or=20 (high positive schizophrenics; HPS), and 8 with total positive score <or=12 (low positive schizophrenics; LPS), and 8 healthy subjects, were analyzed for their complex I activity in platelets mitochondria and underwent FDG-PET scans at rest. Complex I activity was significantly increased only in HPS and was positively correlated with positive PANSS scores. Images were spatially normalized to an SPM template, their intensities normalized based on average brain activity. Hypermetabolism was observed in the basal ganglia, thalamus, amygdala, and brainstem of both patient groups compared with controls, and in LPS patients extended to parts of cerebellum, left and right cingulate gyrus, parietal and frontal lobes. rCGM in basal ganglia and thalamus significantly and positively correlated with complex I activity in the HPS. In the LPS, a negative correlation was identified in the cerebellum and brainstem. In the control group, however, no areas demonstrated significant positive or negative correlation. These results suggest that the correlation between peripheral complex I activity and rCGM in regions implicated in schizophrenia, could be a pathological factor that is differentially expressed in subgroups of schizophrenic patients.
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PMID:Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study. 1732

The aims of this work were to study the mitochondrial function and to evaluate (a) the oxidative stress in real time in an acute model of endotoxemia and (b) the effect of alpha-lipoic acid (LA, 100 mg/kg) as a therapeutic strategy to be considered. In rats treated with lipopolisaccharide (LPS, 10 mg/kg), a 1.4-fold increase was observed in in situ skeletal muscle chemiluminescence. Experimental sepsis increased oxygen consumption in tissue cubes (1 mm(3)) by 30% for heart and diaphragm and impaired state 3 mitochondrial respiration rate in the three organs (liver, diaphragm and heart) studied. Only complex I activity in heart and diaphragm and complex IV activity in diaphragm were found impaired in this septic model. The production of NO by submitochondrial membranes was found increased by 80% in the diaphragm and by 35% in the heart of septic rats. The treatment with LA prevented the oxidative stress and mitochondrial dysfunction observed in this model.
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PMID:The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by alpha-lipoic acid. 1905 Oct 79


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