Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Subversion of mitochondrial electron transport to the production of O2.- has been proposed as a mechanism of tumor necrosis factor (TNF)-mediated cell killing and to a lesser extent interleukin-1 (IL-1) and lipopolysaccharide (LPS) cytotoxicity. We utilized the O2.- -sensitive aconitases to measure changes in steady-state 02.- levels in the mitochondrial matrix and cytoplasm of cultured mammalian cells in response to these inflammatory mediators. TNF alpha did not measurably affect aconitase activity, and thus mitochondrial 02.- production, in either cultured human A549 cells or murine L929 cells while TNF alpha clearly caused cytotoxicity as revealed by impaired mitochondrial respiration. IL-1 alpha and Escherichia coli LPS also failed to affect the aconitase activity in A549 cells. Neither the O2.- scavenger Mn(III) TMPyP nor the H2O2 scavenger catalase protected L929 cells against the cytotoxicity of TNF alpha. In conclusion, TNF, IL-1, and LPS do not appear to exert cytotoxicity, or MnSOD gene induction effects, by eliciting mitochondrial O2.- production.
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PMID:Failure of tumor necrosis factor and interleukin-1 to elicit superoxide production in the mitochondrial matrices of mammalian cells. 883 51

Reactive oxygen species (ROS) are mediators of cellular injury and play a putative role in the onset of hepatic damage during endotoxemia or sepsis. It has been suggested that induction of glucose-6-phosphate (G-6-P) dehydrogenase, the key enzyme of the hexose monophosphate shunt (HMS), may support ROS-producing or ROS-eliminating pathways in hepatic endothelial and Kupffer cells during endotoxemia. The aim of the study was to assess in vivo lipopolysaccharide (LPS)-induced alterations in rat gene expression of selected enzymes that are in functional relationship with the HMS. mRNA levels and activities of glucose transporter GLUT-1, Mn- and CuZn-dependent superoxide dismutases (Mn-SOD and CuZn-SOD), and Se-dependent glutathione peroxidase (Se-GPX) were determined. Cellular extracts were analyzed 7 or 22 h after injection of LPS (Escherichia coli, 2 mg/kg ip) or injection of saline. Exposure to LPS for 7 or 22 h caused a 10- to 25-fold increase in GLUT-1 mRNA levels in endothelial and Kupffer cells. In parenchymal cells, GLUT-1 mRNA expression was low, and LPS caused no marked changes. Cellular levels of Mn-SOD mRNA were 20-40 times greater in all hepatic cells from LPS-treated animals than in cells from control rats. LPS at 22 h increased Mn-SOD activity by 45% in endothelial cells but caused no significant changes in Kupffer or parenchymal cells. Message levels and enzyme activities of CuZn-SOD and Se-GPX were significantly elevated 22 h after LPS injection in endothelial cells only. Thus LPS results in marked upregulation of functionally related genes in hepatic cells. In endothelial cells, the simultaneous upregulation of GLUT-1, G-6-P dehydrogenase, Mn-SOD, CuZn-SOD, and Se-GPX may represent an important mechanism for accelerated elimination of ROS released from activated sinusoidal phagocytes. In Kupffer cells, upregulated GLUT-1 and G-6-P dehydrogenase, together with constitutively present SOD and lack of upregulated Se-GPX, suggest an elevated capacity to produce O2- and H2O2 that is consistent with primed bacterial killing.
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PMID:Endotoxin stimulates gene expression of ROS-eliminating pathways in rat hepatic endothelial and Kupffer cells. 892 96

Interleukin-10 (IL-10) has been reported to be a negative cytokine for monocytes/macrophages. In the present study, we showed that IL-10 is rather a positive cytokine and augments the growth and differentiation of human monocytes stimulated with macrophage colony-stimulating factor (M-CSF). Highly purified adherent human monocytes were cultured for 7 days with M-CSF in the presence or absence of IL-10. The number of recovered cells increased in the culture of monocytes with M-CSF + IL-10 compared to the culture with M-CSF alone. IL-10 alone was not enough to maintain the survival and differentiation of monocytes into macrophages. Morphological change cultured in M-CSF was also accelerated by addition of IL-10, and macrophages cultured in M-CSF + IL-10 were more elongated compared to macrophages cultured with M-CSF alone. Binding of 125I-M-CSF to monocytes incubated with M-CSF + IL-10 was about 1.7-fold higher than that to monocytes incubated with M-CSF alone. In accordance with the binding study, Northern blot analysis showed that the levels of the expression of c-fms, M-CSF receptor, mRNA in macrophages cultured in M-CSF + IL-10 were higher than that in macrophages cultured in M-CSF alone. Macrophages cultured in M-CSF + IL-10 expressed higher level of Fc gamma RI, II, III, and showed augmented Fc gamma receptor mediated phagocytosis. The former also produced higher level of H2O2 and O2-, when stimulated with zymosan, and of IL-6 when stimulated with lipopolysaccharide compared to the latter. These results taken together suggest that IL-10 augments the growth and differentiation of human monocytes cultured in M-CSF.
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PMID:Enhancement of macrophage colony-stimulating factor-induced growth and differentiation of human monocytes by interleukin-10. 897 7

This study examines the effects of chronic alcohol consumption on thymic apoptosis with or without pretreatment with E. coli lipopolysaccharide (LPS). Apoptotic cell death of thymocytes was monitored by DNA fragments in gel electrophoresis and the appearance of apoptotic cells by flow cytometry. Changes in mitochondrial membrane potential (MMP), as indicated by 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] uptake, and hydrogen peroxide (H2O2) production as indicated by oxidation of 2',7'-dichlorofluresin diacetate (DCFH-DA), were used to assess altered mitochondrial function. Glutathione levels were also determined to obtain information concerning alterations in the antioxidant potential in the cells. Male Sprague-Dawley rats, fed a nutritionally adequate liquid diet for 8-9 weeks, were divided in four groups: 1) saline-injected, diet controls; 2) LPS-injected, diet controls; 3) saline-injected, alcohol-consuming; and 4) LPS-injected, alcohol-consuming animals. LPS (0.5 mg/kg in 4 ml saline) or saline (4 ml) was continuously infused i.v. for 12 h before the experiments. The results showed that the weight and cell numbers of thymus from the chronic alcoholic rats were significantly less than values found in diet controls. Administration of LPS aggravated thymic apoptosis, as indicated by the presence of significant DNA fragments in gel electrophoresis and increased rate of apoptotic cells in flow cytometry. The alcohol-induced apoptotic changes were also accompanied by decreased MMP, indicating impaired mitochondrial function. Although H2O2 production by the total thymocyte population did not show marked changes among the experimental groups, the subpopulation of thymocytes exhibiting low H2O2 production was increased markedly in the LPS-treated groups. Ethanol consumption or LPS treatment decreased total glutathione concentration in the thymocytes. In summary, 1) chronic administration of alcohol induces atrophy of the thymus gland; 2) apoptosis is a major factor in thymic atrophy under these conditions; 3) chronic alcohol consumption is accompanied by alterations in mitochondrial function of the thymocytes, as indicated by decreased MMP and an increase in the low H2O2-producing cell subpopulation; 4) chronic alcohol abuse may impair intracellular defense mechanisms as reflected by the depletion of the intracellular antioxidant, glutathione; and 5) administration of LPS further enhances thymic apoptosis in chronic alcohol-consuming rats, suggesting that the dual insults of infection and chronic alcoholism exaggerate in vivo immunosuppression.
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PMID:Alcohol-induced thymocyte apoptosis is accompanied by impaired mitochondrial function. 901 30

Since the early work of Mischell & Dutton (Science 153, 1004-1008, 1966), it has been recognized that certain lymphocyte cultures are exquisitely sensitive to the harsh effects of atmospheric oxygen tension. The influence of oxygen partial pressure (pO2) on normal human peripheral blood mononuclear cell (PBMC) phenotype, proliferative ability, cytokine, immunoglobulin production, and redox status was examined by culturing PBMC under ambient oxygen (high pO2) or a more physiological pO2 (5% O2; low pO2). Low pO2 conditions promoted a significant increase in overall viable PBMC number and enhanced Concanavalin A (Con A)- or pokeweed mitogen (PWM)-stimulated PBMC proliferation by approximately 30% and 50%, respectively. No differential pO2 effects were apparent on phytohemagglutinin (PHA)- or staphylococcal enterotoxin B (SEB)-induced proliferation. Both resting and Con A-stimulated lymphocytes incubated for 24 h under high pO2 had a greater baseline carboxy-2',7'-dichlorofluorescin (C-DCF) fluorescence, and were less able to quench the effect of H2O2 treatment compared to lymphocytes cultured under low pO2 conditions. Supernatant gamma-IFN, IL-2, and IL-4 concentrations were elevated 50-65% when PBMC were stimulated with Con A for 24 h under low pO2; however, lipopolysaccharide (LPS)-stimulated IL-1 beta production was reduced by over 75%. PWM-stimulated IgM production by PBMC was significantly reduced in day 7 cultures incubated under low pO2, whereas IgG and IgA production remained relatively unaltered. Immunophenotyping analyses did not reveal any significant alterations in cell subset or marker distribution at the time points examined; however, an interesting trend of increased CD69 expression was observed for Con A-stimulated PBMC incubated under low pO2. These results demonstrate that O2 is a critical parameter for the in vitro culture of lymphocytes, and suggests that varying pO2 may differentially alter PBMC functionality.
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PMID:Differential in vitro effects of physiological and atmospheric oxygen tension on normal human peripheral blood mononuclear cell proliferation, cytokine and immunoglobulin production. 908 Feb 48

We previously reported cDNA cloning of a novel oxidative stress protein termed A170 from murine macrophages. Further experiments have demonstrated that exposure of the cells to low levels of H2O2 produced by glucose/glucose oxidase markedly induced the 60-kDa A170 protein. This result suggests that the level of A170 protein can also be controlled at posttranscriptional levels, because we showed previously that H2O2 hardly increased the level of A170 mRNA. We have found that proteasome inhibitors markedly induced the A170 protein after 2 to 8 h similarly to glucose/glucose oxidase, suggesting rapid degradation of the A170 protein by proteasome under normal conditions. Activation of cellular signaling pathways either by epidermal growth factor, lipopolysaccharide or tumor necrosis factor-alpha did not enhance the level of the A170 protein. The levels of glucose oxidase-induced A170 protein did not decrease after the addition of cycloheximide. These results suggest that low levels of H2O2 may stabilize the A170 protein, allowing it to accumulate within cells.
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PMID:Low micromolar levels of hydrogen peroxide and proteasome inhibitors induce the 60-kDa A170 stress protein in murine peritoneal macrophages. 912 46

Hypertension is a known risk factor for the development of atherosclerosis, which is characterized by the abnormal accumulation of low-density lipoprotein and other plasma-borne macromolecules. The goal of this study was to measure accumulation of a plasma-borne macromolecular marker, horseradish peroxidase (HRP; 44 kDa), in the aortic intima and media of chronically hypertensive rats. HRP transport in 2-yr-old spontaneously hypertensive rats (SHR) was compared with that in age-matched Wistar-Kyoto rats (WKY) under conditions in which blood pressures were not significantly different during the 15-min HRP circulation. Intimal accumulation and medial HRP concentration profiles were obtained from methacrylate-embedded sections after reaction with 3,3'-diaminobenzidine and H2O2. Data were analyzed using a mathematical model of macromolecular transport to quantify the permeabilities of endothelium and internal elastic lamina (IEL). Chronic hypertension increased endothelial permeability without a change in IEL permeability. An apparent convective flux of HRP into the intima of SHR raised intimal HRP to a concentration higher than that of HRP in the plasma. Our results suggest that the intimal accumulation of plasma-borne macromolecules from pressure-driven convection is normally minimized by an intact endothelium. Similar changes resulted from acute injury by lipopolysaccharide, suggesting endothelial injury could account for transport changes associated with hypertension. After either chronic or acute endothelial damage, transport of macromolecules into the intima increases, but the IEL continues to retard transport of macromolecules beyond the intima, resulting in increased intimal accumulation.
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PMID:Macromolecular transport in the arterial intima: comparison of chronic and acute injuries. 913 37

Polymorphonuclear cells kill microorganisms by the stock of antibiotic proteins and peptides stored in their lysosomal granules and have the ability to produce reactive oxygen intermediates (ROI) such as H2O2, O2-, and HOCl. Since the components involved in the microbicidal functions of buffalo (Bos bubalis) polymorphonuclear cells (PMN) have not been characterized, an assessment was made of the levels of various enzymes, the extent of extracellular release of these enzymes, and also their ability to produce H2O2/O2- upon activation with opsonized zymosan (OZ) or lipopolysaccharide (LPS). Using GPC-HPLC, OZ was shown to be a more potent secretagogue than LPS, causing a significantly greater release of low-molecular-weight components. Varying levels of the enzymes (myeloperoxidase, lactate dehydrogenase, acid and alkaline phosphatases, beta-galactosidase, beta-D-glucuronidase, elastase and lysozyme) were recorded in the buffalo PMN and both the activators (OZ and LPS) caused significant release of all the enzymes except alkaline phosphatase. Both the activators also caused a significant increase in H2O2/O2- production by the PMN. However, OZ caused a more pronounced activation than LPS. The studies revealed the presence of oxygen-dependent and oxygen-independent microbicidal systems with buffalo PMN, which responded more effectively to zymosan activation.
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PMID:The effect of activation of granulocytes on enzyme release and hydrogen peroxide and superoxide production in buffaloes. 915 8

Many alterations with aging occur at the cellular and organic levels in the immune system ultimately leading to a decrease in the immune response. Our aim in the present work was to study apoptosis of polymorphonuclear granulocytes (PMN) with aging under various stimulations since apoptosis might play an important role in several pathologies encountered with aging. The PMN of healthy young (20-25 years) and elderly (65-85 years) subjects were examined after 24 h of sterile culture with and without stimulation. The stimulating agents included: phorbol myristate acetate (PMA), hydrogen peroxide (H2O2), N-formyl-methionyl-leucyl phenylalanine (FMLP), granulocyte-macrophage colony stimulating factor (GM-CSF), reduced glutathione (GSH), lipopolysaccharide (LPS) and interleukin 2 (IL-2). Apoptosis was assessed by traditional staining of the plates, by flow cytometric staining and DNA gel electrophoresis. It was found that without stimulation the susceptibility of PMN to apoptosis was slightly increased with aging. Under various stimulations, such as PMA. H2O2, apoptosis was almost 100%, while the treatment by FMLP, oxLDL and GSH did not change its extent in PMN obtained either from young or elderly subjects. Marked age-related changes were observed in the extent of apoptosis under stimulation with GM-CSF, IL-2 and LPS. These agents were able to significantly prevent apoptosis in PMN of young subjects, while only the GM-CSF was able to slightly modulate it in neutrophils of elderly subjects. From these results, we suggest that changes in apoptosis of PMN with aging could play a role in the increased incidence of certain immune system related pathologies of aging, such as cancer, infections and autoimmune disorders.
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PMID:Changes in apoptosis of human polymorphonuclear granulocytes with aging. 922 8

Western blot analysis of conditioned media from hepatocytes exposed to H2O2 revealed that a 28 kDa protein was released dose-dependently in response to 1-10 mM H2O2. The 28 kDa protein was present in freshly isolated hepatocytes and exhibited cross-reactivity towards an antibody against CINC/gro. The intracellular amount of the protein decreased in parallel to the H2O2-induced release into the medium. The CINC-related protein was absent in media harvested after 1 h of treatment. The delivery of CINC-related protein correlated with the extent of cell damage as judged from lactate dehydrogenase leakage. Likewise, exposure of hepatocytes to 10-50 mM acetaminophen resulted in a dose-dependent release of the CINC-related protein after 24 h of culture. In contrast, monomeric CINC (molecular weight approximately 6.5 kDa) but not the 28 kDa CINC-related protein was released by lipopolysaccharide (LPS)-stimulated Kupffer cells. The amount of monomeric CINC liberated by Kupffer cells was diminished upon acetaminophen-treatment. Also, the release of tumor necrosis factor-alpha by hepatocytes was reduced after exposure to high acetaminophen doses (40-50 mM). In contrast to this finding, TNF-alpha release from hepatocyte cultures was not affected after H2O2 treatment. These data suggest that damaged hepatocytes release proinflammatory cytokines which may aggravate liver injury through activation of neutrophils and monocytes. The results indicate that the appearance of the CINC-related protein is due to impairment of plasma membrane integrity as the consequence of massive cell damage. In addition, APAP inhibited the release of monomeric CINC from LPS-activated Kupffer cells and of TNF-alpha from hepatocytes even at concentrations that were not sufficient to affect cell viability.
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PMID:Influence of acetaminophen treatment and hydrogen peroxide treatment on the release of a CINC-related protein and TNF-alpha from rat hepatocyte cultures. 923 Apr 44


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