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

Inducible vascular cell adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMC) exposed to lipopolysaccharide (LPS) in vitro involves the activation of nuclear factor-kappa B (NF-kappa B) and its interaction with the proximal VCAM-1 promoter. We used a murine model to assess the effect of the antioxidant, N-acetyl cysteine on GMC activation in vivo. Single intraperitoneal administration of N-acetyl cysteine completely suppressed LPS-induced VCAM-1 expression on the GMC surface. When an oligonucleotide spanning the NF-kappa B binding region of the VCAM-1 promoter was incubated with extracts from the renal cortex of LPS-treated animals, a single nucleoprotein complex formed. This complex was composed of p50 and p65, but not p52, c-Rel, or RelB, and its formation was dramatically inhibited by pretreatment with N-acetyl cysteine, D,L-Buthionine-[S,R]-sulfoximide, a compound that depletes glutathione, augmented VCAM-1 expression inducible with a suboptimal amount of LPS to levels comparable with using 50 micrograms of LPS alone, D,L-Buthionine-[S,R]-sulfoximide also potentiated the p50-p65 binding activity induced with a suboptimal amount of LPS. These data provide a redox-sensitive, transcriptional link between NF-kappa B and VCAM-1 in GMC in vivo and implicate oxidative stress as an important regulatory signal in the pathogenesis of glomerular mesangial cell disorders.
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PMID:N-acetyl cysteine blocks mesangial VCAM-1 and NF-kappa B expression in vivo. 935 47

NF-kappaB is a major transcription factor consisting of 50(p50)- and 65(p65)-kDa proteins that controls the expression of various genes, among which are those encoding cytokines, cell adhesion molecules, and inducible NO synthase (iNOS). After initial activation of NF-kappaB, which involves release and proteolysis of a bound inhibitor, essential cysteine residues are maintained in the active reduced state through the action of thioredoxin and thioredoxin reductase. In the present study, activation of NF-kappaB in human T cells and lung adenocarcinoma cells was induced by recombinant human tumor necrosis factor alpha or bacterial lipopolysaccharide. After lipopolysaccharide activation, nuclear extracts were treated with increasing concentrations of selenite, and the effects on DNA-binding activity of NF-kappaB were examined. Binding of NF-kappaB to nuclear responsive elements was decreased progressively by increasing selenite levels and, at 7 microM selenite, DNA-binding activity was completely inhibited. Selenite inhibition was reversed by addition of a dithiol, DTT. Proportional inhibition of iNOS activity as measured by decreased NO products in the medium (NO2- and NO3-) resulted from selenite addition to cell suspensions. This loss of iNOS activity was due to decreased synthesis of NO synthase protein. Selenium at low essential levels (nM) is required for synthesis of redox active selenoenzymes such as glutathione peroxidases and thioredoxin reductase, but in higher toxic levels (>5-10 microM) selenite can react with essential thiol groups on enzymes to form RS-Se-SR adducts with resultant inhibition of enzyme activity. Inhibition of NF-kappaB activity by selenite is presumed to be the result of adduct formation with the essential thiols of this transcription factor.
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PMID:Inhibition of NF-kappaB DNA binding and nitric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. 937 73

The present experiments were conducted to investigate influences of dietary methionine and cysteine on metabolic responses to immunological stress induced by Escherichia coli lipopolysaccharide (LPS) injection, and concanavalin A (Con A)-induced mononuclear cell (MNC) proliferation in male broiler chickens. In Expt 1, chicks (12 d of age) were fed on a S amino acid (SAA)-deficient diet (5.6 g SAA/kg diet) or on three kinds of SAA-sufficient diet (9.3 g SAA/kg diet; low-, medium- and high-cysteine diets) which contained 2.8, 4.65 and 6.5 g cysteine/kg diet, respectively. Plasma alpha-1 acid glycoprotein (AGP) concentration and interleukin (IL)-1-like activity in chicks fed on the SAA-deficient diet were lower following a single injection of LPS than those in chicks fed on the SAA-sufficient diets. At 16 h after LPS injection, plasma Fe and Zn concentrations and body weight were reduced, but AGP concentration and IL-1-like activity in plasma were significantly increased. These changes in body weight, plasma Zn and Fe concentrations following injection of LPS were not affected by dietary methionine: cysteine ratios. Plasma AGP concentration and IL-1-like activity in chicks fed on the high-cysteine diet were, however, greater than those in chicks fed on the other diets following a single injection of LPS. In Expt 2, chicks (7 d of age) were fed on the SAA-sufficient diets as in Expt 1 for 10 d. MNC proliferation in spleen induced by Con A in chicks fed on the high-cysteine diet was greater than that in chicks fed on the low- or medium-cysteine diet. The results suggest that dietary cysteine has an impact on the immune and inflammatory responses.
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PMID:Influences of dietary methionine and cysteine on metabolic responses to immunological stress by Escherichia coli lipopolysaccharide injection, and mitogenic response in broiler chickens. 938 3

The development of the adult respiratory distress syndrome (ARDS) in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophil-mediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant N-acetyl cysteine (NAC) on a rodent model of lung injury. We postulated that NAC might attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS). Male Sprague-Dawley rats were administered NAC systemically either before or after intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary leakage of 125I-labeled albumin, pulmonary myeloperoxidase content, bronchoalveolar lavage fluid cell counts, pulmonary lipid peroxidation and histology. NAC administration significantly attenuated the LPS-induced increases in lung permeability (LPS: .24 +/- .08 vs. LPS + NAC: .12 +/- .03, p < .05) and reduced the LPS-dependent increase in lipid peroxidation. However, total and differential bronchoalveolar lavage cell counts and myeloperoxidase content were not affected by NAC pretreatment. Although neutrophil influx was unaffected, neutrophil activation as assessed by surface CD11b expression and chemiluminescence was significantly down-regulated by NAC. Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPS-induced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.
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PMID:N-acetyl cysteine attenuates acute lung injury in the rat. 942 57

Interleukin-1 beta (IL-1 beta) is a pleiotropic proinflammatory cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature precursor protein into an active secretory form by the intracellular protease caspase-1 (formerly termed IL-1-converting enzyme [ICE]). Caspase-1 belongs to a rapidly growing family of cysteine proteases with substrate specificity for aspartate involved in cellular apoptosis. We have used an assay determining the caspase-1 activity based on cleavage of a fluorogenic peptide substrate to elucidate its role in lipopolysaccharide (LPS)-induced secretion of IL-1 beta. We show that LPS induces moderate caspase-1 activity in the monocytic cell line THP-1, in freshly isolated peripheral blood monocytes, and in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent fashion. Caspase-1 activation by LPS was associated with cleavage of the IL-1 beta precursor protein that was followed by release of the mature IL-1 beta protein in monocytic cells. In contrast, subsequent release of IL-1 beta by HUVECs was not significant. LPS-induced caspase-1 activation appeared not to result from modulation of caspase-1 transcript accumulation and inhibition of caspase-1 activity was accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable of alleviating the release of mature IL-1 beta. Taken together, these results show that LPS moderately activates caspase-1 and that caspase-1 activation contributes to LPS induction of IL-1 beta secretion.
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PMID:Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. 942 12

Heme oxygenase-1 (HO-1) is a stress-response protein, the expression of which is transcriptionally regulated by agents that cause oxidative stress. We have previously shown that lipopolysaccharide (LPS)-induced HO-1 gene transcription in RAW 264.7 macrophage cells is mediated by a distal enhancer called SX2, located 4 kb upstream from the HO-1 transcription initiation site (Am. J. Respir. Cell Mol. Biol. 1995;13:387-398). We have recently identified a second distal enhancer, called AB1, located 6 kb upstream from the SX2 distal enhancer (J. Biol. Chem. 1995;270:11977-11984). Here we report the extension of our studies to investigate whether the AB1 distal enhancer and/or other potential regulatory elements in the entire 5' distal flanking sequences (11-kb region) of the HO-1 gene may also mediate HO-1 gene transcription in response to LPS. Using deletional analysis, we found that the AB1 enhancer also mediates LPS-induced HO-1 gene transcription. Mutational analysis of the AB1 enhancer and electrophoretic-mobility-shift assays of nuclear extracts from LPS-treated cells further demonstrated that the transcription factor activator protein-1 (AP-1) is critical for AB1-mediated HO-1 gene activation by LPS. We also found increased expression of AP-1 family members c-fos and c-jun by Northern blot analyses after treatment with LPS. Further, we observed that LPS-treated RAW 264.7 cells produced high levels of reactive oxygen intermediates (ROI) as measured through flow-cytometric analysis of dichlorofluoroscein (DCF)-stained cells. Treatment of cells with the antioxidants N-acetyl-L-cysteine (NAC) and dimethyl sulfoxide (DMSO) not only blunts LPS-induced production of ROI, but also significantly attenuates LPS-induced HO-1 messenger RNA (mRNA) expression and gene transcription. Taken together, these data suggest that LPS regulates HO-1 gene transcription in part by inducing the production of ROI, which initiate signal-transduction pathway(s) leading to the activation of AP-1-dependent HO-1 gene transcription.
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PMID:Transcriptional activation of the HO-1 gene by lipopolysaccharide is mediated by 5' distal enhancers: role of reactive oxygen intermediates and AP-1. 947 10

In response to bacterial endotoxin (lipopolysaccharide, LPS) monocytes synthesize and express on their surface tissue factor (TF) which triggers the blood coagulation cascade. Since LPS stimulates active oxygen species production by these cells, we investigated the roles of superoxide anion and nitric oxide in the induction of TF in human blood monocytes. Scavengers of reactive oxygen intermediates such as N-acetyl cysteine or pyrrolidine dithiocarbamate were able to block TF induction. In addition, inhibition of NADPH oxidase and/or NO synthase which are major sources of active oxygen species in phagocytes also blocked TF induction. The restoration of TF expression, in monocytes treated with inhibitors of reactive oxygen production, by N,N'-dimethyl-gamma, gamma'-dipyridylium dichloride and/or sodium nitrosylpentacyanoferrate (III), which generate respectively O2- and NO, suggests that these two radicals participate in the induction of TF at the surface of blood monocytes stimulated by LPS.
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PMID:Role of oxygen radicals in tissue factor induction by endotoxin in blood monocytes. 948 74

Invertebrate animals, which lack adaptive immune systems, have developed defense systems, so-called innate immunity, that respond to common antigens on the surface of potential pathogens. One such defense system is involved in the cellular responses of horseshoe crab hemocytes to invaders. Hemocytes contain two types, large (L) and small (S), of secretory granules, and the contents of these granules are released in response to invading microbes via exocytosis. Recent biochemical and immunological studies on the granular components of L- and S-granules demonstrated that the two types of granules selectively store granule-specific proteins participating in the host defense systems. L-Granules contain all the clotting factors essential for hemolymph coagulation, protease inhibitors including serpins and cystatin, and anti-lipopolysaccharide (LPS) factor and several tachylectins with LPS binding and bacterial agglutinating activities. On the other hand, S-granules contain various new cysteine-rich basic proteins with antimicrobial or bacterial agglutinating activities, such as tachyplesins, big defensin, tachycitin, and tachystatins. The co-localization of these proteins in the granules and their release into the hemolymph suggest that they serve synergistically to construct an effective host defense system against invaders. Here, the structures and functions of these new types of defense molecules found in the Japanese horseshoe crab (Tachypleus tridentatus) are reviewed.
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PMID:New types of clotting factors and defense molecules found in horseshoe crab hemolymph: their structures and functions. 950 2

Tumor necrosis factor alpha (TNFalpha) is synthesized as a transmembrane precursor form that is proteolytically processed and released as the soluble mature form. In human monocytes and monocytic cell lines, the production, processing, and release of TNFalpha are co-induced by certain activators, such as lipopolysaccharide. To investigate the mechanism of TNFalpha processing and release, we established a cell line which constitutively produced TNFalpha, by transfecting the TNFalpha precursor form cDNA into NIH/3T3 cells. In these cells, the processing and release of TNFalpha were augmented by phorbol 12-myristate 13-acetate (PMA), mediated through a protein kinase C (PKC) signalling pathway. Various protease inhibitors were tested and it was found that matrix metalloproteinase (MMP) inhibitors blocked the processing and release of TNFalpha both in the absence and presence of PMA. This result is compatible with the recent reports that MMP are involved in the processing and release of TNFalpha. In contrast, 3,4-dichloroisocoumarin, N alpha-p-tosyl-L-phenylalanine chloromethane, iodoacetamide, and o-phenanthroline inhibited the processing and release of TNFalpha only in the presence of PMA, suggesting that serine proteases requiring SH for their activity, a combination of serine proteases and cysteine proteases, or MMP, may be involved in the PKC-mediated induction of TNFalpha processing and release.
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PMID:Processing and release of tumor necrosis factor alpha. 965 52

An optical method based on the oxygen-dependent quenching of a phosphorescent probe (palladium-porphyrin) was used to investigate the effect of bacterial endotoxin [lipopolysaccharide (LPS)] on oxygen consumption (VO2) by vascular cells. Endothelial (EC) and smooth muscle (SMC) cells from pig aorta were suspended in culture medium in the presence of palladium-porphyrin and transferred to glass capillary tubes that were sealed to create a hypoxic environment. Measured PO2 changed as a function of time in a highly predictable fashion when cell suspensions were exposed to agents or treatment known to affect cellular metabolism. Both EC and SMC showed a significant decrease in VO2 as cell density increased, and SMC VO2 was significantly higher than EC (1.94 +/- 0.09 vs. 1.0 +/- 0.15 nmol . min-1 . 10(6) cells-1). Exposure to LPS (1 microg/ml) caused a decrease in VO2 of 46% and 15% for EC and SMC, respectively. Pretreatment of cells with N-acetyl-L-cysteine, a substrate for glutathione synthesis with antioxidant properties, restored VO2 to normal values after exposure to LPS. These data suggest that endotoxin impairs VO2 in cells derived from the vascular wall and indicate the importance of EC and SMC respiration in maintaining vascular homeostasis under conditions of sepsis.
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PMID:Depression of endothelial and smooth muscle cell oxygen consumption by endotoxin. 972 79


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