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)

One mechanism by which chemicals cause cellular injury is the formation of reactive oxygen species. In vitro studies have shown that metallothionein (MT), a small metal-binding, sulfhydryl-rich, readily inducible protein, can scavenge reactive oxygen species, especially hydroxyl radicals. Nevertheless, whether or not MT protects against oxidative stress in the intact animal is not known. Experimental induction of MT could help to clarify this question, however, it is unclear whether agents that induce MT also influence known antioxidant systems. Therefore, the present study was designed to determine whether the well-known MT inducers are specific for induction of MT or whether they might also influence other hepatic systems that protect against oxidative stress. Male rats were administered cadmium chloride (Cd; 30 mumol/kg, s.c.), zinc chloride (Zn; 1000 mumol/kg, s.c.), alpha-hederin (alpha-H, 30 mumol/kg, s.c.) or lipopolysaccharide (LPS; 1 mg/kg, s.c.) 24 h prior to measurement of antioxidant systems. Zn and alpha-H increased hepatic GSH concentration 20% and 55%, respectively. Cd significantly increased, whereas LPS reduced, the activities of selenium-dependent glutathione peroxidase and glutathione reductase. Glutathione S-transferases were not altered by any of the inducers. Cd also increased DT-diaphorase activity. Cd, Zn and alpha-H all decreased catalase activity 20-35%, while the activity of superoxide dismutase was unaffected by the inducers. The amount of total cytochrome P450 enzymes and cytochrome b5 were decreased by LPS, Cd and alpha-H, while Zn appeared to have no effect. The activities of P450 enzymes towards testosterone oxidation were also decreased by LPS, Cd and alpha-H. In conclusion, all four MT inducers examined affect systems known to protect cells against oxidative stress. Therefore, using these chemicals to determine the in vivo role of MT in protecting against oxidative stress poses difficulties.
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PMID:Effect of several metallothionein inducers on oxidative stress defense mechanisms in rats. 856 Apr 99

Because reactive oxygen intermediates derived from xanthine oxidase may have an important role in the pathophysiology of lipopolysaccharide-mediated tissue injury, we studied hydrogen peroxide generation using 3-amino-1,2,4-triazole inactivation of hepatic catalase and the ratio of xanthine oxidase to xanthine dehydrogenase activity in rat livers after in vivo lipopolysaccharide administration. We also studied the effect of tungsten, a potent inhibitor of xanthine oxidase, on the toxicity of lipopolysaccharide. There was increased hydrogen peroxide production and enhanced proteolytic conversion from xanthine dehydrogenase to xanthine oxidase in rat livers after lipopolysaccharide administration. Feeding rats a tungsten-rich diet for 4 weeks greatly diminished hepatic xanthine oxidase activity and lessened the rise in intracellular hydrogen peroxide production after lipopolysaccharide treatment. Liver damage, as assessed by the serum transaminase levels and mortality, was also ameliorated by the tungsten-rich diet. These findings suggest that hydrogen peroxide derived from xanthine oxidase contributes to the development of systemic toxicity and liver damage after lipopolysaccharide administration.
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PMID:Role of reactive oxygen intermediates in lipopolysaccharide-mediated hepatic injury in the rat. 859 24

The effects of the inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) and unstimulated and activated neutrophils (PMNs) on endothelial cell (EC) necrosis were studied using the cultured human EC line (ECV-304) and human PMNs in vitro. LPS and TNF alone or their combination failed to induce EC necrosis. Activated PMNs, as evidenced by augmentations in CD11b expression and respiratory burst, induced significant EC necrosis commencing at 12 hr of coculture, which was strongly dependent on the ratio of PMN:ECs and the duration of PMN:EC coculture. In contrast, unstimulated PMNs induced no significant increases in EC necrosis. To examine the mechanisms of activated PMN-mediated EC necrosis, the oxygen radical scavengers superoxide dismutase (SOD) and catalase, as well as the protease inhibitors phenylmethylsulfonyl fluoride (PMSF), alpha 1-antitrypsin (alpha 1-AT), soybean trypsin-chymotrypsin inhibitor (TCI), and aprotinin, were studied in coculture experiments. EC necrosis induced by activated PMNs could be markedly attenuated by SOD, PMSF, alpha 1-AT, TCI, aprotinin, or their combinations. Although aprotinin enhanced respiratory burst, this agent inhibited necrosis by downregulating PMN CD11b and PMN-EC adhesion. These results demonstrate that the inflammatory mediators LPS and TNF and quiescent PMNs fail to induce EC necrosis. However, PMNs activated by inflammatory mediators can induce EC necrosis through oxidative and nonoxidative mechanisms and this process is dependent on PMN-EC adhesion.
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PMID:Mechanisms involved in the induction of human endothelial cell necrosis. 859 44

Sublethal endotoxemia attenuates cardiac functional injury from global ischemia but it is unknown whether endotoxemia can protect myocardium against infarction. Furthermore, increases in myocardial catalase and heat shock protein (HSP) following endotoxemia have been associated with cardiac ischemic protection. We therefore hypothesized that a 72-hr pretreatment with endotoxin (ETX) would reduce myocardial tissue necrosis in association with augmented catalase activity and stress protein expression. Rabbits were treated with normal saline or lipopolysaccharide (Salmonella typhimurium) at 10, 5, and 1 microgram/kg doses. Three days after saline or ETX injection they were subjected to 45 min of coronary artery occlusion followed by 3 hr of reperfusion. Area of necrosis (tetrazolium staining) was normalized to anatomic risk zone size (Evans blue staining). Catalase activity was measured by a standard assay and HSP 72 was assessed by immunohistochemistry. During regional ischemia and reperfusion there were no differences in heart rate or mean arterial blood pressure between groups. ETX treated rabbits had the same risk zone size as controls. Infarct size was reduced in the ETX treated rabbits at the 10 and 5 microgram/kg doses compared with control rabbits (17.5 +/- 1.5% and 22.2 +/- 3.1% vs 45.3 +/- 2.5%; P < 0.05) but no protective effect was observed at the 1.0 micrograms/kg dose (38.0 +/- 4.6%; P > 0.05 vs control). Catalase activity was not different between control and ETX (5 microgram/kg) treated groups (997.8 +/- 59.1 U/g vs 1099.6 +/- 69.3 U/g myocardium; P > 0.05) but endotoxin induced expression of myocardial HSP 72. We conclude that a single challenge with endotoxin can induce delayed myocardial protection against infarction in vivo. This delayed cardioprotective response involves enhanced stress protein expression without changes in myocellular catalase activity.
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PMID:A single endotoxin challenge induces delayed myocardial protection against infarcation. 866 Nov 96

The long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV-1) contains sequences required for the initiation of gene transcription. Among the substances known to activate the HIV-1 LTR is hydrogen peroxide (H2O2). We report here that H2O2-induced activation of the LTR in the macrophage cell line THP-1 and the lymphocyte cell line, Jurkat, is greatly increased by vanadate. Activation of the LTR by phorbol myristate acetate, tumor necrosis factor alpha, lipopolysaccharide, or Staphylococcus epidermidis extract was not increased by vanadate, indicating some selectivity for H2O2. H2O2 and vanadate also acted synergistically to increase the production of HIV-1 virions by the latently infected macrophage cell line U-1 as determined by p24 antigen release and the detection of intact virions by electron microscopy. Effects were observed at H2O2 and vanadate concentrations down to 3 x 10(-6) M, with high concentrations leading to cell toxicity. Catalase was strongly inhibitory when added prior to the interaction of H2O2 and vanadate, but was considerably less inhibitory when the H2O2 and vanadate were allowed to preincubate prior to the catalase addition. H2O2 reacts with vanadate to form peroxides of vanadate that have potent biological effects. Our findings suggest that among these is the activation of the HIV-1 LTR.
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PMID:Activation of the HIV long terminal repeat and viral production by H2O2-vanadate. 872 29

The inducible isoform of nitric oxide synthase (iNOS) is induced upon stimulation of cells with cytokines and lipopolysaccharide (LPS). Stimulation of rat pleural mesothelial cells with combinations of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and LPS induced the synthesis of nitric oxide as measured by the oxidation products nitrite (NO2-) and nitrate (NO3-). Addition of 25-50 microM H2O2 to the cytokines significantly augmented the synthesis of NO2- and NO3-. Stimulation with IL-1 beta and TNF-alpha plus H2O2 or IL-1 beta and LPS plus H2O2 increased the synthesis of NO2- and NO3- by 3.8- and 3.5-fold, respectively. These effects were inhibited by NG-nitro-L-arginine methyl ester and cycloheximide as well as by catalase. Immunoblotting demonstrated that H2O2 augmented cytokine-induced synthesis of iNOS protein. These effects were inhibited by certain antioxidants and metal chelators, suggesting that the hydroxyl radical may mediate the oxidant-induced effect. Northern blotting demonstrated that H2O2 greatly augmented steady-state levels of iNOS mRNA, suggesting that H2O2 acted in part at the transcriptional level.
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PMID:Augmentation of cytokine-induced nitric oxide synthesis by hydrogen peroxide. 876 Jan 40

This study investigates the effects of either a high-fat diet or endotoxin on peroxisome metabolism as assessed by measuring catalase activity, catalase mass, and peroxisomal beta-oxidation. Three mouse strains C3H/HeJ, BALB/c, and C57BL/6J were fed either a low-fat or a high-fat diet and injected intraperitoneally with 1 microg Escherichia coli lipopolysaccharide. These parameters were not different in C3H/HeJ mice fed a high-fat diet compared with controls fed a low-fat diet. Total liver catalase activity and peroxisomal beta-oxidation were higher in BALB/c mice fed high-fat diet compared with low-fat controls. Total liver catalase activity, catalase mass and peroxisomal beta-oxidation increased to the greatest extent in C57BL/6J mice fed a high-fat diet. Endotoxin treatment did not alter any of the parameters in mice fed a low-fat diet. Among mice fed a high-fat diet, endotoxin did not affect hepatic catalase or peroxisomal beta-oxidation in the C3H/HeJ mice, decreased catalase activity in BALB/c mice (28%), and greatly decreased both catalase (66%) and peroxisomal beta-oxidation (69%) in C57BL/6J mice. The decrease in catalase activity in C57BL/6J mice was apparently because of an inactivation of the enzyme as determined by the activity/mass ratio. Thus, endotoxin is showed to inhibit both catalase and peroxisomal beta-oxidation in mice and the sensitivity to endotoxin is greatest in C57BL/6J mice fed a high-fat diet.
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PMID:Influence of dietary fat on the effect of endotoxin on murine hepatic peroxisomes. 878 30

Nitric oxide release is induced in many cells, including vascular endothelium, as part of the host response to inflammation. Nitric oxide synthase activity is increased in patients with sepsis, associated with increased oxidant demands and decreased antioxidant protection. We used a human vascular endothelial cell line to investigate the influence of antioxidants on nitric oxide synthase activity. Cells were cultured to confluence and incubated with interferon gamma, tumor necrosis factor, and lipopolysaccharide in the combined presence of the antioxidants ascorbic acid, Trolox, catalase, or superoxide dismutase, singly and in combination, for 48 h. Additionally, some cells were incubated with hypoxanthine-xanthine oxidase or a nitric oxide donor. Nitric oxide synthase activity was upregulated by cytokine exposure (p < .0005). Ascorbic acid and superoxide dismutase/ catalase resulted in decreased enzyme activity (p < .05). Superoxide anion release from xanthine oxidase caused increased activity (p < .05) and exogenous nitric oxide tended to suppress synthase activity. We suggest that antioxidants scavenge superoxide anion, enabling feedback inhibition of nitric oxide synthase activity by nitric oxide, and thus reducing enzyme activity. Exogenous nitric oxide also has a similar effect. Superoxide generation suppresses this feedback inhibition. This study has important implications in patients with sepsis in whom nitric oxide synthase inhibitor therapy is currently under investigation.
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PMID:Regulation of nitric oxide synthase activity in cultured human endothelial cells: effect of antioxidants. 879 Oct 97

Reactive oxygen metabolites (ROMs) are thought to play a key role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Accordingly, the use of ROM scavengers, such as N-acetyl-cysteine or dimethylthiourea, as therapeutic adjuncts to prevent oxidant-mediated damage to the lung have been evaluated extensively in animal models of ARDS. Results with this approach have been quite variable among studies. Another strategy that has been examined in animal models of ARDS is the administration of various enzymes, particularly superoxide dismutase (SOD) or catalase (CAT), in an effort to promote the conversion of ROMs to inactive metabolites. In theory, this strategy should be more effective than the use of ROM scavengers since a single molecule of a catalytically active molecule can neutralize a large number of molecules of a reactive species, whereas most scavengers act in a stoichiometric fashion to neutralize radicals on a mole-for-mole basis. This notion is supported by studies showing that prophylactic treatment with CAT provides impressive protection against acute lung injury induced in experimental animals by the administration of lipopolysaccharide (LPS). Results with SOD have been more variable. Recently, we have utilized a porcine model of LPS-induced ARDS to investigate the therapeutic potential of EUK-8, a novel, synthetic, low molecular salen-manganese complex that exhibits both SOD-like and CAT-like activities in vitro. Using both pre- and post-treatment designs, we have documented that treatment with EUK-8 significantly attenuates many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance, and pulmonary edema. These findings support the view that salen-manganese complexes warrant further evaluation as therapeutic agents for treatment or prevention of sepsis-related ARDS in humans.
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PMID:Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury. 882 94

Proteases are known to be involved in regulation of macrophage activation and killing. We examined the effect of a serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), on lysis of leukemic cells by human macrophages. Monocytes, isolated by Histopaque gradients and centrifugal elutriation, were cultured for 5 days in RPMI-1640 medium with 5% AB serum, and then activated with interferon-gamma (IFN-gamma; 100 U/mL) and lipopolysaccharide (LPS) (5 ng/mL), with or without AEBSF, for 2 days. On day 7, macrophages were washed, fresh medium without AEBSF added, and target cells added for 2 days. Lytic activity against two leukemic cell lines (K562 and HL-60) was assessed by an 111indium-releasing assay. Macrophages treated with IFN-gamma + LPS lysed K562 and HL-60 cells. AEBSF (50-150 microM) blocked the killing of these leukemic cells in a concentration-dependent manner. Other protease inhibitors were not effective. AEBSF was nontoxic at the concentrations used, and did not inhibit tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion from the macrophages. The lytic activity against leukemic cells was inhibited by anti-TNF-alpha antibody, but not by anti-IL-1 beta, nor by superoxide dismutase or catalase. However, the leukemic cells were resistant to being killed by recombinant TNF-alpha alone in the absence of macrophages, indicating that TNF-alpha was required for killing, but that other factors that were inhibited by AEBSF were also required. Serum-free culture supernatant of activated macrophages had significant cytotoxic activity against leukemic cells. This cytotoxic activity was not altered by addition of AEBSF to the culture supernatant, suggesting that AEBSF affected macrophage activation, rather than inhibiting cytotoxic proteases secreted by the macrophages, or affecting the target cells themselves. Thus, a protease, which is susceptible to AEBSF, might be involved in the activation of macrophages, and might regulate the secretion of antitumor effector molecules other than TNF-alpha.
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PMID:Lysis of leukemic cells by human macrophages: inhibition by 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor. 883 Jul 89


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