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)

Challenge of mouse small intestinal loops with Salmonella typhimurium invoked the accumulation of luminal fluid, acute inflammation, and extensive structural damage to the small intestinal mucosa, as determined by histology and electron microscopy. Intraperitoneal and intestinal luminal injection of L-histidine, a known antioxidant, reduced the amount of fluid accumulating in the intestinal lumen and protected the intestinal tissue from S. typhimurium-induced damage. The reduction in S. typhimurium-induced fluid accumulation by L-histidine was specific for the L-enantiomer because D-histidine had no significant protective effect. Efficacy of L-histidine in protecting the infected intestinal tissue was attributed to the capacity of the imidazole ring to scavenge reactive oxygen species (ROS) generated by cells in the intestine during the acute inflammatory response. Glutathione levels were markedly reduced in S. typhimurium-challenged, inflamed intestinal tissues as a result of ROS generation. Importantly, after dosing the S. typhimurium-challenged mice with L-histidine, the glutathione content of the small intestinal tissue was not significantly different from mock-challenged controls. Further evidence favoring this mechanism included the capacity of L-histidine to scavenge ROS produced as a result of lipopolysaccharide (LPS) exposure of mononuclear cells (U937), as demonstrated with a redox-sensitive fluorescent dye (2'7'-dichlorodihydrofluorescein [DCF]). Addition of L-histidine, and to a lesser extent D-histidine, to the culture media of U937 cells before LPS exposure, resulted in a significant dose-dependent reduction in LPS-induced intracellular DCF fluorescence, as measured quantitatively by flow cytometry. The potential therapeutic value of anti-inflammatory drugs containing an L-histidine-like structure could protect infected mucosal tissues irrespective of microbial etiology.
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PMID:Anti-inflammatory and antisecretory potential of histidine in Salmonella-challenged mouse small intestine. 960 77

Spermine NONOate (SpNO, a nitric oxide donor) induced apoptosis and caspase-3 activity in the macrophage cell line RAW 267.4. RES cells that have been derived from RAW 267.4 cells by repeated exposure to lipopolysaccharide and interferon-gamma (LPS/INF-gamma), followed by outgrowth of viable cells, are resistant to apoptosis and caspase-3 activation upon exposure to SpNO. In this study we have determined that RES cells have lower levels of glutathione (GSH) and a higher oxidative state than RAW cells. Subsequently, RAW and RES cells were depleted of GSH by using l-buthionine-[S,R]-sulfoximine (BSO), a specific inhibitor of GSH synthesis. GSH depleted cells did not undergo apoptosis nor demonstrate caspase-3 activity when they were exposed to SpNO. These results suggest that the redox status of the cell is one of the key factors mediating the apoptotic pathway in which glutathione plays a critical role in mediating apoptosis via NO* and reactive oxygen species (ROS).
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PMID:Glutathione levels determine apoptosis in macrophages. 964 8

We investigated the mechanism of nitric oxide (NO) action on hepatic methionine adenosyltransferase (MAT) activity using S-nitrosoglutathione (GSNO) as NO donor. Hepatic MAT plays an essential role in the metabolism of methionine, converting this amino acid into S-adenosylmethionine. Hepatic MAT exists in two oligomeric states: as a tetramer (MAT I) and as a dimer (MAT III) of the same subunit. This subunit contains 10 cysteine residues. In MAT I, S-nitrosylation of 1 thiol residue per subunit was associated with a marked inactivation of the enzyme (about 70%) that was reversed by glutathione (GSH). In MAT III, S-nitrosylation of 3 thiol residues per subunit led to a similar inactivation of the enzyme, which was also reversed by GSH. Incubation of isolated rat hepatocytes with S-nitrosoglutathione monoethyl ester (EGSNO), a NO donor permeable through the cellular membrane, induced a dose-dependent inactivation of MAT that was reversed by removing the NO donor from the cell suspension. MAT, purified from isolated rat hepatocytes, contained S-nitrosothiol groups and the addition of increasing concentrations of EGSNO to the hepatocyte suspension led to a progressive S-nitrosylation of the enzyme. Removal of the NO donor from the incubation media resulted in loss of most NO groups associated to the enzyme. Finally, induction in rats of the production of NO, by the administration of bacterial lipopolysaccharide (LPS), induced a fivefold increase in the S-nitrosylation of hepatic MAT, which led to a marked inactivation of the enzyme. Thus, the activity of liver MAT appears to be regulated in vivo by S-nitrosylation.
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PMID:Nitric oxide inactivates rat hepatic methionine adenosyltransferase In vivo by S-nitrosylation. 975 42

Renal tubular epithelial cells are largely resistant to oxidant-induced injury despite their capacity to accumulate relatively high concentrations of potentially damaging prooxidant and thiol-depleting agents. In the present study, we tested the hypothesis that such resistance may be attributable to a lack or deficiency of signaling transduction pathways through which reactive oxidants have been shown to promote the activation of NF-kappaB, a transcriptional factor that is known to mediate the inducible expression of a wide variety of genes that are involved in inflammatory and other cytotoxic reactions in numerous cell types. NF-kappaB was found to be readily activated following exposure of cultured normal rat kidney epithelial (NRK52E) cells to bacterial lipopolysaccharide (LPS). However, in contrast to findings with many other cell types, the activation of NF-kappaB by LPS was not substantially altered either by pretreatment of cells with the thiol antioxidant, N-acetylcysteine, or by glutathione (GSH) depletion. Moreover, reactive oxidants and oxidative stress-generating chemicals were completely without effect with respect to NF-kappaB activation in NRK52E cells, even following GSH depletion. In contrast, LPS activation of NF-kappaB was substantially attenuated by the intracellular Ca2+ chelator, Quin 2AM, and by the Ca-channel inhibitor, ruthenium red. Moreover, thapsigargin, a Ca-ATPase inhibitor, promoted NF-kappaB activation comparable to that observed by LPS. Additionally, staurosporine, a Ca-dependent protein kinase C inhibitor, substantially decreased LPS-mediated NF-kappaB activation. These results demonstrate that the LPS-inducible expression of NF-kappaB in renal epithelial cells, in contrast to many other cell types, is not responsive to oxidative stress and is regulated, at least in part, by redox-insensitive modulation of intracellular calcium levels. These findings provide a basis for the highly tissue-specific expression and function of NF-kappaB in kidney epithelial cells, which may underlie their resistance to oxidant-mediated cytotoxicity.
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PMID:Activation of NF-kappaB in normal rat kidney epithelial (NRK52E) cells is mediated via a redox-insensitive, calcium-dependent pathway. 993 Dec 81

The purpose of this study was to determine if exacerbation of apoptosis precedes liver injury during chronic exposure of rats to alcohol. After 7 weeks of feeding an alcohol- or dextrin-containing liquid diet, the animals were treated with gram-negative bacterial lipopolysaccharide (1 mg x kg(-1) body weight, intravenously) or sterile saline and sacrificed 3 hr after the treatment. Alanine:2-oxoglutarate aminotransferase (ALT) and lactate:NAD oxidoreductase [lactate dehydrogenase (LDH)] were measured in plasma. The caudate lobe of the liver was resected for histology, while the rest of the organ was perfused with collagenase to isolate hepatocytes, Kupffer cells (KCs), and sinusoidal endothelial cells (SECs) by centrifugal elutriation. Hepatocyte mitochondria were isolated by differential centrifugation of the cell homogenate. Reduced and oxidized glutathione (GSH and GSSG) in isolated hepatocytes and hepatocyte mitochondria, and malondialdehyde in hepatocytes were assayed. Caspase-3 activity and Fas ligand mRNA expression were determined in hepatocytes, KCs, and SECs. Plasma ALT and LDH activity, liver histology, GSH, GSSG and their ratio, and malondialdehyde content were not affected by alcohol treatment Caspase-3 activity was significantly increased in alcohol-treated rats in all three cell types, with the lowest response observed in hepatocytes and the highest in KCs. Fas ligand mRNA expression, which had the highest level in SECs, followed by KCs and hepatocytes, was not affected by alcohol administration. Lipopolysaccharide had the following effects: an increase in ALT in both pair- and alcohol-fed rats, and LDH only in alcohol-fed rats, a decrease in GSH + GSSG levels in both mitochondria and hepatocytes, an elevation of malondialdehyde content in hepatocytes, a raise in caspase-3 activity in all groups and cell types, and an augmentation of Fas ligand expression in hepatocytes and KCs, but not in SECs. These data suggest that, during chronic alcohol consumption, an exacerbated apoptosis precedes alcohol-induced liver injury.
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PMID:Modulation of caspase-3 activity and Fas ligand mRNA expression in rat liver cells in vivo by alcohol and lipopolysaccharide. 1006 67

Treatment of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/ml) increased mRNA expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the pentose phosphate pathway (PPP), in a time-dependent fashion (0-24 h). This effect was accompanied by an increase in G6PD activity (1.74-fold) and in the rate of glucose oxidation through the PPP (6.32-fold). Inhibition of inducible nitric oxide synthase (iNOS) activity by 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; 50 microM) did not alter the LPS-mediated enhancement of G6PD mRNA expression or PPP activity. Blockade of nuclear factor-kappaB (NF-kappaB) activation by N-benzyloxycarbonyl-Ile-Glu-(O-tert-butyl)-Ala-leucinal (1 microM) prevented the expression of both iNOS mRNA and G6PD mRNA, suggesting that iNOS and G6PD are co-induced by LPS through a common transcriptional pathway involving NF-kappaB activation. Incubation of cells with LPS for 24 h increased intracellular NADPH concentrations (1.63-fold) as compared with untreated cells, but GSH concentrations were not modified by LPS treatment up to 60 h of incubation. However, inhibition of G6PD activity by dehydroepiandrosterone (DHEA; 100 microM), which prevented LPS-mediated enhancements in PPP activity and NADPH concentrations, caused a 50% decrease in the GSH/GSSG ratio after 24-36 h and in GSH concentrations after 60 h of incubation. Furthermore, the changes in glutathione concentrations caused by DHEA were abolished by AMT, suggesting that nitric oxide and/or its reactive derivatives would be involved in this process. From these results, we conclude that LPS-mediated G6PD expression prevents GSH depletion due to nitric oxide and suggest that this phenomenon may be a contributing factor in the defense mechanisms that protect astrocytes against nitric oxide-mediated cell injury.
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PMID:Induction of glucose-6-phosphate dehydrogenase by lipopolysaccharide contributes to preventing nitric oxide-mediated glutathione depletion in cultured rat astrocytes. 1009 86

Antioxidant action of various molds, which are traditionally used for the production of foods or alcoholic beverages in Japan, was studied in vitro and in vivo. Antioxidant action was evaluated by scavenging stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation of rat liver microsomes. Among 40 molds, 16 species showed the DPPH scavenging action, and the molds that can scavenge the DPPH radical inhibited lipid peroxidation. The mold with the strongest action, Monascus anka, was chosen for the investigation of a protective action against liver injury of rats. When galactosamine (GalN, 400 mg/kg) or GalN plus lipopolysaccharide (LPS, 0.5 microg/kg) was given intraperitoneally to rats (Sprague-Dawley), aspartate aminotransferase (AST) and glutathione (GSH) S-transferase (GST) activities in serum were significantly increased. However, such hepatotoxicities seen in the increase in serum enzyme levels were depressed when the extract prepared from M. anka was given 1 and 15 h before the toxic insultant. Liver microsomal GST activity, which is known to be activated by oxidative stress, was increased by GalN or GaIN plus LPS treatment and the increase was also inhibited by pretreatment with the extract. Pathomorphological changes in the liver caused by GalN treatment also were prevented by the mold extract. These results indicate that the extract of M. anka has radical scavenging action and ameliorates chemically induced hepatotoxicity.
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PMID:Screening of antioxidant action of various molds and protection of Monascus anka against experimentally induced liver injuries of rats. 1018 24

Oxidation of low density lipoprotein (LDL) has been recognized as playing an important role in the initiation and progression of atherosclerosis. We recently reported that aged garlic extract (AGE) inhibited LDL oxidation and minimized oxidized LDL-induced cell injury. In this study, the antioxidant effects of AGE were further examined using bovine pulmonary artery endothelial cells (PAEC) and murine macrophages. Lactate dehydrogenase (LDH) release, as an index of membrane injury, and intracellular glutathione (GSH) levels were determined. Oxidized LDL (Ox-LDL) caused an increase of LDH release and depletion of GSH. Pretreatment with AGE prevented these changes. AGE exhibited an inhibition of Ox-LDL-induced peroxides in PAEC. AGE suppressed peroxides in murine Macrophage (J774 cells) dose-dependently. The J774 cells were also incubated with AGE, interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) and nitric oxide (NO) production was measured. AGE inhibited NO production in J774 cells. In a cell free system, AGE was shown to scavenge H2O2 dose-dependently. Our data demonstrate that AGE can protect the endothelial cells from oxidized LDL-induced injury by preventing depletion of intracellular GSH and by removing peroxides. AGE also reduces levels of NO and peroxides in macrophages. These data suggest that AGE is a useful protective agent against cytotoxicity associated with Ox-LDL and NO, and it may thus be useful for the prevention of atherosclerosis and cardiovascular diseases.
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PMID:Aged garlic extract attenuates intracellular oxidative stress. 1037 52

Resolution of neutrophil mediated inflammation is achieved, in part, through induction of neutrophil apoptosis. This constitutively expressed programme can be delayed by inflammatory mediators and induced by ligation of the Fas receptor. However, functional activation of the neutrophil results in resistance to Fas signalled death. We evaluated the effects of Fas antibody engagement on caspase activation and mitochondrial permeability, and the impact of co-stimulation by lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM-CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted in enhanced caspase 3 and 8 activity and increased mitochondrial permeability. Studies with pharmacological inhibitors of caspase activity showed that activation of caspase 8 occurred before, and activation of caspase 3 occurred after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8 activity was also inhibited by co-stimulation through a mechanism independent of mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8 activity. We conclude inhibition of Fas antibody induced apoptosis by inflammatory proteins is associated with augmented mitochondrial stability and reduced caspase 3 activity that may be glutathione mediated.
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PMID:Regulation of Fas antibody induced neutrophil apoptosis is both caspase and mitochondrial dependent. 1040 77

Astrocytes play a pivotal role in CNS detoxification pathways, where glutathione (GSH) is involved in the elimination of oxygen and nitrogen reactive species such as nitric oxide. We have previously demonstrated that the specific activity of gamma-glutamyl transpeptidase (gamma-GT), an enzyme of central significance in GSH metabolism, is regulated in vivo in astrocytes by 1,25-dihydroxyvitamin D3 (1,25-D3). The aim of the present work was to investigate, in primary cultures of newborn rat astrocytes, the effects of this hormone on gamma-GT synthesis and on GSH and nitrite levels after lipopolysaccharide (LPS) treatment. This study demonstrates that both gamma-GT gene expression and specific activity, induced by LPS, are potentiated by 1,25-D3. In contrast, 1,25-D3 does not regulate the expression of other enzymes involved in astrocyte detoxification processes, such as superoxide dismutase or GSH peroxidase. In parallel, 1,25-D3 enhanced intracellular GSH pools and significantly reduced nitrite production induced by LPS. Taken together, these results suggest that gamma-GT, GSH, and 1,25-D3 play a fundamental role in astrocyte detoxification pathways.
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PMID:1,25-dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. 1042 85


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