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)

N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats.
 ...
PMID:Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. 872 70

Oxidative damage to the liver of lipopolysaccharide-treated rats was evaluated using four parameters: level of lipid peroxidation, changes in total GSH and GSSG concentrations and hepatic morphology. Bacterial lipopolysaccharide (10 mg/kg b.w.) was injected i.p. either at 6, 16 or 24 h before animals were killed. Lipopolysaccharide increased lipid peroxidation most dramatically when it is injected 6 h before killing. Hepatic total GSH increased after lipopolysaccharide in a time-dependent manner. The highest level of GSSG and largest GSSG/total GSH ratio were also observed in the group of animals injected with lipopolysaccharide 6 h before tissue collection. In a second study, lipopolysaccharide was injected 6 h before the animals were killed, with or without 1 mg/kg b.w. melatonin. Melatonin totally abolished lipopolysaccharide-induced increase in lipid peroxidation, exaggerated the rise in total GSH and reversed the increase in GSSG concentration. The liver showed obvious histological degenerative changes after lipopolysaccharide, effects that were counteracted by melatonin administration. The protection conferred by melatonin is presumably due to its antioxidant activity.
 ...
PMID:Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin. 874 85

Glutathione is one of the most abundant thiols in mammalian tissues and plays important roles in the defense mechanism and detoxification of various metabolites, such as reactive xenobiotics and free radicals. Nitric oxide (NO) readily reacts with thiol compounds, thereby generating chemically stable S-nitrosothiols. Although endotoxin has been known to induce NO synthase in various organs, particularly liver and spleen, and enhances the production of NO, correlation between NO and glutathione metabolism in endotoxemic subjects remains to be elucidated. The present work examines the changes in NO and glutathione metabolism in endotoxemic rats. Administration of lipopolysaccharide (LPS) markedly decreased the glutathione levels in plasma and bile, whereas it decreased the hepatic level only slightly. NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor, inhibited the LPS-induced decrease of glutathione in plasma and bile. Administration of LPS increased the biliary levels of gamma-glutamyl transpeptidase (gamma-GTP) without affecting its thiol levels. Acivicin, a gamma-GTP inhibitor, inhibited the LPS-induced decrease of glutathione in plasma and bile without affecting its hepatic levels. Analysis with the use of L-buthionine sulfoximine revealed that the turnover of hepatic glutathione significantly increased in LPS-treated rats by some L-NNA-inhibitable mechanism. These results suggest that endotoxin might enhance the NO production in the liver and other tissues and significantly modulate the interorgan metabolism of reduced glutathione.
 ...
PMID:Dynamic aspects of glutathione and nitric oxide metabolism in endotoxemic rats. 889 75

When administered with D-galactosamine, lipopolysaccharide endotoxins produce a good experimental animal model of hepatitis. This galactosamine plus endotoxin model has been used widely, but the acute effect of this fixed combination of two chemicals on hepatic and extrahepatic biotransformation has not been determined. Therefore, either 2 or 4 hr after a single intraperitoneal dose of 300 mg/kg galactosamine plus 30 micrograms/kg lipopolysaccharide was administered, serum, liver, kidney, intestine, and spleen were collected. Serum enzymes (alanine and aspartate aminotransferases, sorbitol dehydrogenase, and gamma-glutamyltranspeptidase) were elevated dramatically 2 and 4 hr after treatment. Cytochrome P450 monooxygenase activity toward benzo-[a]pyrene was increased in kidney 4 hr after treatment, whereas dealkylation of 7-methoxycoumarin or 7-ethoxyresorufin was unchanged in any tissue at either time point. An increase in UDP-glucuronosyltransferase activity toward 4-methylumbelliferone and 4-hydroxybiphenyl was noted in the intestine. Conjugation of 1-chloro-2,4-dinitrobenzene with glutathione was increased in intestine and spleen 2 hr after treatment. gamma-Glutamyltranspeptidase activity was unaltered in all tissues studied. Reduced glutathione concentrations were increased significantly by different amounts depending on which organs were studied 2 or 4 hr after treatment. These results indicate that galactosamine/lipopolysaccharide-induced liver injury is not accompanied by major effects on the examined biotransformation reactions.
 ...
PMID:Minimal effect of acute experimental hepatitis induced by lipopolysaccharide/D-galactosamine on biotransformation in rats. 895 52

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.
 ...
PMID:Alcohol-induced thymocyte apoptosis is accompanied by impaired mitochondrial function. 901 30

In previous studies, we found that lipid A, the biologically active component of lipopolysaccharide, triggers a rapid release of intracellular calcium, the activation of nitric oxide synthase (NOS), and nitric oxide (NO) production in rat proximal tubules. This pathway leads ultimately to cell death [as measured by the release of lactate dehydrogenase (LDH)], initiated by early generation of NO. In the present studies we found that lipid A produces a time- and concentration-dependent increase in lipid peroxidation [malondialdehyde (MDA) formation] prior to cell death. Furthermore, preventing lipid peroxidation protected against cell death. Lipid A (50 micro;g/ml) produced significant MDA formation in 30 min. The addition of two antioxidants 5 min prior to lipid A completely inhibited MDA formation and LDH release at 90 min. Preincubation with 5 mm GSH also significantly reduced MDA formation. The involvement of NOS activation in lipid A-induced lipid peroxidation was established when an NOS inhibitor and an inhibitor of intracellular calcium release completely blocked MDA formation. In addition, superoxide generation was significantly increased in the presence of lipid A, and the involvement of superoxide was established when superoxide dismutase protected against oxidant injury. The iron chelators deferoxamine (also a scavenger of peroxynitrite) and diethylenetriaminepentaacetic acid prevented lipid A-induced lipid peroxidation and cell death, indicating a role for iron and peroxynitrite. The addition of an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl, prior to lipid A also completely protected tubule cells from lipid peroxidation and subsequent cell death. These results indicate that lipid A-stimulated NO generation in the rat proximal tubule initiates oxidant injury.
 ...
PMID:Nitric oxide generation mediates lipid A-induced oxidant injury in renal proximal tubules. 902 63

Recent studies suggest that in some cell types, the activity of nitric oxide (NO) is influenced by the endogenous antioxidant, reduced glutathione (GSH). The present study has examined the role of GSH in NO-induced cytotoxicity in cells harvested from the rat gastric mucosa. Cell integrity was assessed by Trypan blue exclusion and alamar blue dye absorbance. Pretreatment of rats with bacterial endotoxin lipopolysaccharide increased Ca(2+)-independent NO synthase (iNO synthase) activity (as detected by the radiolabeled conversion of [14C]arginine to [14C]citrulline, lowered GSH content and increased cell injury. Lipopolysaccharide treatment also resulted in a significant increase in the in vitro production of reactive oxygen metabolites as assessed by the fluorescent probe 2',7'-dichlorofluorescein diacetate. Inhibition of iNO synthase activity by dexamethasone and NG-nitro-L-arginine methyl ester prevented these effects. Similarly, the NO donor, S-nitroso acetyl-penicillamine depleted GSH stores and damaged cells in a dose-dependent manner. The effects of S-nitroso acetyl-penicillamine were diminished by the NO scavenger, 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide. In contrast, incubating cells with N-acetyl-L-cysteine to augment endogenous GSH synthesis, prevented the effects of S-nitroso acetyl-penicillamine. Reduction of GSH stores by pretreatment of rats with buthionine sulfoximine or incubating cells in vitro with diethyl maleate, increased oxidant production and exacerbated NO-induced cell injury. These results suggest that excessive levels of NO alter GSH homeostasis and increase the generation of oxidants leading to increased gastric cellular injury.
 ...
PMID:Role of glutathione in nitric oxide-mediated injury to rat gastric mucosal cells. 904 9

Under pathological conditions, the induction of nitric oxide synthase (NOS) in macrophages is responsible for NO production to a cytotoxic concentration. We have investigated changes to, and the role of, intracellular glutathione in NO production by the activated murine macrophage cell line J774. Total glutathione concentrations (reduced, GSH, plus the disulphide, GSSG) were decreased to 45% of the control 48 h after cells were activated with bacterial lipopolysaccharide plus interferon gamma. This was accompanied by a decrease in the GSH/GSSG ratio from 12:1 to 2:1. The intracellular decrease was not accounted for by either GSH or GSSG efflux; on the contrary, rapid export of glutathione in control cells was abrogated during activation. The loss of intra- and extracellular glutathione indicates either a decrease in synthesis de novo, or an increase in utilization, rather than competition for available NADPH. All changes in activated cells were prevented by pretreatment with the NOS inhibitor L-N-(1-iminoethyl)ornithine. Basal glutathione levels in J774 cells were manipulated by pretreatment with (1) buthionine sulphoximine (glutathione synthase inhibitor), (2) acivicin (gamma-glutamyltranspeptidase inhibitor), (3) bromo-octane (glutathione S-transferase substrate) and (4) diamide/zinc (thiol oxidant and glutathione reductase inhibitor). All treatments significantly decreased the output of NO following activation. The degree of inhibition was dependent on (i) duration of treatment prior to activation, (ii) rate of depletion or subsequent recovery and (iii) thiol end product. The level of GSH did not significantly affect the production of NO, after induction of NOS. Thus, glutathione redox status appears to plays an important role in NOS induction during macrophage activation.
 ...
PMID:Induction of nitric oxide synthesis in J774 cells lowers intracellular glutathione: effect of modulated glutathione redox status on nitric oxide synthase induction. 906 66

Nitric oxide (NO) plays an important role in the cytotoxic activity of macrophages towards tumour cells and microbial pathogens. We investigated whether alteration of intracellular thiol levels modulates the cytotoxic effects of different NO donors and lipopolysaccharide-induced NO in the murine macrophage cell lin J774A.1. The NO-releasing compound S-nitroso-N-acetylpenicillamine caused a significant concentration-dependent loss of viability of the macrophages only under glucose-limiting conditions. The cytotoxic effect of S-nitroso-N-acetylpenicillamine was prevented by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO). Depletion of total glutathione before exposure to S-nitroso-N-acetylpenicillamine further decrease cell viability while pretreatment with N-acetylcysteine was protective. Comparing equimolar concentrations of various NO donors including S-nitrosoglutathione, S-nitrosocysteine and 3-morpholino-sydnonimine hydrochloride, cytotoxicity appeared to be related to the relative stability of the test compound. Both the order of stability and the order of potency for cell killing was S-nitrosoglutathione > S-nitroso-N-acetylpenicillamine > S-nitrosocysteine = 3-morpholino-sydnonimine hydrochloride. Stimulation of the macrophages with lipopolysaccharide and interferon-gamma resulted in dose-dependent cell injury and NO production. Glutathione depletion prior to stimulation considerably decreased macrophage viability as well as the NO production. In contrast to the protective effect on S-nitroso-N-acetylpenicillamine-mediated injury, pretreatment with N-acetylcysteine did not influence the lipopolysaccharide-mediated cytotoxicity. These results demonstrate that (a) reduction in the availability of glucose and intracellular glutathione renders the cells more vulnerable to the cytotoxic effects of NO donors, (b) in this model of cytotoxicity, long-lived NO donors were more cytotoxic than short-lived NO donors, (c) the differential effects of N-acetylcysteine on S-nitroso-N-acetylpenicillamine-induced and bacterial lipopolysaccharide-mediated cytotoxicity support the existence of other toxic species different from NO or NO-related compounds with a potent cytotoxic activity in immunostimulated macrophages, and (d) other non-protein thiols like N-acetylcysteine may substitute for glutathione as a major component of the cellular antioxidant defense system.
 ...
PMID:The protective role of thiols against nitric oxide-mediated cytotoxicity in murine macrophage J774 cells. 908 90

1. Glutathione concentrations in liver and lung fall when food intake or sulphur amino acid intake is inadequate. However, concentrations may be restored during inflammation, despite anorexia, provided that prior sulphur amino acid intake is adequate. 2. We studied the mechanisms of these changes by measuring the effect of sulphur amino acid and protein intake on hepatic glutathione synthesis and gamma-glutamylcysteine synthetase activity, hepatic and lung glutathione concentrations, glutathione reductase and glutathione peroxidase activities in young rats given an inflammatory challenge by intraperitoneal injection of tumour necrosis factor-alpha or endotoxin (lipopolysaccharide). 3. Diets containing 200 g of casein and 8 g of L-cysteine/kg (normal-protein diet), or 80 g of casein and 8 g of L-cysteine, or isonitrogenous amounts of L-methionine or L-alanine (low-protein diets) were fed ad libitum to young Wistar rats for 8 days. Dietary groups were subdivided into three: one subgroup continued feeding ad libitum, a second was given tumour necrosis factor or lipopolysaccharide and killed 24 h thereafter, while the third was pair-fed to the intakes of the second subgroup for 24 h before being killed. 4. Glutathione concentrations in liver and lung were reduced in rats fed the low-protein diet containing alanine, and in all dietary groups when food intake was restricted. The inflammatory challenges restored hepatic glutathione concentrations in all groups but the diet supplemented with alanine, which had an inadequate sulphur amino acid content. In lung, restoration occurred only in animals fed the normal-protein diet. 5. The activity of gamma-glutamylcysteine synthetase, which is rate limiting for glutathione synthesis, was unaffected by dietary or sulphur amino acid intake or by the inflammatory response. Substrate supply may therefore be a major determinant in glutathione synthesis in vivo. 6. Total hepatic glutathione synthesis was affected by food intake, the type and amount of sulphur amino acids in the diet and by inflammation. Total synthesis was 207, 137, 421 and 90 mumol/day for animals fed ad libitum the normal-protein diet, or low-protein diets supplemented with cysteine, methionine or alanine respectively, ad libitum. Pair-feeding resulted in values of 76, 31, 71, and 0 mumol/day respectively. After lipopolysaccharide injection, rates increased to 200, 117, 151 and 56 mumol/day respectively. 8. Reductase and peroxidase activities increased in liver and lung, when low-protein diets which contained supplemental methionine or alanine were consumed ad libitum. A reduction in food intake resulted in enzyme activity changes, which suggested that recycling of glutathione increased in lung and decreased in liver. Injection of tumour necrosis factor reversed this effect. 9. The restoration of glutathione concentrations in liver after an inflammatory challenge is closely associated with an enhanced rate of synthesis and increased recycling. The former is impaired when inadequate sulphur amino acid is consumed before the challenge. In lung, increased recycling of glutathione may help maintain concentrations when food intake is restricted, but not during inflammation.
 ...
PMID:Dietary sulphur amino acid adequacy influences glutathione synthesis and glutathione-dependent enzymes during the inflammatory response to endotoxin and tumour necrosis factor-alpha in rats. 909 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>