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A method was devised to search for yeast mutants impaired in peroxisome functioning, indicating cross-talk between metabolic pathways. Two mutants were isolated; they are impaired in oleate utilisation and carry mutations in the KGD1 and LIP5 genes encoding the E1 component of the mitochondrial α-ketoglutarate dehydrogenase complex and lipoic acid synthase, respectively. The results presented indicate that the Kgd1 and Lip5 proteins are important for the expression of genes encoding peroxisomal matrix proteins, although they are not necessary for the biogenesis of this cellular compartment.
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A lipopolysaccharide (LPS) stimulates the synthesis and releases several metabolites from phagocytes which can lead to an endotoxic shock characterized by multiple organ injury with the earliest to occur in the lungs. Among LPS-induced metabolites, reactive oxygen species are considered to play a crucial pathogenetic role in the lung damage. In this study, the effect of early administration of an antioxidant, alpha-lipoic acid (LA), on pulmonary lipid peroxidation, lung hydrogen peroxide (H202) concentration, and lung sulfhydryl group content was evaluated in rats with endotoxic shock induced by administration of LPS (Escherichia coli 026:B6, 30 mg/kg, i.v.). In addition, lung edema was assessed with wet-to-dry lung weight (W/D) ratio. Animals were treated intravenously with normal saline or LA 60 mg/kg or 100 mg/kg 30 min after LPS injection. After a 5 h observation, animals were killed and the lungs were isolated for measurements. Injection of LPS alone resulted in the development of shock and oxidative stress, the latter indicated by a significant increase in the lung thiobarbituric acid reacting substances (TBARS) and H202 concentrations, and a decrease in the lung sulfhydryl group content. The increase in the W/D ratio after the LPS challenge indicated the development of lung edema in response to LPS. Administration of LA after the LPS challenge resulted in an increase in the sulfhydryl group content and a decrease in TBARS and H202 concentration in the lungs as compared with the LPS group. An insignificant decrease in the W/D ratio was observed in rats treated with either dose of LA. These results indicate that the LPS-induced oxidative lung injury in endotoxic rats can be attenuated by early treatment with LA. Administration of LA could be a useful adjunct to conventional approach in the management of septic shock.
Lipopolysaccharide (LPS) from gram-negative bacteria is a major factor that contributes to multiple organ failure including lung injury. Among LPS-induced metabolites, reactive oxygen species are considered to play a crucial pathogenic role in the lung damage. In this study, the effect of early administration of an antioxidant, a-lipoic acid (LA), on bronchoalveoar lavage fluid (BALF) lipid peroxidation, hydrogen peroxide (H2O2), sulphydryl group (-SH) concentration and total protein concentration was evaluated in rats with endotoxic shock induced by administration of LPS (Escherichia coli 026:B6, 30 mg/kg, i.v.). The animals were treated intravenously with normal saline or LA (60 mg/kg or 100 mg/kg i.v.) 30 min after LPS injection. Five hours after LPS or saline administration, the animals were sacrificed and BALF was obtained for measurements. The results showed that the levels of oxidative markers, thiobarbituric acid reactive substances (TBARS) and H2O2 were increased significantly in BALF, whereas they were decreased significantly on treatment with LA. The concentrations of -SH groups were significantly increased and total protein concentration was insignificantly decreased in the LPS/LA group. There was no difference in oxidative stress reduction between 60 mg/kg and 100 mg/kg doses. These results indicate that early administration of lipoic acid provides protective effects against endotoxin-induced oxidative stress in the lung and supports the idea that alpha-lipoic acid is a free radical scavenger and a potent antioxidant.
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Effect of alpha-lipoic acid on LPS-induced oxidative stress in the heart

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Lipopolysaccharide (LPS) is a gram-negative bacterial endotoxin and a major factor that contributes to multiple organ failure, including heart injury. Myocardial dysfunction in septic shock depends on the presence of proinflammatory cytokines and reactive oxygen/nitrogen species. In this study, the effect of early administration of an antioxidant, -lipoic acid (LA) on lipid peroxidation, hydrogen peroxide (H2O2), sulphydryl groups (-SH groups) and total protein concentration and the glutathione redox system was evaluated in the heart homogenates obtained from LPS-induced endotoxic shock rats (Escherichia coli 026:B6, 30 mg/kg, i.v.). The animals were treated intravenously with saline or LA (60 mg/kg or 100 mg/kg i.v.) 30 min after LPS injection. Five hours after LPS, LA or saline administration, the animals were sacrificed and their hearts were isolated for measurements. Injection of LPS alone resulted in the development of shock and oxidative stress that was indicated by a significant increase in thiobarbituric acid reactive substances (TBARS) and H2O2 concentrations, a decrease in concentration of -SH groups and reduced glutathione, and by decrease in glutathione redox ratio reduced glutathione (GSH)/oxidized glutathione (GSSG) in the heart. Administration of LA after the LPS challenge resulted in an increase in the sulfhydryl group content and a decrease in TBARS and H202 concentrations in the heart as compared with the LPS group. In addition, the treatment of LA after LPS challenge significantly decreased the level of GSSG, increased the level of GSH in heart homogenates resulting in an increase of the GSH/GSSG ratio compared with the LPS group. There was no difference in oxidative stress reduction between 60 mg/kg and 100 mg/kg doses. These results indicate that early administration of LA is highly effective in dampening endotoxin-induced oxidative stress in the heart and in improving the glutathione redox system. This study supports the idea that -LA is a free radical scavenger and a potent antioxidant.
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