α-Lipoic acid modulates liver fibrosis: A cross talk between TGF-ß1, autophagy, and apoptosis.

Autophagy and apoptosis are important players in the progression of hepatic fibrosis via activation of hepatic stellate cells (HSCs). Despite the recently depicted antifibrotic effects of alpha-lipoic acid (ALA), however, its modulatory effects on HSCs autophagy remain unverified. Our study aimed to elucidate the underlying antifibrotic mechanisms through which ALA mediates HSC autophagy and apoptosis. Liver fibrosis was induced via thioacetamide (TAA) intoxication in rats; TAA-intoxicated rats were treated with either silymarin or ALA. Effect of ALA on biochemical parameters and immunohistopathological examinations was measured and compared to silymarin. ALA restored normal hepatic architecture (S1 vs. S4), liver functions, hepatic glutathione, and transforming growth factor-ß1 levels. ALA ameliorated hepatic levels of malondialdehyde, platelet-derived growth factor, tissue inhibitor metalloproteinases-1, hydroxyproline, and expression of alpha-smooth muscle actin. Moreover, ALA significantly reduced messenger RNA expression of LC3-II genes and triggered caspase-3 expression. Interestingly, ALA exhibited superior activities over silymarin regarding suppression of proliferation, activation and autophagy of HSCs, collagen deposition, and induction of HSCs apoptosis. In conclusion, treatment of TAA-intoxicated rats with ALA inhibited autophagy and induced apoptotic clearance of activated HSCs. Accordingly, this study provides mechanistic insights into the possible applicability of ALA in the treatment of hepatic fibrosis.

Effect of artemether alone and in combination with grapefruit juice on hepatic drug-metabolising enzymes and biochemical aspects in experimental Schistosoma mansoni.

Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Grapefruit juice increases the oral availability of a variety of the CYP3A4 substrates. This study was designed to evaluate the effect of repeated administration of grapefruit juice with artemether on the hepatic activities of cytochrome P-450 (CYP450) and cytochrome b5 (cyt b5), on the serum levels of some biochemical enzymes and antischistosome efficacy. Results showed that administration of grapefruit juice alone induced more inhibition in the hepatic activities of CYP450 and cyt b5 than that produced by Schistosoma mansoni infection. Moreover, it enhanced degeneration of eggs and accelerated healing of the pathological granulomatous lesions. Treatment of S. mansoni-infected mice with artemether at a total dose of 300 mg/kg resulted in total and female worm burden reductions of 66.7 and 90.1%, respectively, hence protecting the host from damage induced by schistosome eggs. Treatment of S. mansoni-infected mice with artemether at 150 mg/kg reduced the total and female worm numbers by 43.3 and 54.4%, respectively, thus somewhat ameliorating hepatic granulomatous lesions compared with the infected untreated group. This was associated with no change in the hepatic activities of CYP450 and cyt b5 and in the serum levels of total protein, albumin, globulin and alanine aminotransferase compared with the uninfected control group. Coadministration of grapefruit juice with the lower dose (150 mg/kg) of artemether eliminated eggs and granulomatous reactions. In this group, the inhibitory effects of grapefruit juice on CYP450 and cyt b5 were apparent but serum liver enzymes were unchanged compared with the uninfected control group. Coadministration of grapefruit juice with artemether achieved complete protection of the host from damage induced by schistosomal infection.

Effect of Schistosoma mansoni infection and treatment on drug metabolizing enzymes.

The effect of Schistosoma mansoni infection on drug-metabolizing enzymes was investigated before and after treatment of S. mansoni-infected male albino mice with the antibilharzial drug praziquantel (CAS 55268-74-1). The drug was given in a total dose of 1000 mg/kg, and was administered at 500 mg/kg of body weight for two consecutive days each of 500 mg/kg of body weight. The drug was given 49 days after infection with 80 Egyptian strains of S. mansoni cercariae/mouse. The hepatic content of cytochrome P-450, cytochrome b-5 and NADPH cytochrome P-450 reductase were determined at 4, 8, 24, 72 h, one and two weeks after the second dose of treatment. The enzymes were determined in the microsomal fraction after homogenization and ultracentrifugation at 105,000 x g. The results indicate a marked decrease of most enzymes in the infected groups compared to normal controls. Two weeks after treatment there was an improvement of the level of most enzymes towards the normal values. The levels of liver function tests were also improved. Concerning the oogram pattern, there was a rapid change even after 8 h after the second dose of treatment. It was concluded that the antibilharzial drug could be considered as a safe drug with a rapid onset of action.