Betulin attenuated liver damage by prevention of hepatic mitochondrial dysfunction in rats with alcoholic steatohepatitis

Betulin, a pentacyclic triterpene, possesses antioxidant, anti-inflammatory and hepatoprotective properties. The aim of this study was to evaluate the impact of liver mitochondria in hepatoprotection of betulin using a rat model of alcoholic steatohepatitis induced by ethanol administration (4 g/kg, intragastric) for 8 weeks. The treatment with betulin (50 and 100 mg/kg b.w., intragastric) during this period attenuated the histological signs of steatohepatitis and lowered the serum and liver triglyceride contents, as well as the serum activities of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Betulin (100 mg/kg) decreased the liver/body weight ratio and inhibited the increase in the serum levels of TNFα, IL-1β, TGFβ, and hyaluronic acid, demonstrating hepatoprotective, anti-inflammatory, and antifibrotic potential. Betulin also inhibited the formation of superoxide anions in mitochondria and the end-products of lipid peroxidation in liver tissue, the amount of which was significantly increased in ethanol-treated rats. The disturbances in mitochondrial respiration, uncoupling of oxidative phosphorylation and decreasing of mitochondrial complex I, II, and IV activities in rats with steatohepatitis, were reverted by betulin administration. The increased susceptibility of mitochondria to Ca2+-induced permeability transition pore formation in the hepatitis group was improved in rats treated with betulin. In conclusion, betulin, having antioxidant properties, exerts a beneficial effect in the rat model of alcoholic steatohepatitis via prevention of liver mitochondria dysfunction, which may be attributed to the inhibition of mitochondrial permeability transition

Changes in Hepatic Gene Expression upon Oral Administration of Taurine-Conjugated Ursodeoxycholic Acid in ob/ob Mice

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with considerable morbidities. Unfortunately, there is no currently available drug established to treat NAFLD. It was recently reported that intraperitoneal administration of taurine-conjugated ursodeoxycholic acid (TUDCA) improved hepatic steatosis in ob/ob mice. We hereby examined the effect of oral TUDCA treatment on hepatic steatosis and associated changes in hepatic gene expression in ob/ob mice. We administered TUDCA to ob/ob mice at a dose of 500 mg/kg twice a day by gastric gavage for 3 weeks. Body weight, glucose homeostasis, endoplasmic reticulum (ER) stress, and hepatic gene expression were examined in comparison with control ob/ob mice and normal littermate C57BL/6J mice. Compared to the control ob/ob mice, TUDCA treated ob/ob mice revealed markedly reduced liver fat stained by oil red O (44.2±5.8% vs. 21.1±10.4%, P<0.05), whereas there was no difference in body weight, oral glucose tolerance, insulin sensitivity, and ER stress. Microarray analysis of hepatic gene expression demonstrated that oral TUDCA treatment mainly decreased the expression of genes involved in de novo lipogenesis among the components of lipid homeostasis. At pathway levels, oral TUDCA altered the genes regulating amino acid, carbohydrate, and drug metabolism in addition to lipid metabolism. In summary, oral TUDCA treatment decreased hepatic steatosis in ob/ob mice by cooperative regulation of multiple metabolic pathways, particularly by reducing the expression of genes known to regulate de novo lipogenesis

Chromatographic Examinations of Tea's Protection Against Lipid Oxidative Modifications

Ethanol metabolism is accompanied by generation of free radicals that damage cell components, especially lipids. The present study was designed to investigate the efficacy of the preventive effect of black tea on the lipid oxidative modifications in different tissues (plasma, liver, brain, kidney, stomach, lung, intestine, and spleen) of 12-month-old rats chronically intoxicated with ethanol. Ethanol intoxication caused changes in the level/activity of antioxidants that led to the significant increase in the level of lipid oxidative modification products. Oxidative modifications were estimated by measuring lipid hydroperoxides, malondialdehyde, and 4-hydroxynonenal by high-performance liquid chromatography (HPLC) and by spectrophotometric determination of conjugated dienes. These lipid-modification marker levels were increased in almost all examined tissues (3%–71%) after ethanol intoxication. Described changes were in accordance with the liver level of the most often used marker of arachidonic acid oxidation, isoprostane (8-isoPGF2α), determined by the LC/MS system. Administration of black tea to ethanol-intoxicated rats remarkably prevents the significant increase (by about 15%–42%) in concentrations of all measured parameters regarding all examined tissues, but especially the plasma, liver, brain, stomach, and spleen. The preventive effect of black tea in the other organs (kidney, lung, intestine) caused a decrease in examined markers in a smaller degree (by about 7%–28%). To determine in the liver the major constituents of black tea mainly responsible for antioxidative action such as catechins and theaflavins, which were absorbed in organism, the present study indicates their protective effect against ethanol-induced oxidative modifications of lipids

High-Loading Dose of Microencapsulated Gliclazide Formulation Exerted a Hypoglycaemic Effect on Type 1 Diabetic Rats and Incorporation of a Primary Deconjugated Bile Acid, Diminished the Hypoglycaemic Antidiabetic Effect

Background and objective: Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. Methods: Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. Results: Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. Conclusion: Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM