[Metformin slows down ageing processes at the cellular level in SHR mice].

It has been shown recently that metformin, the indirect mTOR-kinase inhibitor, significantly increases medium (by 37.8%) and maximum (by 10.3%) life span of SHR mice (Anisimov et al., 2008). We obtained fibroblasts from skin of 11-, 16-, 19- and 23-months-old SHR mice treated with metformin since the third and ninth day of life. We studied markers of cellular senescence in these fibroblasts. Significant differences were observed between the average number of senescence-associated heterochromatic foci (SAHF), the average of area nuclei and fluorescence intensity of nucleus after staining for gamma-H2AX in control and experimental animals. Also, we showed that metformin prevented the accumulation of fibroblasts with large area of nuclei; high activity of senescence-associated beta-galactosidase (SA-beta-gal), and high fluorescence intensity after staining for gamma-H2AX. It appears that accumulation of large quantity of senescence markers within a cell triggers it to enter the aging process. It appears that the increase of "old" cell population above the threshold disrupts the normal function of certain tissues, organs, and finally, the whole organism. It appears that metformin delays the "old" cells accumulation and prolongs the organism youth.

[Hepatocyte mitochondrion respiratory chain in rats with experimental toxic hepatitis].

The purpose of this study was to examine hepatocyte mitochondrion respiratory chain in rats subjected to ethanol and CCl4 administration within 4 weeks to induce an experimental hepatitis. Oxygen consumption was determined as a measure of mitochondrion respiration chain function. The development of liver pathology was accompanied by fat accumulation, fibrosis, triglycerides and lipid peroxidation increase. Respiratory chain characteristics damage was found. Endogenous oxygen consumption by hepatocytes isolated from pathological liver was found 34% higher compared to control. Exogenous malate and pyruvate substrates delivery didn't stimulate cell respiration. Rotenone (the inhibitor of the I complex) decreased 27% oxygen consumption by pathological hepatocytes while dinitrophenol produced 37% cell respiration increase. States 3 (V3) and 4 (V4) mitochondrial respiration with malate + glutamate as substrates were found to be 70 and 56% higher accordingly compared to control level. V3 and Vd (dinitrophenol respiration) for mitochondria from pathological liver didn't differ from control when being tested with malate + glutamate or succinate as substrates. Cytochrome c oxidase activity increased (+ 80%) as compared to control. Administration of hypolipidemic agent simvastatin simultaneously with ethanol and CC14 resulted in decrease liver fat accumulation, fibrosis and peroxidation products. Simvastatin administration caused hepatocyte endogenous respiration decrease while malate + pyruvate, dinitrophenol or rotenone delivery produced oxygen consumption alterations similar to control. However, when isolated mitochondria from liver of simvastatin treated animals being tested the decrease of oxidative phosphorylation coupling for substrates malate + glutamate was found. While simvastatin did not cause changes in cytochrome c oxidase activity. We propose the hypothesis that the NCCR complex in rat mitochondria with experimental toxic hepatitis works extensively on superoxydanion production. Alterations of SCCR, Coenzyme Q-cytochrome c-reductase, cytochrome c oxidase and ATP-synthase activities have an adaptive nature to compensate for impaired NCCR function.

[New protective effect of simvastatin in rats with experimental steatohepatitis].

The intragastric introduction of carbon tetrachloride (CCl4) (0.2 ml/kg in 50% oil suspension, twice a week) and ethyl alcohol (5% solution ad libitum as the only available drink) in rats over a period of four weeks results in the development of inflammation, fibrosis, and fatty dystrophy in the liver. Such a fast formation of liver damage is obviously caused by potentiating effect of alcohol in combination with CCl4. Simultaneous injection of simvastatin (1 mg/kg, intragastrically) in rats with ethanol--CCl4 hepatitis decreased fatty dystrophy and produced certain anticytolytic and anticholestatic effects without potentiation of microsomal oxidation system damage by hepatotoxins. In addition, simvastatin shows hypolipidemic activity, which is manifested primarily by a decrease in the general holesterol level in the blood serum.

[Kinetic features of a white rat hepatocyte population under hormonal disbalance before and after partial hepatectomy].

Bilateral adrenalectomy, followed in 4 days by a partial hepatectomy, was performed using white rats weighing as much as 120-140 g. Under hormonal disbalance caused by bilateral adrenalectomy, the number of polyploid (4c, 4c x 2, and 8c) hepatocytes significantly increased, compared to that in non-operated control rats. Six hours after a partial hepatectomy, the share of highly ploid hepatocytes falls, being accompanied by a 9-fold increase in mitotic index. It is supposed that under hormonal disbalance condition, a partial hepatectomy may induce "early" mitoses in hepatocytes blocked in G2-phase of the cell cycle.