V. I. Kaledin

Chitotriosidase as a Marker of Macrophage Stimulation

Serum chitotriosidase activity was determined in different conditions accompanied by macrophage stimulation. Stimulation of macrophages with zymosan, yeast polysaccharide carboxymethylglucan (fraction II), and lysosomotropic preparation Triton WR-1339 1.5-2.0-fold increased enzyme activity. Chitotriosidase activity in intact Wistar rats was similar to that in humans, while in CBA and A/Sn mice this parameter was 5-fold higher. Sharp increase in chitotriosidase activity in the serum from patients with type I Gauchers disease was probably related to intense secretion of the enzyme by macrophages. Under experimental conditions, stimulation of rat and mouse macrophages (mainly liver cells) caused no increase in chitotriosidase activity typical of patients with Gauchers disease.

Correlation between hepatocarcinogenic effect of estragole and its influence on glucocorticoid induction of liver-specific enzymes and activities of FOXA and HNF4 transcription factors in mouse and rat liver

It is known that the carcinogenic effect of estragole, a component of essential oils of many spicy plants, is characterized by species, tissue, and sex specificity. It causes mainly liver tumors in female mice but is not carcinogenic for male mice and for rats. In this work, the estragole hepatocarcinogenicity was shown for female mice of previously not studied ICR line. The strict correlation between estragole hepatocarcinogenicity and its ability to decrease the level of glucocorticoid induction of liver-specific enzymes tyrosine aminotransferase (TAT) and tryptophan oxygenase (TO) was found. Inhibition of TAT and TO inducibility by estragole takes place only in female mice but not in male mice and in rats. Studying the estragole effect on DNA-binding activity of transcription factors, present mainly in liver and regulating expression of genes encoding liver-specific proteins, has shown that estragole decreases FOXA and HNF4 activities but not activities of C/EBP and HNF1, and this happens only in female mice, for which this substance is hepatocarcinogen, but not in male mice and in rats. Pentachlorophenol, preventing hepatocarcinogenic effect of estragole, abolishes inhibitory influence of the latter on the TAT and TO glucocorticoid induction and restores DNA-binding activity of FOXA and HNF4. Thus, a correlation was revealed between the estragole hepatocarcinogenic effect and decrease in DNA-binding activity of transcription factors FOXA and HNF4, which might be indicative of the role of these factors in tumor suppression mechanisms in liver.

Influence of atorvastatin and carboxymethylated glucan on the serum lipoprotein profile and MMP activity of mice with lipemia induced by poloxamer 407

The effects of atorvastatin and carboxymethylated β-glucan (CMG) on the lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subfractions at the early stage of murine hyperlipidemia, and its pleiotropic anti-inflammatory effects, were studied. Atorvastatin and CMG were administered in ICR male mice with acute lipemia induced with a single injection of poloxamer 407 (P-407). A novel small-angle X-ray scattering method for the determination of fractional and subfractional composition of LP-C and LP-TG was used. In P-407-treated animals, there was a drastic increase of total cholesterol and especially TG. Atorvastatin decreased both the total cholesterol and TG, but not to control levels. CMG primarily decreased TG and was not as potent as atorvastatin. P-407 increased atherogenic LDL-C (IDL-C and LDL(1-3)-C subfractions) and very low-density lipoprotein-C (VLDL-C) (VLDL(1-2)-C and VLDL(3-5)-C subfractions) fractions, with an increase of the total anti-atherogenic HDL-C fraction (HDL(2)-C subfraction). Atorvastatin treatment of lipemia was followed by a decrease in the total LP-C, total LDL-C (LDL(1-3)-C subfraction), and the LDL(1-3)-TG subfraction. Additionally, atorvastatin treatment resulted in an increase in the serum matrix metalloproteases activity both in control and P-407-treated mice. In general, high-dose atorvastatin therapy exerts its lipid-lowering and pleiotropic effects in the early stages of acute lipemia induced in mice by treatment with P-407.

Hepatocarcinoma-29, a metastasizing transplantable mouse tumor inducing cachexia.

Here we describe an experimental tumor, hepatocarcinoma-29: transplantable strain of this tumor is maintained in an ascitic form in СВА/LacYIcgn mice in Institute of Cytology and Genetics of SD of RAS. After inoculation into the thigh muscles, the tumor induces anorexia, progressing loss of fat and muscle tissues, and physiological changes specific for cachexia: leukocytosis, hypoglycemia, and hypercorticism. The tumor metastasizes to all vital viscera and leads to animal death from renal failure.

Glutathione S-transferase activity in the liver of mice with different sensitivity to hepatocarcinogenic effects ofo-aminoazotoluene

Glutathione S-transferase activity was detected in the liver of inbred mice sensitive (CBA) and resistant (CC57BR and C57B1) to hepatocarcinogenic effects ofo-aminoazotoluene. High liver glutathione S-transferase activity was found in CC57BR and C57B1 and low in CBA mice treated with this carcinogen. Thus, interstrain differences in glutathione S-transferase activity probably determine the resistance too-aminoazotoluene-induced hepatocarcinogenesis.

Inhibitor of Indoleamine-2,3-Dioxygenase 1-Methyl-D-Tryptophan Can Stimulate the Growth of Immunogenic Tumors

We studied the effect of 1-methyl-D-tryptophan, an inhibitor of indoleamine-2,3-dioxygenase, on the growth of transplanted hepatocarcinoma-29 in C3HA mice. Hepatocarcinoma-29 transplanted into the thigh muscles undergoes immunological rejection in more than 50% non-syngeneic recipients. Chronic local administration of 1-methyl-D-tryptophan promotes progressive growth of the tumor in recipient mice leading to 100% animal death. The stimulating effect of 1-methyl-D-tryptophan on tumor growth is discussed.

Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia

Objectives  The effects of atorvastatin on the atherogenic and anti‐atherogenic lipoprotein‐cholesterol (C‐LP) and lipoprotein‐triglyceride (TG‐LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti‐inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied.

Mutagenic activation and carcinogenicity of aminoazo dyes ortho-aminoazotoluene and 3′-methyl-4-dimethylaminoazobenzene in experiments on suckling mice

It is found that after administration of 3′-methyl-4-dimethylaminoazobenzene (3′-Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3′-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3′-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation.

Mutagenic Activation Reduces Carcinogenic Activity of Ortho-Aminoazotoluene for Mouse Liver

Pentachlorophenol (aromatic amine and azo stain metabolic stimulation inhibitor) reduced the hepatocarcinogenic activity of 4-aminoazobenzene and reduced that of ortho-aminoazotoluene in suckling mice. Both 4-aminoazobenzene and ortho-aminoazotoluene exhibited mutagenic activity in Ames’ test in vitro on S. typhimurium TA 98 strain with activation with liver enzymes; this mutagenic activity was similarly suppressed by adding pentachlorophenol into activation medium. Induction of xenobiotic metabolism enzymes, stimulating the mutagenic activity of ortho-aminoazotoluene, suppressed its carcinogenic effect on mouse liver. Hence, ortho-aminotoluene (the initial compound), but not its mutagenic metabolites, was the direct active hepatocarcinogen for mice.

Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein

RLS lymphosarcoma characterized by enhanced expression of mdr1a and mdr1b genes encoding P-glycoprotein is insensitive to low doses of cyclophosphamide, but is susceptible to its high doses approximating the maximum tolerated doses. Induction of apoptotic death of RLS cells by high doses of cyclophosphamide was demonstrated by cytofl uorometry and electrophoresis. Experiments on RLS40 tumor cells derived from RLS lymphosarcoma and characterized by more intensive expression of mdr1a/1b genes showed that the therapeutic effects of cyclophosphamide increased under conditions of simultaneous suppression of these genes by specifi c small interfering RNA (siRNA). These fi ndings suggest that active cyclophosphamide metabolite can be a substrate for P-glycoprotein.