Tatiana G. Tolstikova

Control of in vivo transport and toxicity of nanoparticles by tea melanin

Nanoparticles are unfamiliar to researchers in toxicology. Toxicity may be generated simply due to the reduction in size. Compounds that prevent or cure toxic materials may not work on nanoparticles. Furthermore, as there are more and more applications of nanoparticles in drug delivery and in vivo imaging, controlling the transport and toxicity will be primary concerns formedical application of nanoparticles. Gold nanoparticles (GNPs) if injected intraperitoneally intomice can enter hippocampus and induce cognitive impairment. GNPs caused a global imbalance of monoamine levels, specifically affecting the dopaminergic and serotonergic neurons. Pretreatment of tea melanin significantly prevented the deposition of GNPs in mouse brains, especially in the hippocampus. Pretreatment of melanin completely alleviated GNP-induced impairment of cognition. Preadministration of melanin stably maintained monoamines at normal profiles. Melanin completely prevented the invasion of GNPs into the Cornu Ammonis region of the hippocampus shown by coherent anti-Stoke Raman scattering microscopy. Here we show that the administration of tea melanin prevented the accumulation of Au in brain, the imbalance of monoamines, and the impairment of cognition in mice. The current study provides a therapeutic approach to toxicity of nanoparticles and a novel strategy to control the transport of GNP in mouse brain.

Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity.

(5Z,9Z)-11-Phenylundeca-5,9-dienoic acid was stereoselectively synthesized, based on original cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran and buta-2,3-dien-1-ylbenzene with EtMgBr in the presence of Cp2TiCl2 catalyst giving 2,5-dialkylidenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and the Jones oxidation of the resulting 2-{[(5Z,9Z)-11-phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2Н-pyran afforded (5Z,9Z)-11-phenylundeca-5,9-dienoic acid in an overall yield of 75%. A high inhibitory activity of the synthesized acid with respect to human topoisomerase I (hTop1) and II (hTop2α) was determined.

nZ,(n + 4)Z-Dienoic fatty acids: a new method for the synthesis and inhibitory action on topoisomerase I and IIα

An original, effective approach to the stereoselective method for the synthesis of higher unsaturated acids containing a 1Z,5Z-diene group in 61–75xa0% yields and with >98xa0% selectivity based on the new intermolecular Cp2TiCl2-catalyzed cross-cyclomagnesiation of terminal aliphatic and O-containing 1,2-diene with Grignard reagents has been developed. The inhibitory action of the obtained dienoic acids on the human topoisomerase I and II was studied. Resorting to the data of molecular docking, a probable mechanism of inhibition was proposed.Graphical Abstract

Ethological Analysis of the Effects of Fluoglyzine on Mice Exposed to Chronic Social Stress

Ethological study of a new agent fluoglyzine (fluoxetine analog) was carried out. Porsolt test revealed a positive antidepressant effect of fluoglyzine in mice with pronounced depression-like state. This effect was more pronounced than the effect of fluoxetine. Both drugs effectively improved communicative activity of experimental animals. Anxiety tests showed no anxiolytic effects of fluoglyzine and fluoxetine.

Combined effects of social stress and liver fluke infection in a mouse model

The effects of two influences, social stress and acute opisthorchiasis, were investigated in inbred C57BL/6J male mice. In the model of social stress, mice were repeatedly attacked and defeated by aggressive outbred ICR male mice and were in continuous sensory contact with an aggressive conspecific mouse in their home cage for 20 days. Acute opisthorchiasis was provoked by invasion of Opisthorchis felineus (50 larvae per animal) on the fourth day after the social stress was induced. Simultaneous action of both factors caused the hypertrophy of adrenal glands, as well as elevated the activity of cathepsins B and L in the spleen. This effect on the activity of the cysteine proteases in the hippocampus and hypothalamus following O. felineus invasion was the predominant result of simultaneous action with social stress. Acute opisthorchiasis, social stress, and their combination caused an increase in the level of blood IL-6 in approximately 30% of the animals. Social stress induced a more pronounced effect on mouse plus-maze behavior than O. felineus invasion. Our results suggest a more severe negative effect of the simultaneous influence of both factors on most of the parameters that were investigated.

Changes in Blood Biochemistry in Mice during Development of Experimental Depression

Biochemical parameters of the plasma were studied in mice at different stages of the development of depression-like states in males after social defeats in 10 and 20 intermale confrontations (T10 and T20 victims, respectively). Glucose and cholesterol levels were increased in T10 victims in comparison with intact animals. In T20 victims the increase in glucose level was paralleled by an increase in total protein. T20 victims differed from T10 victims by lower catalase activity.

Social Defeat Stress Exacerbates the Blood Abnormalities in Opisthorchis felineus-infected mice

A model of chronic opisthorchiasis combined with social stress is examined; this situation is more likely for humans and animals than a separate impact of the infectious factor. For this purpose, we evaluated the effects of Opisthorchis felineus (OP group) and 30-day social stress (confrontations between males, SS group) alone and in combination (OPxa0+xa0SS group) in inbred C57BL/6 male mice and compared these effects according to the parameters listed below. The animals exposed to neither factor formed the control group (CON). All animals were assayed for blood biochemical parameters, changes in blood cell composition, and pattern of bone marrow hematopoiesis. By the end of the experiment, we have observed crucial effects of the two factors on the blood and liver of OP and OPxa0+xa0SS. Eosinophil and basophil counts increased and relative segmented neutrophil and monocyte counts decreased in OPxa0+xa0SS mice on the background of activated myelopoiesis, mainly determined by social stress. Despite depressed erythropoiesis, OP mice displayed no changes in the relative peripheral erythrocyte counts. On the contrary, social stress, which stimulated erythropoiesis in SS and OPxa0+xa0SS mice, was accompanied by a decrease in the relative erythrocyte counts and hematocrit. Hepatosplenomegaly was observed on the background of these two impacts. Changes in transaminase (ALT and AST) and alkaline phosphatase activities as well as an increase in cholesterol and product of lipid peroxidation suggest a pronounced destruction of the liver. Altogether, social stress exacerbates many of the assayed blood parameters in the mice infected with the liver fluke.

Effect of betulonic acid and its derivative [3-oxo-20(29)-lupene-28-oyl]-3-aminopropionic acid on liver structure in mice with RLS lymphoma.

Morphological study of the effects of semisynthetic derivatives of betulin (betulonic acid and [3-oxo-20(29)-lupene-28-oyl]-3-aminopropionic acid) on the liver of CBA/Lac mice with transplanted RLS lymphoma was studied in the control and after cytostatic polychemotherapy. The number of small focal necroses decreased, while the counts of hepatocytes in a state of slight hyaline droplet degeneration increased. Morphometry of the main elements of liver parenchyma showed that alanine amide derivative of betulonic acid decreases the severity of necrotic and degenerative changes in the liver parenchyma, induced by cytostatic polychemotherapy. Betulonic acid exhibited no appreciable hepatoprotective effect under these conditions.