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Group of Experimental pharmacology

The research interests of collective are concentrated in the area of modern lymphology, which includes three components as the object of its investigation: lymphatic (drainage, vascular) system, lymphoid (immune) system with its central and periphery branches and system of loose connective tissue (interstice). All these components in their interaction create a unified protective system (Member of the Russian Academy of Science V.I. Konenkov), which morphofunctional unit is lymphatic region, which include carrier and detoxicative components (Member of the Russian Academy of Science Yu. I. Borodin).

The head of experimental pharmacology group – principal researcher, PhD, Professor Svetlana V. Michurina. She is a member of the Scientific Council of the Interregional Scientific-Advisory center of the endoecological rehabilitation, Russian society of lymphologists, Siberian society of lymphologists, Society of anatomists, histologists and embryologists. The author of more than 320 works, including three monographs, 5 patents. Under the auspices of Michurina eight theses, including one doctoral thesis and seven PhD have been prepared and defended.

For her productive work, she was awarded an honorary certificate of the Presidium of the Russian Academy of Medical Science, of the Presidium of the Russian Academy of Medical Science Siberian branch, of the governor of the Novosibirsk region, medal and certificate of Rudolf Virchow (European Academy of Natural Science, Germany, Hanover). She completed internal and external training in the rules of preclinical investigation in accordance with GLP standards on the base of the center for genetic resources of laboratory animals of the Federal Research Center Institute of Cytology and Genetics of the Siberian branch of the Russian Academy of Medical Science.

Aims and objectives of the Group

- development of methodological and experimental basic concepts for resolving actual problems of publick health and medicine;

- research into the area of creation and investigation of new high-efficiency and safety drugs with lymphotropic effect;

- scientific rationale and engineering support of the rational medical practice and evidence-based medicine from the perspective of lymphatic prevention, correction and protection.

Key topics of the research work

- «comparative bioinformatics analysis assembly of genes of the regulation of the activity of the inflammation, angiogenesis, remodeling of connective tissue, taking part in the development of socially important human diseases of oncologic, inflammatory and dysmetabolic nature for development of the innovative technologies for individual forecast of its development, and also early diagnostic and individualization of therapy» (0539-014-0015) (head PhD Korolev M.A.) reg.№1150918500064;

- «study of molecular mechanisms, detection of genomic and postgenomic markers, development of new approach to correction pathological remodeling of blood, lymphatic vessels and connective tissue in case of endocrine pathology» (0539-2014-0011) (head PhD Klimontov V.V.) reg №115091850008.

Current research:

- development and verification of experimental models of pathology process for investigation of morphological and functional restructuring of different parts of the protective system;

- studying of structure-time, functional principles of organization of lymphatic region of different organs, lymphoid mass and system of loose connective tissue, that provide homeostasis and biological safety for healthy and sick organism in the ontogenesis and in the experimental pathology;

- detection of molecular peculiarities of the angio- and lymphoangiogenesis (influence of differentiation, functional activity and metabolism of endothelium of lymphatic vessels and lymphoid cells on the process of the development of the programmed cell’s death in the lymphatic regions and other organs), in the light of sexual dimorphism and lymphatic endocrine relation in the norm and pathology, directed on the development of new approach to strategy of management of the adaptative process of the prevention and correction of the pathological shift in organism;

- participation in development of medicaments and technology of preventive and curative influence on the lymphatic system (lymphatic prevention, lymphatic correction and lymphatic protection) on the base of substitution of import material by domestic one with propose to receive original domestic medicaments for the treatment and prevention of socially important diseases;

- realization of biomedical trial and valuation of biological acceptability of chemical and biological substance, stuff, materials and equipment of the medical, manufacturing and domestic use.

Clinical directions:

Hepatology, Rheumatology, Endocrinology, Oncology, Neuropathology, Neuro-immune-endocrine relation and other.

Methods of investigation:

Light microscopy, fluorescein microscopy, electronic microscopy, histochemical methods, immunohistochemical methods, quantitative valuation of molecular particularities of liver and lymphatic nodes, methods of morphometric analysis of the micro- and ultrastructural peculiarities of the lymphatic regions of organs.

Experiments are realizing on the base of Common use center “SPF-vivarium” Institute of Cytology and Genetics of the Siberian branch of the Russian Academy of Medical Science.

Experimental animals: homozygous mice db/db line BKS.Cg-Dock7m+/+Leprdb/J with model of obesity and diabetes mellitus type 2, SPF mice С57Bl/6J, rats Wistar and other.

Within a realization of trials of new medicaments group of “Experimental farmacology” initiator and, шт cooperation with Common use center “SPF-vivarium” Institute of Cytology and Genetics of the Siberian branch of the Russian Academy of Medical Science, creator of the cluster “Farmakon”, which connects efforts of high-grade specialists in area of microscopy and work with laboratory animals. Aim of cluster “Farmakon” is supporting realization of wide-ranging scientific investigations in the area of actual medicine for deciphering of mecanisms of action of the biologically active substance and creation original domestic medicaments with hemorrheological, lymphotropic, anxiolytic, antidepressant, nootropic and antihypoxic activity for its using in personalized treatment and prevention of socially important diseases. These investigations are realizing with use of modern high-technology laboratory animals - models of human pathology.

Within the confines of activity of “Farmacon” it’s planning to realize an investigation on valuation:

Hematotropic effects of medicaments

Muscular endurance of animals effected by medicaments

Blend composition of animal’s body: content of fat, water, free stock with use of low-floor MRI-scanner;

Neuro-vegetative reaction of animals caused by medicaments.

Results of investigation of group of “Experimental farmacology”

Using the integral approach, with the evaluation of the studied objects at the subcellular, cellular, tissular, molecular levels and the level of inter-system interworking, taking into account the biorhythms, which are a necessary component of the adaptative process, let to obtain a whole series of new data on the morphofunctional role of the lymphatic regions of the liver, reproductive system organs in the formation of adaptive and pathological reactions under the influence of ecological damaging factors of the anthropogenic nature ( Benz (A) pyrene (BaP), Malathion, tetrachloromethane, ethanol, influence of the power frequency magnetic field, high temperature, full-time light, alimentary obesity and other:

Were identified peculiarities of the daily time organization of the liver and its lymphatic region in condition of the disturbance of the light regime, which leads to disturbance of melatonin synthesis (functional epiphysectomia of the melatonin-producing function of the epiphysis) and the development of desynchronosis. Were determined the possibility of correction of disturbed circadian biorhythms of the lymphatic region of the liver and organs of the reproductive system with use of melatonin (Patent No. 2418586).

Were studied interrelation between the lymphatic region of the liver and regulatory and metabolic systems (lymphatic, immune, endocrine).

Selected Publications

2019

Hepato-immune-epiphysis axis of inter system interactions. Melatonin and structural-functional changes in the liver and immune system during obesity and diabetes mellitus type 2 / Michurina S.V., Letyagin A.Yu., Shurlygina A.V., Korolev M.A.,Ishenko I.

Yu., Vasendin D.V., Archipov S.A. – Novosibirsk «Manuscript Press», 2019. – 320 pages.ISBN 978-5-93240-306-8

The book can be useful for anatomists, histologists, lymphologists, immunologists, pathophysiologists, hepatologists, doctors (endocrinologists, therapists), students and teachers of biological and medical universities.

Reviewer

Honored Worker of the Higher School of the Russian Federation, Doctor of Medical Sciences, Professor Department of Histology, Embryology and Cytology of Novosibirsk State medical university (FGBOU VO NGMU of the Ministry of Health of Russia)

Yu.I. Sklyanov

Doctor of Medical Sciences, professor, Head of the Department of Pharmacology, clinical pharmacology and evidence-based medicine of Novosibirsk State medical university (FGBOU VO NGMU of the Ministry of Health of Russia) P.G. Madonov

The monograph contains the results of many years of work of the employees of Research Institute of Clinical and Experimental Lymрhology and the SPF Vivarium (branches of the Institute of Cytology and Genetics of the SBRAS) dedicated to the study of the micro, ultrastructural organization of liver and the main homeostatic systems of the body (lymphatic, immune) in conditions of metabolic syndrome, obesity, sugar Type 2 diabetes, which in modern society is one of the most pressing problems of medicine. According to the latest scientific data, these pathological conditions develop against the background of a disturbance or/and decrease in melatonin production. In the above studies, an integral approach was used with the assessment of the objects under study at the molecular,subcellular, cellular, tissue levels and the level of intersystem interactions taking biochemical data into account.

The book provides extensive factual material based on the results of our own research, which characterizes the morphological changes in the liver of BKS.Cg-Dock7m + / + Leprdb / J mice with genetically determined development of obesity and type 2 diabetes and under conditions of melatonin correction. The micro, ultrastructural and molecular characteristics of the liver of breeding animals (db / db mice of different sexes and ages) in the dynamics ofthe development of T2D are supplemented. Structural changes in hepatocytes of adult db / db mice, indicating the development of non-alcoholic fatty liver disease (NAFLD), were detected. At the ultrastructural level, a violation of the morphological organization of the hemato-lymphatic barrier of the liver has been established, 9which was manifested in the stagnation of the lymph, impaired energy and protein synthesizing cell apparatus, lipid accumulation, glycogen. An important set of questions concerns the study of the molecular features of programmed cell death in the liver in db / db mice, in postnatal ontogenesis with regard to sexual dimorphism. It has been shown that in childhood, female and male animals do not have differences in the expression of the Bcl-2 family of the P 53 gene: the double expression of the anti-apoptotic protein Bcl-2 over the pro-apoptotic protein Bad revealed in these animals indicates the creation of anti-apoptotic protection and the blocking of mitochondrial "branches” of apoptosis. It has been established that antiapoptotic protection remains in the liver cells of mature BKS.Cg-Dock7m + / + Leprdb / J female mice, while in adult males of this line a change in the ratio of apoptosis regulating proteins is found: minimal Bcl-2 expression in the background a threefold increase in the expression of Bad, which indicates the activation of apoptosis. The effects of intragastric administration of the complex created on the basis of melatonin, aluminum oxide and polymethylsiloxane (“Complex M”) developed by NIICEL, RF patent No.

2015100920/05 (001238) in db / db mices were studied. It has been shown that in the experimental model of obesity and diabetes mellitus(type 2), Complex M exhibits lymphotropic, hepatotropic and cytoprotective effects, which makes it possible to consider this drug as a promising drug for the complex therapy of obesity and type 2 diabetes.

The results of studies of the immune system in rats with induced alimentary obesity, indicating a shift in the ratio of mature and immature subpopulations of thymocytes towards more differentiated cells, are presented. In rats that were on a high-fat diet, changes in the cellular composition of the secondary organs of the immune system – the spleen and mesenteric lymph nodes were de10 tected. At the same time, in spleen was showed increasing of proportion of B lymphocytes with a simultaneous decrease in the percentage of T cells, antigen presenting (CD11b / c +) and activated splenocytes (CD25 +). In the lymph nodes, where most of the cells are represented by T-cells, the percentage of activated CD25 +lymphocytes was also reduced. It is concluded that a fatty diet leads to an imbalance between the B and T cell levels of the immune system.

The use of melatonin leveled changes in lipid metabolism in the blood and liver, which is consistent with the literature data on the possibility of using melatonin as a hypolipidemic agent and as an effective protector of fatty hepatosis. Evidence is given that treatment with melatonin leads to the normalization of a number of parameters of the cellular composition of the organs of the immune system, which can be regarded as the restoration of immunoregulatory mechanisms.

Thus, it was found that both substanses (melatonin and Complex M), which have potent antioxidant, lipid-lowering, immunomodulating, lymphotropic, hepatotropic and сytoprotective effects, are promising means for correcting disorders of lipid metabolism and immune status in alimentary obesity. At the same time, Complex M has a more pronounced effect.

Bulletin of Experimental Biology and Medicine December 2019, Volume 168, Issue 2, pp 205–209| Cite as DOI 10.1007/s10517-019-04675-x. Expression of Apoptosis Regulator Proteins Bcl-2 and Bad in Rat Ovarian Follicular Apparatus during Recovery after Extreme Hypothermia

S. V. Michurina,S. I. Kolesnikov,A. L. Bochkareva,I. Yu. Ishchenko,S. A. Arkhipov

GENERAL PATHOLOGY AND PATHOPHYSIOLOGY

The expression of molecular and cellular regulators of apoptosis (proapoptotic protein Bad and antiapoptotic protein Bcl-2) was measured in the follicular apparatus of rat ovaries during the recovery period (days 7 and 14) after hyperthermia (up to rectal temperature 43.5°C). The Bcl-2/Bad index was calculated. The expression of Bcl-2 in the follicular apparatus of rat ovaries increased on day 7 after the exposure. The Bcl-2/Bad index also increased, which suggests that the development of apoptosis by the mitochondrial pathway in follicles was limited at this term after hyperthermia. On day 14 after hyperthermia, the area of immunohistochemical staining for the antiapoptotic protein Bcl-2 significantly decreased in cells of the ovarian follicular epithelium, but the expression of the proapoptotic protein Bad significantly increased; these changes led to a decrease in Bcl-2/Bad index, which attested to weakening of the antiapoptotic defense and activation of oocyte apoptosis by the mitochondrial pathway. Springer Nature 2019 Bulletin of Experimental Biology and Medicine November 2019, Volume 168, Issue 1, pp 28–32|. DOI10.1007/s10517-019-04638-2 Cite as Effects of Melatonin on the Body Composition, Physical Performance, and Blood Erythrocyte Indexes of C57Bl/6J Mice Exposed to Continuous Illumination

S. V. Michurina,I. Yu. Ishchenko,M. A. Korolev,A. Yu. Letyagin,L. N. Rachkovskaya,A. S. Khotskina,N. V. Khotskin,S. O. Maslennikova,E. L. Zavjalov

Male C57Bl/6J mice were exposed to daily 24-h illumination over 14 days and daily intragastrically received melatonin (1 mg/kg) or water (placebo). Controls were kept under standard day/night (14/10 h) conditions. Melatonin prevented the development of anemia in mice exposed to continuous illumination, which was proven by higher blood hemoglobin levels by the end of the experiment in melatonin-treated animals in comparison with the placebo group. Studies by the low-field NMR spectrometry detected lower lean body mass, total body water, and especially, fat content (by ~13%) in animals receiving placebo.

Melatonin treatment led to an increase in the lean body mass and total body water on day 7 (in comparison with the placebo group) without affecting fat mass. On day 14 of continuous illumination, lean body mass increased in comparison with the corresponding parameter in the control and placebo groups. Melatonin had no effect on the physical endurance of mice exposed to continuous illumination (assessed by the grid hanging test). Springer Nature 2019

Svetlana V. Michurina1, Irina Yu. Ishchenko1, Andrey Yu. Letyagin, Maksim A. Korolev, Liubov N. Rachkovskaya, Anna S. Khotskina, Nikita V. Khotskin, Svetlana O. Maslennikova, Evgenii L. Zavjalov Effects of Melatonin on the Body Composition, Physical Performance, and Blood Erythrocyte Indexes of C57Bl/6J Mice Exposed to Continuous Illumination Bulletin of Experimental Biology and Medicine, 2019. 168 (1), 28-32 DOI10.1007/s10517-019-04638-2 Springer

Effects of Melatonin on the Body Composition, Physical Performance, and Blood Erythrocyte Indexes of C57Bl/6J Mice Exposed to Continuous Illumination.S. V. Michurina1, I. Yu. Ishchenko1, M. A. Korolev1, A. Yu. Letyagin1,2,L. N. Rachkovskaya1, A. S. Khotskina2, N. V. Khotskin2,S. O. Maslennikova2, and E. L. Zavjalov2 DOI10.1007/s10517-019-04638-2 Springer

Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 168, No. 7, pp. 33-38, July, 2019. Original article submitted January 23, 2019

Studies by the low-field NMR spectrometry detected lower lean body mass, total body water,and especially, fat content (by ~13%) in animals receiving placebo. Melatonin treatment ledto an increase in the lean body mass and total body water on day 7 (in comparison with theplacebo group) without affecting fat mass. On day 14 of continuous illumination, lean bodymass increased in comparison with the corresponding parameter in the control and placebogroups. Melatonin had no effect on the physical endurance of mice exposed to continuousillumination (assessed by the grid hanging test).

2018

Michurina S.V., Bochkareva A.L., Arkhipov S.A., Ishchenko I.Yu., Kolesnikov S.I. Expression of Bcl-2 Family Proteins in the Ovarian Follicular Apparatus in the Acute Period after Experimental Hypertermia. // Bulletin of Experimental Biology and Medicine.- 2018.- T.164, N6.- c.780-783. Scopus Web of Science PMID: 29658076 DOI:10.1007/s10517-018-4079-9

СKazakov, OV; Kabakov, AV ; Poveshchenko, AF; Raiter, TV; Strunkin, DN; Bogachev, SS; Ishchenko, IY; Lykov, AP; Michurina, SV; Konenkov, VI Effect of Various Treatment Modes of Experimental Mammary Gland Tumor on Structure of Anterior Mediastinal Lymph Nodes // BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE. - 2018. - Т.164, Выпуск:5. - С.661-665.WOSDOI:10.1007/s10517-018-4054-5

S. V. Michurina ; I. Yu. Ishchenko ; M. A. Cherepanova ; S. A. Arkhipov ; Yu. I. Borodin ; E.L. Zavjalov, D.V. Vasendin. Apoptosis in the liver of db/db Mice Female in Postnatal Ontogenesis. 2018 11th International Multiconference Bioinformatics of Genome Regulation and StructureSystems Biology (BGRSSB) 20-25 Aug. 2018.-Publication Year: 2018, Page(s):5 – 9.

Yuriy I. Borodin ; Lybov N. Rachkovskaya ; Tatyana. V. Popova ;Anastasiya A.Kotlyarova ; Svetlana V. Michurina ; Anna V. Shurlygina ; Edmund E.Rachkovskiy ; Margarita V. Robinson ;Pavel G. Madonov ; Maxim A. Korolev ; Andrey Yu.Letyagin ;Vladimir I. Konenkov.Modified Sorbents for Pharmacology. 2018 11th International Multiconference Bioinformatics of Genome Regulation and StructureSystems Biology (BGRSSB),20-25 Aug. 2018.-Publication Year: 2018, Page(s):47 – 50.

Borodin Yu.I., Rachkovskaya L.N., Popova T.V., Kotlyarova A.A., Michurina S.V., Shurlygina A.V., Rachkovsky E.E., Robinson M.V., Madonov P.G., Korolev M.A., Letyagin A.Yu., Konenkov V.I. Modified sorbents for pharmacology. // Systems Biology and Biomedicine (SBioMed-2018): Symposium (21-22 Aug. 2018, Novosibirsk,Russia).- Novosibirsk: ICG SB RAS, 2018.- c.29.

Michurina S.V., Ishchenko I.Yu., Cherepanova M.A., Arkhipov S.A., Klimontov V.V., Zavyalov E.L. Linagliptin effect on expression of apoptosis regulators Bcl-2 and Bad in db/dbmice liver. // Systems Biology and Biomedicine (SBioMed-2018): Symposium (21-22 Aug. 2018, Novosibirsk, Russia).- Novosibirsk: ICG SB RAS, 2018.- c.90.

Michurina S.V., Ishchenko I.Yu., Cherepanova M.A., Arkhipov S.A., Zavyalov E.L. Apoptosis in the liver of db/db mice female in postnatal ontogenesis. // Systems Biology and Biomedicine (SBioMed-2018): Symposium (21-22 Aug. 2018, Novosibirsk,Russia).- Novosibirsk: ICG SB RAS, 2018.- c.91.

S. V. Michurina ; I. Yu. Ishchenko ; M. A. Cherepanova ; S. A. Arkhipov ; Yu. I. Borodin ; E.L. Zavjalov ; D.V. Vasendin Apoptosis in the liver of db/db Mice Female in Postnatal Ontogenesis. 2018 11th International Multiconference Bioinformatics of Genome Regulation and StructureSystems Biology (BGRSSB)20-25 Aug. 2018. EEE Xplore Digital Librar. Publication Year: 2018, Page(s):5 – 9.

Yuriy I. Borodin ; Lybov N. Rachkovskaya ; Tatyana. V. Popova ;Anastasiya A. Kotlyarova ; Svetlana V. Michurina ; Anna V. Shurlygina ; Edmund E. Rachkovskiy ; Margarita V. Robinson ;Pavel G. Madonov ; Maxim A. Korolev ; Andrey Yu. Letyagin ;Vladimir I. Konenkov. Modified Sorbents for Pharmacology Xplore Digital Librar.Publication Year: 2018, Page(s):47 – 50.

2017

Michurina C.V., Ishenko I.Yu., Archipov S.A., Klimontov V.V., Cherepanova M.A.¹, Korolev M. A., Rachkovskaya L. N., Konenkov V.I., Zavyalov E.L.INFLUENCE OF COMPLEX FROM MELATONIN, ALUMINUM OXIDE AND POLYMETHYLSILOXANE ON LIVER CELL APOPTOSIS IN A MODEL OF OBESITY AND DIABETES MELLITUS TYPE 2.// Springer,- Bulletin of Experimental Biology and Medicine, 2017, 164 (2), 165-169, DOI 10.1007 / s10517-017-3949-x

Kasakov O.V., Kabakov A.V., Ishchenko I.Y., Poveshchenko A.F., Raiter T.V., Strunkin D.N., Michurina S.V., Konenkov V.I. The Thymus in Experimental Mammary Carcinogenesis and Polychemotherapy // Bulletin of Experimental Biology and Medicine, 2017. - Vol.162, N4. - P.479-482/