Activities:

• Study of molecular biology and gene expression of the xenobiotic metabolism system and molecular mechanisms of socially significant diseases in clinical and experimental studies.
• Study of the Effects of Newly Created Synthetic Potential Drug Compounds on Regulatory Molecules and Their Associated Signal Enzyme Cascades, mediating the pharmacokinetics of drugs.

Grishanova Alevtina Yurievna graduated from Novosibirsk State University in 1975 G.

S 1975 after 1992. worked at the Institute of Clinical and Experimental Medicine of the Siberian Branch of the USSR Academy of Medical Sciences, then with 1992 on 1998 years. – at the Research Institute of Molecular Pathology and Ecological Biochemistry, Siberian Branch of the Russian Academy of Medical Sciences, and with 1998 d - at the Research Institute of Molecular Biology and Biophysics of the Siberian Branch of the Russian Academy of Medical Sciences

The main direction of scientific activity of Grishanova A.Yu.. are fundamental and applied studies of the processes of biotransformation of foreign chemicals in the human and animal body by the system of monooxygenases.

The studies were devoted to the mechanisms of regulation of cytochrome P450 gene expression, negative regulation of induction of cytochrome P450 subfamily 1A, induced by polycyclic aromatic hydrocarbons and involved in the metabolic activation of these procarcinogens, as well as the study of cellular mechanisms of multidrug resistance of tumors and the role of genetic polymorphism of xenobiotic biotransformation enzymes and transport proteins in the protein expression of these genes and the formation of multidrug resistance of tumors of various etiologies.

Laboratory research results are mainly associated with the study of the mechanisms of regulation of the activity of enzymes of the metabolism of foreign compounds (cytochrome P450), with elucidation of the consequences of single nucleotide substitutions in the genes of cytochromes P450, involved in the biotransformation of anticancer drugs, for the effectiveness of drug therapy and detection of CYP genes, which influence the individual response to anticancer drugs, with the clarification of the experimental model of molecular genetic prerequisites for the development of macular degeneration, associated with aging, as well as studies of newly created synthetic compounds as potential medicinal agents.

In studies of the phenomenon of induction of enzymes of the monooxygenase system of the liver, an inducing effect of cold on the activity of cytochromes P450 of the subfamily 1A was found. – CYP1A, rat liver. Mechanism research, underlying increase in the activity of cytochromes P450 subfamily 1A in the liver of rats when exposed to moderate cold, made it possible to establish the mechanism of CYP1A1 induction in the liver when exposed to cold, which consists in the transcriptional activation of the CYP1A1 gene with the participation of AhR. Shown, that alpha-tocopherol may be an endogenous mediator of CYP1A1 induction by cold.

The possible role of tyrosine protein kinases in the activation of CYP1A in the liver of experimental animals under the influence of cold was studied using tyrosine kinase inhibitors as a research tool. – genistein, gerbimycin A and geldanamycin. Was shown, that CYP1A2 activation occurs at the post-transcriptional level. CYP1A1 activation, caused by exposure to cold or classic CYP1A inducers, is AhR-dependent and occurs at the level of transcription. The use of protein tyrosine kinase inhibitors has revealed differences between molecular mechanisms, underlying effects of classical CYP1A inducers and cold induction.

In the study of the role of genetic polymorphism of xenobiotic biotransformation enzymes and transport proteins in the protein expression of these genes and the formation of multidrug resistance of tumors of various etiologies. The results of the study showed, that polymorphism of the cytochrome P4502C9 gene is associated with the progression of breast cancer in women, and GSTP1 gene polymorphism, MDR1 and MRP1 may be an important factor, determining predisposition to lymphoproliferative diseases, as well as drug resistance.

A study of gene expression was carried out, functionally associated both with antioxidant defense processes, and capable of mediating the development of oxidative stress, in the retina of two sublines of OXYS rats, differing in clinical signs of retinopathy, and “healthy” Wistar rats. The expression of the transcription factor genes AhR and Nrf2 was studied, as well as phase I genes of xenobiotic metabolism enzymes, regulated AhR/XRE (SYP1A1, СYP1A2, СYP1B1), phase II genes enzymes of xenobiotic metabolism, regulated AhR/XRE (UGT1A1,ADH 3A1), phase II genes enzymes of xenobiotic metabolism, regulated AhR/XRE and Nrf2/ARE (NQO1, GSTA2, UGT1A6) in retinal cells of sublines of OXYS rats and Wistar rats of different ages. Interstrain Differences in Gene Expression Revealed, responsible for the balance in the cell of redox events – transcription factors AhR, Nrf2 and the genes they regulate, as well as features of the expression profile of these genes in prematurely aging OXYS rats with a high incidence of retinopathy during the development of retinopathy. The results suggest, that one of the triggers for the development of oxidative stress in the development of age-related macular degeneration may be an innately reduced level of AhR expression.

The ability of melatonin to modulate the gene expression of the AhR-Nrf2 signaling pathways in the retina was studied. In the retina of OXYS and Wistar rats, mRNA levels of Nrf2 and Nrf2-dependent genes were determined, mRNA levels of AhR and AhR-dependent genes and genes, dependent as on AhR, and from Nrf2. Shown, what is the melatonin dose, equivalent to that recommended for humans, does not cause significant changes in the expression of Nrf2-dependent genes in the retina of OXYS rats in OXYS rats, but reduces the mRNA level of AhR-dependent genes CYP1A2 and CYP1B1.

The ability of the mitochondrial antioxidant SkQ1 to modulate the expression of genes of the AhR-Nrf2 signaling pathways in the retina of OXYS rats was studied and shown, that Cyp1a2 and Cyp1b1 may be a therapeutic target for SkQ1.

Research done, that formed methodological approaches for the study of microvesicles of various origins secreted by cells, as well as antitumor therapeutic targets, which may have clinical perspectives in the future.

So, studies were conducted on the formation of methodological approaches to identify, identification and characterization of extracellular vesicles from the blood plasma of healthy donors and patients with chronic lymphocytic leukemia, studied extracellular vesicles from cell lines of lymphocytic origin U937 and Raji, secreted by chemotherapy, included in the treatment regimens for lymphoproliferative diseases.

The results of the CYP1A downregulation study showed, that menadione can prevent the inducing effect of benzopyrene on CYP1A activity, α-tocopherol and quercetin, and inhibition of CYP1A1 and CYP1A2 activity by menadione and quercetin occurs due to a decrease in the level of transcription of the corresponding genes, caused by a decrease in the DNA-binding capacity of AhR.

In the search for new antitumor agents in the series of phenolic antioxidants and transition metal complexes, cytotoxic, cytostatic, antioxidant activities of new original compounds, as well as their ability to modulate the expression of cytochromes P450 3A4, 2C9 and 2C19. The established patterns of changes in biological properties depending on the structure of the complexes can subsequently be used for the targeted synthesis of new compounds with desired functional properties.. Of the studied compounds, a number for further research as potential antitumor agents has been identified.. A phenotypic screening method using Hoechst and DiD dyes was proposed., which allows you to identify connections, active, similar to the activity of compounds with a known mechanism of action, and can be used for further research.

Publications

1. Grishanova, A. Y.; Perepechaeva, M. L. Aryl hydrocarbon receptor in oxidative stress as a double agent and its biological and therapeutic significance // International Journal of Molecular Sciences. — 2022. — Vol. 23. P. 6719. doi: 10.3390/ijms23126719
2. Klyushova L. S., Kandalintseva N. V., Grishanova A. Y. Antioxidant activity of new sulphur- and selenium-containing analogues of potassium phenosan against H2O2-induced cytotoxicity in tumour cells // Curr. Issues. Mol. Biol. – 2022 – July – T. 44, № 7. – C. 3131-3145. DOI: 10.3390/cimb44070216
3. Manakhov A.M., Solovieva A.O., Permyakova E.S., Sitnikova N.A., Klyushova L.S., Kiryukhantsev-Korneev P.V., Konopatsky A.S., Shtansky D.V. Adhesion and Proliferation of Mesenchymal Stem Cells on Plasma-Coated Biodegradable Nanofibers// J. Compos. Sci. – 2022– July – T.6. Article number: 193. DOI: 10.3390/jcs6070193
4. Klyushova L.S., Perepechaeva M.L., Grishanova A.Y. The Role of CYP3A in Health and Disease// Biomedicines – 2022 – Oct. - T. 10, №11. Article number: 2686. DOI: 10.3390/biomedicines10112686
5. Eremina, J.A., Smirnova, K.S., Leader, E.V., Klyushova L.S., Sheven’ D.G., Potkin V.I. Nickel(II) and cobalt(II) complexes with 4,5-dichloro-isothiazole-3-carboxylic acid and 1,10-phenanthroline: synthesis, crystal structures and cytotoxicity// Transit. Met. Chem. – 2022 – Jun – T. 47. – S. 19–30. DOI: 10.1007/s11243-021-00490-4.
6. Klyushova L. S., Golubeva Yu. A., Vavilin V. A., Grishanova A. Yu. Modulating action of Cu complexes(II) with enamine and tetrazole derivatives on CYP2C and CYP3A and their cytotoxic and antiproliferative properties in HepG2 spheroids // Acta Biomed. Scientist. – 2022 - T. 7 – № 5.
7. Eremina J. A., Lider E. V., Kuratieva N. V., Samsonenko D. G., Klyushova L. S., Sheven D. G., Trifonov R. E., Ostrovskii V. A. Synthesis and crystal structures of cytotoxic mixed-ligand copper(II) complexes with alkyl tetrazole and polypyridine derivatives // Inorganic Chemistry Acta. – 2021. – Feb. – T. 516. Article number: 120169 DOI: 10.1016/j.ica.2020.120169 WOS:000605618300006 ISSN: 0020-1693 eISSN: 1873-3255
8. Eremina J. A., Smirnova K. S., Klyushova L. S., Berezin A. S., Lider E. V. Synthesis and cytotoxicity evaluation of copper(II) complexes with polypyridines and 5-benzyltetrazole // Journal of Molecular Structure. – 2021. – Dec. – T. 1245. Article number: 131024 DOI: 10.1016/j.molstruc.2021.131024
9. Eremina Y. A., Ermakova E. A., Sukhikh T. S., Klyushova L. S., El'tsov I. V., Samsonenko D. G., Dotsenko V. V., Zubenko A. A., Fetisov L. N., Kononenko K. N., Lider E. V. Synthesis, structure, and study of the biological activity of Co(II), In(II), AND With(II) complexes with an enaminedione derivative // Journal of Structural Chemistry. – 2021. – Feb. – T. 62, № 2. – C. 309-320. DOI: 10.1134/S0022476621020165
10. Ivanova A. D., Kuz'menko T. A., Komarov V. Y., Glinskaya L. A., Sheludyakova L. A., Klyushova L. S., Lavrenova L. G. Synthesis and study of complexes of cobalt(II), nickel(II), and copper(II) halides with 2-(3,5-dimethylpyrazol-1-yl)benzimidazole // Russian Chemical Bulletin. – 2021. – Aug. – T. 70, № 8. – C. 1550-1559. DOI: 10.1007/s11172-021-3251-y
11. Julia A.. Erminea, Elizabeth V. leader, Taisiya S. Sukhikha, Lyubov S. Klyushova, Maria L.. Perepechaeva, Dmitriy G. Sheven, Alexey S. Berezina, Alevtina Y.. Grishanova, Vladimir I. Potkin/ Water-soluble copper(II) complexes with 4,5-dichloro-isothiazole-3-carboxylic acid and heterocyclic N-donor ligands: Synthesis, crystal structures, cytotoxicity, and DNA binding study. // Inorganic Chemistry Acta. – 2020 – V. 510 – 119778. DOI: 10.1016/j.ica.2020.119778,
12. M. L. Perepechaeva , N. V. Gubanova & A. Y. Grishanova. Effects of prolonged subchronic benzo(a)pyrene exposure on rat liver morphology and CYP1A expression during treatment with menadione, quercetin, or tocopherol // Drug and Chemical Toxicology Published Online: 19 Nov 2020. https://doi.org/10.1080/01480545.2020.1849270.
13. Perepechaeva M.L. and Grishanova A.Y. The Role of Aryl Hydrocarbon Receptor (AhR) in Brain Tumors. // International Journal of Molecular Sciences, 2020, 21.
14. Kokina T.E., Komarov V.Yu., Glinskaya L.A., Bizyaev S.N., Sheludyakova L.A., Eremina Yu.A., Klyushova L.S., Tkachev A.V./ Synthesis, structure and cytotoxicity of Pd complexes(II) and Su(II) with 1-terpenyl-3-thiosemicarbazides of the pinane and para-menthane series. // Journal of Structural Chemistry. – 2020 - Vol. 61, №1. p. 48. DOI: 10.26902/JSC_id49663
15. E.D. Rechitskaya, N.V. Kuratieva, E.V. Leader, J.A.. Eremina, L.S. Klyushova, I.V. Eltsov, G.A.Kostin/ Tuning of cytotoxic activity by bio-mimetic ligands in ruthenium nitrosyl complexes.// Journal of Molecular Structure. – 2020 – V. 1219. DOI: 10.1016/j.molstruc.2020.128565
16. Couture fox, I. A.; Goreva, O. B.; Mazur, O. E.; Mordvinov, V. A. A Study of Protein Fractional Composition during Incubation of Diphyllobothrium dendriticum (Cestode) Plerocercoids in a Medium Containing Blood Serum of the Host, the Baikal Man Coregonus migratorius (Coregonidae) // Biology Bulletin 2020.V.47.N.5.P.490-496. Doi 10.1134/S1062359020040081
17. Eremina, J.A.a,b,c, Leader, E.V.a,b, Sukhikh, T.S.a,b, Eltsov, I.V.b, Kuratieva, N.V.a,b, Zakharov, B.A.b,d, Sheludyakova, L.A.a,b, Klyushova, L.S.c,g, Ermakova, E.A.a,b, Dotsenko, V.V.e,f . Synthesis, crystal structures, spectroscopic, and cytotoxicity study of Cu(II), Co(II), In(II) and Pd(II) complexes with 2-anilinomethylidene-5,5-dimethylcyclohexane-1,3-dione(Article). Polyhedron . Volume 178, 1 March 2020, Article number 11432
18. J.A.. Eremina, E.V. leader, D.G. Samsonenkoa, L.A. Sheludyakova,
19. A.S. Berezina, L.S. Klyushova, V.A. Ostrovskii, BID. Trifonov. Mixed-ligand copper(II) complexes with tetrazole derivatives and 2,2′-bipyridine, 1,10-phenanthroline: Synthesis, structure and cytotoxic activity. Inorganic Chemistry Acta,. 2019 V. 487, p 138-144. https://doi.org/10.1016/j.ica.2018.12.011
20. Alexander N. Makhinya, Julia A.. Eremina, Taisiya S. Sukhikh, Iraida A. Baidina,Maxim A. Il'in, Lyubov S. Klyushova, and Elizaveta V. Leader. Cytotoxicity and Crystal Structures of Nitrosoruthenium Complexes mer-[Ru(NO)Py2Cl3] and mer-[Ru(NO)(c-Pic)2Cl3]. ChemistrySelect 2019, 4, 5866 –5871
21. Tatyana E. Kokina, Ludmila A. Glinskaya, Liliya A. Sheludyakova, Yuliya A.Ereminaa, Lubov S.Klyushova, Vladislav Yu.Komarov, Dmitry A. Piryazev, Alexey V. Tkachev, Stanislav V. Larionov. Synthesis, structure, and cytotoxicity of complexes of zinc(II), palladium(II), and copper(I) chlorides with (−)-camphor thiosemicarbazone. Polyhedron Volume 163, 1 May 2019, Pages 121-130
22. Anna Lyamkina, Maria Perepechaeva, Alevtina Grishanova, Olga Berezina, Igor Kovynev, Tatiana Pospelova. The expression level of the miR203a gene in patients with chronic myeloid leukemia in different phases of the disease. 24th Congress of European Hematology Association, Amsterdam, Netherlands, 2019
23. M.L. Perepechaeva, D.V. Telegina, A.Yu. Grishanova. AhR gene expression- and NF-kB-Dependent Signaling Pathways in the Brain and Retina of Prematurely Aging OXYS Rats. Journal of Nature, 2019, special issue volume 2, p. 210.

Laboratory staff

1. Goreva Olga Borisovna, PhD.
   https://orcid.org/0000-0002-8129-9176
   obgoreva@frcftm.ru, +7 (383) 274-95-55
2. Perepechaeva Maria Leonidovna, PhD.
   https://orcid.org/0000-0001-5791-3714
   mlperepechaeva@frcftm.ru
3. Klyushova Lyubov Sergeevna, PhD.
   https://orcid.org/0000-0003-4820-2536
   klyushovals@mail.ru
4. Golubeva Yulia Alexandrovna, Ph.D..
   https://orcid.org/0000-0002-5404-5357