Activities – study of the molecular genetic foundations for the formation of socially significant multifactorial diseases; development of personalized medicine technologies.

Vavilin V.A.. – specialist in the field of genetics and biochemistry of the enzymatic system of biotransformation of foreign compounds, its role in the development of multifactorial diseases. The main scientific activity is connected with the study of the role of the enzymatic system of the metabolism of foreign compounds in the development of human pathology in order to develop personalized medicine.. In this work, along with biochemical approaches, including non-invasive methods for assessing the activity of this system in humans, actively uses the methodology and arsenal of molecular and genetic epidemiology. Scientific activity is also associated with experimental studies of the molecular mechanisms of pathology., experimental study of the biological effects of potentially medicinal chemical substances in vitro and in vivo conditions. author 245 scientific works, of them 2 monographs and 2 study guides; 7 copyright certificates and patents. Conducts teaching work. Leader and consultant 11 PhD and 1 doctoral dissertation. RAS expert, member of the editorial board of the journal “Pharmacogenetics and pharmacogenomics”, member of dissertation councils 24.1.242.02 and D 24.1.242.01 on the basis of the Federal State Budgetary Scientific Institution "Federal Research Center for Fundamental and Translational Medicine".

Currently, the laboratory is studying the possibilities of "omics" technologies for the development of personalized therapy for patients with socially significant diseases., in particular, the study of the influence of the differentiation factor HLDF on the differentiation of breast cancer cells, the evidence base of the effectiveness of the synthetic HLDF peptide as a drug for the differential therapy of breast cancer is being collected (in cooperation with the Institute of Bioorganic Chemistry named after. academicians M.M.. Shemyakina and Yu.A. Ovchinnikova). Development of a personalized approach to the diagnosis and treatment of socially significant diseases.

The study of molecular cell markers in lymphogenous metastasis of breast cancer and associated with cellular atypism in some non-malignant breast diseases is underway., as well as conjugation of cytokine production – tumor growth regulators with expression of their respective receptors.

The effects of newly created potentially medicinal substances and substances of plant origin in relation to xenobiotic-metabolizing systems and cytokines are being studied..

Methodological arsenal of the laboratory includes: PCR analysis of polymorphic variants and gene expression, work with cell cultures, HPLC analysis of low molecular weight compounds using various types of detection, determination of enzymatic activities, etc..

Main results of the work:

The fundamental basis of the work of the laboratory is the previously obtained knowledge about the increase in the toxicity of xenobiotics instead of its decrease as a result of biotransformation., as well as significant interindividual variability in the activity of the xenobiotic metabolism system, made it possible to formulate ideas about the "imbalance of the processes of toxification and detoxification" and the presence of subpopulations of people, subject to the damaging action of chemical factors. Discovery of more and more polymorphic variants of genes, encoding enzymes of the xenobiotic metabolism system provided ample opportunities in understanding the significance of this system in pharmacotherapy and the formation of human pathology..

For the purpose of medical application of this knowledge, the need arose for safe non-invasive assessments in humans of the activity of individual isoenzymes of the biotransformation system.. This problem was solved at NIIMBB by studying the selectivity of a number of highly purified cytochromes P450 for theophylline in the reconstructed system, showing its diagnostic value for the cytochrome P4501A subfamily (CYP1A). The subsequent use of theophylline in a cocktail with other test preparations provided a simultaneous pharmacokinetic characterization of CYP1A activity., CYP2D6, CYP3A and N-acetyltransferase 2. The use of this method in combination with estimates of genetic polymorphism in samples of European Caucasians in Siberia showed, that with the similarity of the frequencies of polymorphic variants of these genes with the Caucasians of North America and Western Europe, there are pronounced pharmacokinetic differences for inducible genes.

in a physiological sense, these data are important in understanding the role of specific environmental conditions in shaping the activity of the xenobiotic metabolism system, and through it - the "general reactivity" of the organism, and in a narrower therapeutic sense indicate the need for laboratory assessments of the activity of this system, determining the pharmacokinetics of most drugs, for effective dosing regimens. On the example of isoniazid, we have identified a significant (up to 7 times) variability of its clearance within individual N-acetyltransferase genotypes 2, the possibility of placing the same genotype as in the "fast" phenotype, and "slow" acetylator. The accuracy of predicting the phenotype by genotype was 86,5%. This points to the different roles and sequencing of genetic and pharmacokinetic evaluations in order to optimize individual pharmacotherapy.

In the 1990s, hypotheses were formulated, based on the mechanisms of xenobiotic metabolism, and studies were carried out to study associations of polymorphic variants of FBK genes (glutathione transferase M1, T1 and P1, N-acetyltransferase 2 и CYP1A1) with a predisposition to such multifactorial diseases, like lung cancer, atopic bronchial asthma and atopic dermatitis in children. The results obtained naturally corresponded to the data on the metabolic function of proteins., encoded by these genes, notions of “toxification/detoxification imbalance” and made it possible to identify sensitive subpopulations. Associations found for individual genotypes, shown a regular increase in predisposition with a combination of "defective" options (gene-gene interactions) or the influence of such a factor, like passive smoking (gene-environment interactions). Significantly, that links were also found with the clinical features of atopic diseases, i.e. the studied signs had a prognostic value. Similar patterns have been identified for the development of isoniazid-induced hepatotoxicity, taking into account the polymorphic variants of NAT2 involved in its metabolism., CYP2E1 and in the detoxification of "reactive metabolites" GSTA2, GSTP1, M1 and T1.

Technological re-equipment of scientific research in the post-genomic era has opened up the possibility of moving to functional genomics in assessing the biological effects of exposure to chemical substances on cells. The ability of phenolic antioxidants to exert pleiotropic effects on gene expression of the xenobiotic metabolism system and various signal transduction pathways was revealed in studies on the biological effects of potentially medicinal compounds using high-performance array technologies in the evaluation of gene expression., not related to their own antioxidant properties and the inherent involvement of the antioxidant-response element.

Grant support for research, conducted in the laboratory:

• FTP "Scientific and scientific-pedagogical personnel of innovative Russia" at 2009-2013 years, lot number 4 Code 2009-1.5-504-005 "Conducting scientific research by teams led by visiting researchers in the field of medicine", Work theme: "Metabolic regulation of the generation of reactive oxygen species in the mitochondria of the brain, heart and liver and protection against oxidative stress" 2009 – 2010 years, state. Contract 02.740.11.5039
• RFBR Project No. 05-04-48819, 2005-2007 years,
• Scientific program "Semipalatinsk test site - Altai" (1993 – 1994 years), project “Assessment of the biotransformation system of xenobiotics in humans, subjected to the complex effects of radiation and chemical factors of environmental pollution "
• Program "Health of the population of Siberia" (within the SSTP "Health of the population of Russia") (1996-1998 years) project "Identification of children with a high risk of chronic bronchopulmonary diseases by assessing the polymorphism of xenobiotics biotransformation enzyme genes"
• Interdisciplinary integration project N 53 (2006-2008 years)
• Interacademic integration project N 11 (2009 – 2011 years).
• Interacademic integration project N 19 (2012 – 2014 years).

Publications

1. Korolenko T. A., Ovsyukova M.V., Bgatova N.P., Ivanov I. D., Makarova S. I., Vavilin V. A., Popov A. V., Yuzhik E.I., Koldysheva E.V., Korolenko E.C., Zavjalov E.L. Trehalose Activates Hepatic and Myocardial Autophagy and has Anti-Inflammatory Effects in db/db Diabetic Mice” Life 2022. Vol.12, №3 103390/life12030442
2. Molecular genetic markers and metabolic disorders in non-alcoholic fatty liver disease / Krivosheev A.B., Maksimov V.N., Boyko K.Yu., Levykina E.E., Mihailova E.S., Varaksin N.A., Kondratova M.A., Krivosheeva I.A., Autenslyus A.I.. // breast cancer. Medical review. – 2022. - T. 6. – № 5. – S. 206-212. – DOI 10.32364/2587-6821-2022-6-5-206-212.
3. Alexsander Autenshlyus, Kristina Davletova, Nikolay Varaksin Igor Marinkin and Vyacheslav Lyakhovich Cytokines in various molecular subtypes of breast cancer//International Journal of Immunopathology and Pharmacology Volume 35: 1–13 DOI: 10.1177/20587384211034089 (WoS)
4. A. I. Autenshlyus A. A. Studenikina, N. A. I would save, and Academician V. V. Lyakhovich Cytokine Production by Tumor Bioptate at Different Pathological Prognostic Stages in Breast Cancer// Doklady Biochemistry and Biophysics, 2021, Vol. 497, pp. 86–89 published in Doklady Rossiiskoi Akademii Nauk. Science about Zhizni, 2021, Vol. 497, pp. 180–184. DOI: 10.1134/S1607672921020010 (WoS)
5. Autenshlyus A., Arkhipov, S., Mikhaylova E., Marinkin I., Arkhipova, V., Varaksi N., Lyakhovich V. Effects of polyclonal activators on cell differentiation and cytokine production of cultured invasive breast carcinoma of no special type, their association with tumour histopathological parameters and lymph node metastasis. International journal of immunopathology and pharmacology. – 2020. – Vol. 34. – paper N 2058738420950580. DOI10.1177/2058738420950580.
6. Autenshlyus A., Arkhipov, S., Mikhaylova E., Marinkin I., Arkhipova, V., Varaksi N., Vavilin V.A., Lyakhovich V. Analyzing the relationship between the cytokine profile of invasive breast carcinoma, its histopathological characteristics and metastasis to regional lymph nodes. SCIENTIFIC REPORTS. – 2021. – V. 11, Issue 1. – paper N 11359. DOI10.1038/s41598-021-90930-z.
7. Makarova S.I., Mitrofanov D.V., Shintyapina A.B., Komova E.G., Zelenskaya V.V., Kartseva T.V., Kondyura E.G., Vavilin V.A.. Search for associations of polymorphic variants of the human acid chitinase gene with bronchial asthma in children. Novosibirsk. Siberian Journal of Clinical and Experimental Medicine. – 2021. - T. 36, N 4. – C. 92-98. https://doi.org/10.29001/2073-8552-2021-36-4-92-98.
8. Makarova S.I., Mitrofanov D.V., Komova E.G., Kaloshkin I.V., Shintyapina A.B., Kaznacheeva L.F., Zelenskaya V.V., Kondyura E.G., Batychko O.A., Vavilin V.A.. The role of filaggrin gene mutations, leading to a decrease in protein, in the development of atopic dermatitis and bronchial asthma in children. Siberian scientific medical journal. 2021. T. 41. № 3. S. 58-63. DOI: 10.18699/SSMJ20210308
9. Ivanov I.D., Mosalev K.I., Vavilin V.A., Lipeeva A.V., Schultz E.E. Study of the mechanisms of anti-inflammatory and immunomodulatory activity of betulinic acid compounds with furocoumarins. Experimental and clinical pharmacology. – 2021. - Volume 84, № 6. - with. 28-34. DOI 10.30906/0869-2092-2021-84-6-28-34.
10. Cheremnykh K.P., Savelyev V.A., Borisov S.A., Ivanov, I.D., Baev D.S.,Vavilin V.A. Tolstikova T.G., Shults E.E. Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency. MOLECULES. – 2020. – V. 25, Issue 23. – article N 5578. DOI10.3390/molecules25235578.
11. Autenshlyus A.I., Golovanova A.V., Studenikina A.A., Brusentsov I.I., Proskura A.V., Zhurakovskiy I.P., Arkhipov S.A., Sidorov S.V., Vavilin V.A., Lyakhovich V.V.Personalized Approach to Assessing mRNA Expression of Histidine-Rich Glycoprotein and Immunohistochemical Markers in Diseases of the Breast.DoklBiochemBiophys. 2019 May;484(1):59-62. doi: 10.1134/S1607672919010162.
12. Autenslyus A.I., Ivanov I.D., Golovanova A.V., Studenikina A.A., Mihailova E.S., Varaksin N.A., Vavilin V.A., Lyakhovich V.V. Comparison of cytokine mRNA expression with their concentration in the supernatant of U937 cell culture exposed to polyclonal activators. medical immunology. 2019. T. 21. № 4. S. 737-742.
13. Tyumentsev M.A., Stefanova N.A., Muraleva N.A., Rumyantseva Y.V., Kiseleva E., Vavilin V.A., Kolosova N.G.Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer’s Disease-Like Pathology in OXYS Rats.J Alzheimers Dis. 2018;63(3):1075-1088. doi: 10.3233/JAD-180065.
14. Shintyapina A.B., Vavilin V.A., Safronova O.G., Lyakhovich V.V.The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3′-tert-butyl-4′-hydroxyphenyl) propylthiosulfonate of sodium. PLoS One. 2017 May 3;12(5):e0176939. doi: 10.1371/journal.pone.0176939
15. PatrushevS.S., Rybalova T.V., IvanovI.D., Vavilin V.A., ShultsE.E..Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines. Tetrahedron – 2017. – 73. – V. 19. – P. 2717-2726DOI10.1016/j.tet.2017.03.016
16. Pakharukova MY, Vavilin VA, Sripa B, Spread T, Brindley PJ, Mordvinov VA. Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus.PLoS Negl Trop Dis. 2015 Dec 1;9(12):e0004258. doi: 10.1371/journal.pntd.0004258
17. Vavilin V.A., Shintyapina A.B., Safronova O.G., Antontseva E.V., Mordvinov V.A., Nikishina M.V., Kandalintseva N.V., Prosenko A.E., Lyakhovich V.V..
18. Position of an Active Thiosulfonate Group in New Phenolic Antioxidants is Critical for ARE-Mediated Induction of GSTP1 and NQO1. J. Pharm. Sci. & Res. – 2014. – Vol. 6, N 4. – P. 178-183.
19. Komova E.G., Shintyapina A.B., Makarova S.I., Ivan M.K., Chekryga E.A., Kaznacheeva L.F., Vavilin V.A. Filaggrin Mutations in a Western Siberian Population and Their Association with Atopic Dermatitis in Children Genetic Testing and Molecular Biomarkers. Genet Test Mol Biomarkers. 2014 Dec;18(12):791-6. doi: 10.1089/gtmb.2014.0247.
20. Shintyapina A.B., Safronova O.G., Vavilin V.A., Kandalintseva N.V., Prosenko A.E., Lyakhovich V.V.Effect of 3-(3′-Tert-Butyl-4′-Hydroxyphenyl)Propyl Thiosulfonate Sodium on Expression of GSTP1 and NQO1 Genes and Protein Transcription Factors in BALB/c Mouse Liver.Bull ExpBiol Med. 2014 Aug;157(4):473-5. doi: 10.1007/s10517-014-2594-x.
21. Menshchikova E., Tkachev V., Himza A., Sharkova T., Kandalintseva N., Vavilin V., Safronova O., Zenkov N.Water-soluble phenol TS-13 combats acute but not chronic inflammation. Inflamm Res. 2014 Sep;63(9):729-40. doi: 10.1007/s00011-014-0746-0.
22. Panov A., Orynbayeva Z., Lyakhovich Vavilin V., Lyakhovich V. Fatty Acids in Energy Metabolism of the Central Nervous System. Biomed Res Int. 2014; 2014: 472459.
23. Stakhneva E.M., Vavilin V.A. Ragino Yu.I.,., Safronova O.G., Shintyapina A.B., Ivanova M.V. Effects of Simvaglyzin and Atorvaglyzin on the Expression of 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase in Rat Liver. Bull. Exp. Biol. With. 2013. V. 156, № 7. P. 74-77
24. Vavilin V.A., Nepomnyashchikh D.L., Shchetpotina E.G. , Karavaeva Yu.Yu., Makarova S.I., Vinogradova E.V., Kudryashov A.V., Nokhryna Zh.V., Lyakhovich V.V. Cytochrome P450 4F2 gene polymorphism in patients with liver cirrhosis. Bull. Expert. Biol. Med. – 2013 . – T. 156, № 8. – S. 144-148
25. Nepomnyashchikh D.L., VavilinV.A., Aidagulova S.V., Makarova S.I., KaravaevaYu.Yu., ShchepotinaE.G., Postnikova O.A., Nokhrina Zh.V., Vinogradova E.V., LyakhovichV.V. CytochromeP450 2D6 polymorphism is a molecular genetic marker of liver cirrhosis progression // Bull. Exp. Biol. With. – 2012. – V.152, N 5. – P. 633-636.
26. A. V. Kudryashov, V. A. Vavilin, T. A. Kolpakova,Zh. Mutaykhan, V. A. Krasnov, and V. V. Lyakhovich. Relationship between CYP2E1 Polymorphism and Increase of ALT Activity during Therapy of Patients with Pulmonary Tuberculosis // Bull. Exp. Biol. With. 2013 – Vol. 151, No. 6. – P. 741-746.
27. Kolosova N. G., Akulov A. E., Stefanova N. A., Moshkin M. P., Savelov A. A., I. V. Koptyug I. V., Panov A. V., and Vavilin V. A. Effect of malate on the development of rotenone-induced brain changes in Wistar and OXYS rats: An MRI study Doklady Biological Sciences, 2011. – Vol. 437. – P. 72-75.
28. Ragino THIS, Vavilin VA, Salakhutdinov NF, Makarova SI, Stakhneva EM, Safronova AND, Lyakhovich VV, Nikitin YP, Tolstikov GA.Antioxidant and endothelium-stabilizing effects of simvaglyzin on rabbits with experimental hypercholesterolemia. Bull Exp Biol Med. 2008 Aug;146(2):206-9.
29. Ragino THIS, Vavilin VA, Salakhutdinov NF, Makarova SI, Stakhneva EM, Safronova AND, Nikitin YP, Tolstikov GA. Study of cholesterol-lowering effect and safety of simvaglisin on rabbit model of hypercholesterolemia. Bull Exp Biol Med. 2008 Mar;145(3):317-9
30. Vavilin V.A., Salakhutdinov N.F., Ragino You.I., Polyakov N.E., Taraban M.B., Leshina T.V., Stakhneva E.M., Lyakhovich V.V., Every Yu.P., Tolstikov G.A..The Cholesterol Lowering Properties of the Complex Compound Simvastatin with Glycyrrhizic Acid (Simvaglyzin) in Experimental Models // Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry. – 2008. – Vol. 2, No. 4. – P. 373–338
31. Nikishina M.V., Makarova S.I., Lyakhovich V.V. Analysis of associations of NAT2 gene polymorphisms with the risk of lung cancer. Bull. Expert. Biol. Honey – 2007 – T. 143, № 1. – S. 89 – 92.
32. Schwartz Y.S., Dushkin M.I., Vavilin V.A., Melnikova E.V. Khoschenko O.M., et al. Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2006 Jun;50(6):1982-8.
33. Shchepotina EG, Vavilin VA, Goreva OB, Lyakhovich VV. Some mutations of exon-7 in cytochrome P450 gene 3A4 and their effect on 6beta-hydroxylation of cortisol. Bull Exp Biol Med. 2006 Jun;141(6):701-3
34. Lyakhovich VV, Vavilin VA, Zenkov NK, Menshchikova EB. Active defense under oxidative stress. The antioxidant responsive element. Biochemistry (Musk). 2006 Sep;71(9):962-74.
35. Vavilin V.A., Safronova O.G., Manankin N.A., Kaznacheeva L.F., Lyakhovich V.V. Polymorphism of glutathione-S-transferases and clinical features of acute drug poisoning in children. Bull. expert. biol. honey. – 2005. - T. 139, № 4. – S. 424-427.
36. Makarova S.I., Vavilin V.A., Safronova O.G., Batychko O.A., Gavalov S.M., Lyakhovich V.V. Indicators of atopy in children with bronchial asthma increase with the accumulation of null alleles of glutathione S-transferase M1. Bull. expert. biol. honey. – 2004. - T. 138, № 11. – S. 520-522.
37. Vavilin V.A., Shchetpotina E.G., Manankin N.A., Kaznacheeva L.F., Lyakhovich V.V. Cytochrome P450 3A activity in children. Bull. expert. biol. honey. – 2004. - T. 138, № 9. – S. 272-274.
38. Lyakhovich V.V., Vavilin V.A., Grishanova A.Yu., Makarova S.I., Kovalenko S.P.. Pharmacogenetics and modern medicine. Herald of RAMS. – 2004. – № 10. – S. 40-45
39. Safronova AND, Vavilin VA, Lyapunova AA, Makarova SI, Lyakhovich VV, Kaznacheeva LF, Depend on NA, Batychko OA, Gavalov SM.Relationship between glutathione S-transferase P1 polymorphism and bronchial asthma and atopic dermatitis. Bull Exp Biol Med. 2003 Jul;136(1):73-75.
40. Vavilin VA, Safronova AND, Lyapunova AA, Lyakhovich VV, Kaznacheeva LF, Depend on NA, Molokova A.V.. Interaction of GSTM1, GSTT1, and GSTP1 genotypes in determination of predisposition to atopic dermatitis. Bull Exp Biol Med. 2003 Oct;136(4):388-391.
41. Nikishina M.V., Akishev A.G., Makarova S.I., Vavilin V.A., Degtyarev S.Kh., Lyakhovich V.V. Analysis of NAT1 Restriction Fragment Length Polymorphism in Caucasoids of Western Siberia. Bull. expert. biol. honey. – 2003. - T. 136, № 11. – S. 544 – 546.
42. Vavilin V.A., Makarova S.I., Lyakhovich V.V., Gavalov S.M. Polymorphic genes of xenobiotic-metabolizing enzymes associated with predisposition to bronchial asthma in hereditarily burdened and nonburdened children. Russian Journal of Genetics, Vol. 38, No. 4, 2002, pp. 439–445.
43. Vavilin V.A., Makarova S.I., Chasovnikova O.B., Lyakhovich V.V., Ryabova O.A., Gavalov S.M.. Polymorphism of glutathione S-transferase M1 and T1 in children, patients with bronchial asthma. Vopr. honey. chem. – 2000. - T. 46, issue. 4. – S. 388-397.
44. Lyakhovich V.V., Vavilin V.A., Makarova S.I., Gavalov S.M., Ryabova O.A., Chasovnikova O.B, Gutkin. N.I. The role of enzymes of biotransformation of xenobiotics in the predisposition to bronchial asthma and the formation of features of its clinical phenotype. Herald of RAMS. –2000. – № 12. – S. 36-41.
45. Lyakhovich V.V. Vavilin V.A., Makarova S.I., Gutkina N.I., Laktionova I.P., Mitrofanov D.V.. etc. Genes and enzymes of the xenobiotic metabolism system in oncopathology. Vopr. honey. chemistry. –1997. – issue. 5. – S. 330-338.

Laboratory staff

1. Autenschluss Alexander Isaevich. Chief Researcher, d.b.n., professor
   aiautenshlyus@frcftm.ru; WOS Researcher ID: AAB-2531-2020; Scopus Author ID: 6602253534; ID RINC: 79826
2. Makarova Svetlana Ivanovna. Senior Researcher, d.b.n., docent
   simakarova@frcftm.ru; WOS Researcher ID: Y-9076-2018; Scopus Author ID: 7003456791; ID RINC: 98050
3. Ivanov Igor Diadorovich. Senior Researcher, PhD.
   WOS Researcher ID: z-4942-1987; Scopus Author ID: 57197556781; ID RINC: 125626
4. Popov Alexey Viktorovich. Junior Research Fellow
5. Mosalyov Kirill Igorevich. Junior Research Fellow, kimosalev@frcftm.ru
6. Tkachenko Victor Ivanovich. Research Engineer