1. Federal Research Center for Fundamental and Translational Medicine, Moscow, Russia 2. Research Institute of Neurosciences and Medicine, Novosibirsk, Russia 3. Scientific Research Institute of Clinical and Experimental Lymphology — Branch of the Federal Research Center of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia 4. Vorozhtsov Novosibirsk Institute of Organic Chemistry, the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
The immunomodulatory activity of a betulonic acid-based compound with furocoumarin (BABCF; 2-azido, 9-N-methylpiperazinomethyl oreozelone) has been investigated. Male C57BL/6 mice (aged 3 months) treated with the cytostatic agent cyclophosphamide (CP) and intact individuals served as experimental models. The expression of genes was studied in bone marrow (IL-12, IL-10, IL-1β, TNF-α, TGF-β, M-CSF, GM-CSF) or in the suspension of peritoneal cells (IL-12, IL-10; as the injection site). The surface markers of T-lymphocytes (CD3, CD4, and CD8) in fractions of venous blood mononuclear cells (MNCs) were determined by means of flow cytometry using antibodies. Histological and morphometric studies were performed to assess the impact of CP and BABCF on the thymus. BABCF caused a pronounced (about 3-fold) increase in relative expression of the GM-KSF gene. BABCF caused a local increase in the expression of IL-12 in the peritoneal cavity cells and restored the relative content of T-lymphocytes in the blood of CP-treated mice treated affecting mainly CD3⁺CD4⁺ lymphocytes. This substance reduced the tissue density of the thymic cortex and thymic medulla in CP-treated mice. Thus, results of this study suggest that BABCF exhibits a stimulating effect on the cellular link of immunity and promotes maintenance of the number of T-lymphocytes in the blood due to their migration from the central organs of the immune system.
Keywords: betulonic acid, furocoumarins, cytokines, bone marrow, thymus, T-lymphocytes
Mosalev K.I., Ivanov I.D., Miroshnichenko S.M., Tenditnik M.V., Bgatova N.P., Shults E.E., Vavilin V.A. (2023) The immunomodulatory activity of the betulonic acid based compound. Biomeditsinskaya Khimiya, 69(4), 219-227.
Mosalev K.I. et al. The immunomodulatory activity of the betulonic acid based compound // Biomeditsinskaya Khimiya. - 2023. - V. 69. -N 4. - P. 219-227.
Mosalev K.I. et al., "The immunomodulatory activity of the betulonic acid based compound." Biomeditsinskaya Khimiya 69.4 (2023): 219-227.
Mosalev, K. I., Ivanov, I. D., Miroshnichenko, S. M., Tenditnik, M. V., Bgatova, N. P., Shults, E. E., Vavilin, V. A. (2023). The immunomodulatory activity of the betulonic acid based compound. Biomeditsinskaya Khimiya, 69(4), 219-227.
Tolstikova T.G., Sorokina I.V., Tolstikov G.A., Tolstikov A.G., Flekhter O.B. (2006) Biological activity and pharmacological prospects of lupane terpenoids: I. Natural lupane derivatives. Russian Journal of Bioorganic Chemistry, 32(1), 42-55. CrossRef Scholar google search
Oliveira Costa J.F., Barbosa-Filho J.M., de Azevedo Maia G.L., Guimarães E.T., Meira C.S., Ribeiro-dos-Santos R., Pontes de Carvalho L.C., Pereira Soares M.B. (2014) Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia. Int. Immunopharmacol., 23(2), 469-474. CrossRef Scholar google search
Lipeeva A.V., Shul’ts E.E., Shakirov M.M., Bagryanskaya I.Yu., Tolstikov G.A. (2013) Plant coumarins: XIII. Synthesis of 2,3,9-trisubstituted furocoumarins. Russian Journal of Organic Chemistry, 49(3), 403-411. CrossRef Scholar google search
Serrano-Perez J.J., Gonzalez-Luque R., Merchan М., Serrano-Andres L. (2008) The family of furocoumarins: Looking for the best photosensitizer for phototherapy. J. Photochem. Photobiol., 199, 34-41. CrossRef Scholar google search
Lipeeva A.V., Dolgikh M.P., Shults E.E., Tolstikova T.G. (2020) A study of plant coumarins. 18. Conjugates of coumarins with lupane triterpenoids and 1,2,3-triazoles: Synthesis and anti-inflammatory activity. Russian Journal of Bioorganic Chemistry, 46(2), 125-132. CrossRef Scholar google search
Ketlinsky S.A., Simbirtsev A.S. (2008) Cytokines. — St. Petersburg: Foliant Publishing LLC, pp. 70-79, 144-151, 235-243. Scholar google search
Sun L., Wang X., Saredy J., Yuan Z., Yang X., Wang H. (2020) Innate-adaptive immunity interplay and redox regulation in immune response. Redox Biology, 37, 101759. CrossRef Scholar google search
Gaidai D.S., Katelnikova A.E., Kryshen K.L., Gaidai E.A., Gushchin Ya.A., Makarova M.N. (2019) Development of a model of immunosuppression in rabbits caused by intravenous administration of cyclophosphamide. Laboratory Animals for Scientific Research, 2, 1-13. CrossRef Scholar google search
Bracci L., Moschella F., Sestili P., LaSorsa V., Valentini M., Canini I., Baccarini S., Maccari S., Ramoni C., Belardelli F., Proietti E. (2007) Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin. Cancer Res., 13(2), 644-653. CrossRef Scholar google search
Ivanov I.D., Mosalev K.I., Lipeeva A.V., Shults E.E., Vavilin V.A. (2021) Studying the mechanisms of anti-inflammatory and immunomodulatory activity of betulinic acid compounds with furocoumarins. Experimental and Clinical Pharmacology, 84(6), 28-34. CrossRef Scholar google search