Combined effect of methotrexate and phytoextracts of medow clover and common chicory on the in vitro production of pro-inflammatory cytokines
- Authors: Mikhailova I.V.1, Chaynikova I.N.1, Ivanova E.V.1, Sinegovets A.A.1
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Affiliations:
- Orenburg State Medical University
- Issue: Vol 28, No 3 (2025)
- Pages: 475-480
- Section: SHORT COMMUNICATIONS
- URL: https://journals.rcsi.science/1028-7221/article/view/319888
- DOI: https://doi.org/10.46235/1028-7221-17163-CEO
- ID: 319888
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Abstract
Usage of herbal remedies may present a tool limiting toxicity of methotrexate (MTX). The herbal products are characterized by availability, safety, high biological activity, and very low toxicity. One should highlight the meadow clover and common chicory among medicinal plants containing a variety of biologically active polyphenolic substances, possessing antioxidant, anti-inflammatory, immunocorrective and other favorable properties. Phytoextracts obtained from these plants may be used in order to protect against immunosuppressive effects of MTX and enhance its anti-inflammatory properties without inducing MTX toxicity. At the same time, it should be noted that information on the mechanisms of anti-inflammatory activity of individual phytoextracts is multidirectional. The aim of our work was to evaluate the effect of clover and chicory phytoextracts on secretion of proinflammatory cytokines TNFα, IL-6 and IL-17 by human peripheral blood mononuclear cells under MTX-induced immunosuppression. Dry extracts from clover grass and chicory grass were obtained by percolation with ethyl alcohol. The production of cytokines TNFα, IL-6 and IL-17 in the supernatants of unstimulated and concanavalin A (Con A)- stimulated human peripheral blood mononuclear cell cultures was assessed using the enzyme immunoassay method. Evaluation of immunoregulatory activity of dry extracts from clover and chicory grass, as well as their combinations with MTX using the in vitro model of human peripheral blood mononuclear cells showed that the phytoextracts suppressed the production of proinflammatory cytokines in this system, both spontaneous (TNFα, IL-6), and induced (TNFα, IL-6 and IL-17). It should be noted that the degree of inhibitory effect caused by phytoextracts was not inferior, and, in relation to individual cytokines (TNFα and IL-17), was superior to Immunal, an Echinacea-derived preparation. We have revealed inhibitory effects of clover and chicory phytoextracts, as well as their combinations with MTX, on the production of proinflammatory cytokines (TNFα, IL-6, IL-17) by human peripheral blood mononuclear leukocytes. Potentiating action of phytoextracts manifested as enhanced inhibitory effect of cytostatic MTX on the production of IL-6 by lymphocytes and the appearance of an anti-inflammatory effect on TNFα and IL-17. The most pronounced immunoregulatory effect and potentiation of anti-inflammatory MTX action was obtained by the chicory phytoextract, with both extracts exceeding the effect of Immunal, a commercial comparison drug.
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##article.viewOnOriginalSite##About the authors
I. V. Mikhailova
Orenburg State Medical University
Email: a.a.sinegovets@yandex.ru
PhD, MD (Biology), Associate Professor, Head of the Department of Pharmaceutical Chemistry
Russian Federation, OrenburgI. N. Chaynikova
Orenburg State Medical University
Email: a.a.sinegovets@yandex.ru
PhD, MD (Medicine), Professor at the Department of Normal Physiology
Russian Federation, OrenburgE. V. Ivanova
Orenburg State Medical University
Email: a.a.sinegovets@yandex.ru
PhD, MD (Medicine), Associate Professor at the Department of Pharmaceutical Chemistry
Russian Federation, OrenburgA. A. Sinegovets
Orenburg State Medical University
Author for correspondence.
Email: a.a.sinegovets@yandex.ru
Assistant Professor at the Department of Pharmaceutical Chemistry
Russian Federation, OrenburgReferences
- Drenin A.A., Botirov E.H. Flavonoids and isoflavonoids of plants of the genus Trifolium L. Structural diversity and biological activity. Khimiya rastitelnogo syrya = Chemistry of Plant Raw Materials, 2017, no. 3, pp. 39-53. (In Russ.)
- Mikhailova I.V., Sinegovets A.A., Bondarenko A.I., Ivanova E.V. Phytochemical characteristics and antioxidant properties of the herb of meadow clover growing on the territory of the Orenburg region. Mediko-farmatsevticheskiy zhurnal “Puls” = Medical and Pharmaceutical Journal “Pulse”, 2023, Vol. 25, no. 1, pp. 29-33. (In Russ.)
- Mikhailova I.V., Ivanova E.V., Sinegovets A.A., Smolyagin A.I., Kuzmicheva N.A. Method for producing an agent with antioxidant and immunomodulatory activity based on the herb Trifolium pratense L. Patent RU 2828665 C1, 15.10.2024.
- Mikhailova I.V., Ivanova E.V., Smolyagin A.I., Bondarenko A.A., Sinegovets A.A., Kuzmicheva N.A., Filippova Yu.V., Voronkova I.P., Vinokurova N.V. Method for producing an agent with antioxidant and immunomodulatory activity. Patent RU 2803502 C1, 14.09.2023.
- Sinegovets A.A., Mikhailova I.V., Ivanova E.V., Kuzmicheva N.A. Selection of optimum parameters for extraction of phenolic compounds from the herb of Cichorium intybus L. Mediko-farmatsevticheskiy zhurnal “Puls” = Medical and Pharmaceutical Journal “Pulse”, 2023, Vol. 25, no. 8, pp. 58-67. (In Russ.)
- Frolov B.A., Kalinina O.V., Kirillova A.V., Shtil A.A. Overcoming the hepatotoxicity of methotrexate: the role of triterpenoids. Klinicheskaya onkogematologiya = Clinical Hematology. 2013, Vol. 6, no. 1, pp. 1-10. (In Russ.)
- Bedoui Y., Guillot X., Sélambarom J., Guiraud P., Giry C., Jaffar-Bandjee M.C., Ralandison S., Gasque P. Methotrexate an old drug with new tricks. Int. J. Mol. Sci., 2019, Vol. 20, no. 20, 5023. doi: 10.3390/ijms20205023.
- Cronstein B.N., Aune T.M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol., 2020, Vol. 16, no. 3, pp. 145-154.
- Freeman M.L., Clagett B.M., Moisi D., Yeh E., Morris C.D., Ryu A., Rodriguez B., Stein J.H., Deeks S.G., Currier J.S., Hsue P.Y., Anthony D.D., Calabrese L.H., Ribaudo H.J., Lederman M.M. Methotrexate inhibits T cell proliferation but not inflammatory cytokine expression to modulate immunity in people living with HIV. Front. Immunol., 2022, Vol.13, 924718. doi: 10.3389/fimmu.2022.924718.
- Hosseinzade A., Sadeghi O., Naghdipour Biregani A., Soukhtehzari S., Brandt G.S., Esmaillzadeh A. Immunomodulatory effects of flavonoids: possible induction of T CD4+ regulatory cells through suppression of mTOR pathway signaling activity. Front. Immunol., 2019, Vol. 10, 51. doi: 10.3389/fimmu.2019.00051.
- Martínez G., Mijares M.R., De Sanctis J.B. Effects of flavonoids and its derivatives on immune cell responses. Recent Pat. Inflamm. Allergy Drug Discov., 2019, Vol. 13, no. 2, pp. 84-104.
- Miyazono Y., Gao F., Horie T. Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats. Scand. J. Gastroenterol., 2004, Vol. 39, no. 11, pp. 1119-1127.
- Sakuma S., Kato Y., Nishigaki F., Magari K., Miyata S., Ohkubo Y., Goto T. Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. Int. Immunopharmacol., 2001, Vol. 1, no. 4, pp. 749-757.
- Shinde C.G., Venkatesh M.P., Kumar T.M., Shivakumar H.G. Methotrexate: a gold standard for treatment of rheumatoid arthritis. J. Pain Palliat. Care Pharmacother., 2014, Vol. 28, no. 4, pp. 351-358.
- Xu W., Wu H., Tahara K., Chen S., Wang X., Tanaka S., Sugiyama K., Sawada T., Hirano T. Effects of vitamin K2 combined with methotrexate against mitogen-activated peripheral blood mononuclear cells of healthy subjects and rheumatoid arthritis patients. Fundam. Сlin. Pharmacol., 2021, Vol. 35, no. 5, pp. 832-842.
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