Immunomodulatory Effect of Tinospora cordifolia with Special Reference to Suppression of Cytokine Storm Induced in SARS-CoV-2

Aishath Thahuseen Waheed¹, Thurga Ayavoo^2,3, Karthikeyan Murugesan^2,3,  Fouad Saleih R. AL-Suede^4,5, Ashok Gnanasekaran^2,3*

Development of anti-inflammatory herbal drug.

Abstract

Background: Tinospora cordifolia (T. cordifolia) is one such plant that has been studied for its many medicinal properties. Objective: The objective of this study was to investigate the in vitro exposure of human peripheral blood mononuclear cells to T. cordifolia plant might stimulate the induction of anti-inflammatory cytokines, interleukin-10 and interleukin-37. Methods: T. cordifolia plant powder was sterilized by several methods to eliminate presence of microorganisms in plant powder. The sterilized T. cordifolia plant powder was exposed to peripheral blood mononuclear cells to determine the inhibitory concentration by conducting a cytotoxicity test. ELISA test was performed to check whether T. cordifolia stimulates the peripheral blood mononuclear cells into producing anti-inflammatory cytokines. Results: Pasteurization technique was a success as there was no bacterial or fungal growth observed on nutrient agar, blood agar and sabouraud dextrose agar. The optimal inhibitory concentration of T. cordifolia is 72 mg/ml. The results of the ELISA tests showed the production of interleukin-10 and interleukin-37 when stimulated by T. cordifolia. Conclusion: T. cordifolia plant powder could be a potential alternative for non-steroidal anti-inflammatory drugs as the plant induces secretion of interleukin-10 and interleukin-37 that subsidizes the interleukin-6.

Keywords: Cytokine storm, ELISA, Interleukin-10, Interleukin-37, Tinospora cordifolia

References

Adil, M. T., Rahman, R., Whitelaw, D., Jain, V., Al-Taan, O., Rashid, F.,& Jambulingam, P. (2021). SARS-CoV-2 and the pandemic of COVID-19. Postgraduate medical journal, 97(1144), 110-116.. https://doi.org/10.1136/postgradmedj-2020-138386.

 Al-Suede, F.S.R., Ahamed, M.B.K., Abdul, M.A.S., et al. (2021). Immunomodulatory and antiangiogenic mechanisms of polymolecular botanical drug extract C5OSEW5050ESA OS derived from Orthosiphon stamineus. Journal of Angiotherapy,5(1),194-206. https://doi.org/10.25163/angiotherapy.51211411913130321.

Al-Suede, F. S. R., Elham, F., Mohamed B. Khadeer Ahamed, Z. Ismail, Majid, A. S. A., & A. M. S. Abdul Majid. (2012). Marked antitumor activity of cat's whiskers tea (Orthosiphon stamineus) extract in orthotopic model of human colon tumor in nude mice. Journal of Biochemical Technology, 3(5), S 170-176.

Bahuguna, A., Khan, I., Bajpai, V.K., et al. (2017). MTT assay to evaluate the cytotoxic potential of a drug. Bangladesh Journal of Pharmacology, 12(2): 8. https://pdfs.semanticscholar.org/29e3/abf4dd6bb771e435b3b65c59851675f8b591.pdf.

Cennimo, D.J. (2021). Coronavirus disease 2019 (COVID-19): practice essentials, background, route of transmission. Medscape. https://emedicine.medscape.com/article/2500114-overview.

Conti, P., Ronconi, G., Caraffa, A., et al. (2020). Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVID-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents, 34(2): 327-331. https://doi.org/10.23812/CONTI-E.

Conti, P., Caraffa, A., Gallenga, C. E., Ross, R., Kritas, S. K., Frydas, I., & Ronconi, G. (2020). Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: a promising inhibitory strategy. J Biol Regul Homeost Agents, 34(6), 1971-1975.. https://doi.org/10.23812/20-1-E.

Fadhilah, N., Soegiarto, G., & Budhy, T. I. (2021). Potential of IL-10 as Targeted Therapy in Severe COVID-19 Patients. Malaysian Journal of Medicine and Health Sciences, 165-168.

Ghatpande, N. S., Misar, A. V., Waghole, R. J., Jadhav, S. H., & Kulkarni, P. P. (2019). Tinospora cordifolia protects against inflammation associated anemia by modulating inflammatory cytokines and hepcidin expression in male Wistar rats. Scientific reports, 9(1), 1-11.https://doi.org/10.1038/s41598-019-47458-0.

Ghosh, S., Saha, S. (2012). Tinospora cordifolia: one plant, many roles. Ancient Science of Life, 31(4): 151. https://doi.org/10.4103/0257-7941.107344.

González-Monroy, A. D., Rodríguez-Hernández, G., Ozuna, C., & Sosa-Morales, M. E. (2018). Microwave-assisted pasteurization of beverages (tamarind and green) and their quality during refrigerated storage. Innovative Food Science & Emerging Technologies, 49, 51-57.. https://doi.org/10.1016/j.ifset.2018.07.016.

Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020). How COVID-19 induces cytokine storm with high mortality. Inflammation and regeneration, 40(1), 1-7.

Iannaccone, G., Scacciavillani, R., Del Buono, M. G., Camilli, M., Ronco, C., Lavie, C. J., & Aspromonte, N. (2020). Weathering the cytokine storm in COVID-19: therapeutic implications. Cardiorenal medicine, 10(5), 277-287. https://doi.org/10.1159/000509483.

Jantan, I., Ahmad, W., Bukhari, S.N.A. (2015). Plant-derived immunomodulators: an insight on their preclinical evaluation and clinical trials. Frontiers of Plant Science, 6(AUG): 1-27.  https://doi.org/10.3389/fpls.2015.00655.

Kessler, B., Rinchai, D., Kewcharoenwong, C., Nithichanon, A., Biggart, R., Hawrylowicz, C. M., ... & Lertmemongkolchai, G. (2017). Interleukin 10 inhibits pro-inflammatory cytokine responses and killing of Burkholderia pseudomallei. Scientific reports, 7(1), 1-11. https://doi.org/10.1038/srep42791.

Koelman, L., Pivovarova-Ramich, O., Pfeiffer, A.F.H. (2019). Cytokines for evaluation of chronic inflammatory status in ageing research: reliability and phenotypic characterisation. Immunity and Ageing, 16(11). https://doi.org/10.1186/s12979-019-0151-1.

Koppada, R., Norozian, F. M., Torbati, D., Kalomiris, S., Ramachandran, C., & Totapally, B. R. (2009). Physiological Effects of a Novel Immune Stimulator Drug,(1, 4)-α-d-Glucan, in Rats. Basic & clinical pharmacology & toxicology, 105(4), 217-221. https://doi.org/10.1111/j.1742-7843.2009.00383.x.

Kunnumakkara, A.B., Rana, V., Parama, D., et al. (2021). COVID-19, cytokines, inflammation, and spices: how are they related? Life Sciences, 119201. https://doi.org/10.1016/j.lfs.2021.119201.

Panda, S. K., & Ravindran, B. (2013). Isolation of human PBMCs. Bio-protocol, 3(3), e323-e323.. https://doi.org/10.21769/bioprotoc.323.

Pruthvish, R., & Gopinatha, S. M. (2018). Antiviral prospective of Tinospora cordifolia on HSV-1. International Journal of Current Microbiology and Applied Sciences, 7(01), 3617-3624.

Singh, D., & Chaudhuri, P. K. (2017). Chemistry and pharmacology of Tinospora cordifolia. Natural product communications, 12(2), 1934578X1701200240.https://doi.org/10.1177/1934578x1701200240.

Sharma, P., Dwivedee, B. P., Bisht, D., Dash, A. K., & Kumar, D. (2019). The chemical constituents and diverse pharmacological importance of Tinospora cordifolia. Heliyon, 5(9), e02437. https://doi.org/10.1016/j.heliyon.2019.e02437.

Smetana, K., & Brábek, J. (2020). Role of interleukin-6 in lung complications in patients with COVID-19: Therapeutic implications. in vivo, 34(3 suppl), 1589-1592.. https://doi.org/10.21873/invivo.11947

Soy, M., Keser, G., Atagündüz, P., Tabak, F., Atagündüz, I., & Kayhan, S. (2020). Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clinical rheumatology, 39, 2085-2094. https://doi.org/10.1007/s10067-020-05190-5.

Sultani, M., Stringer, A. M., Bowen, J. M., & Gibson, R. J. (2012). Anti-inflammatory cytokines: important immunoregulatory factors contributing to chemotherapy-induced gastrointestinal mucositis. Chemotherapy research and practice, 2012.. https://doi.org/10.1155/2012/490804.

Tabana, Y. M., Al-Suede, F. S. R., Ahamed, M. B. K., Dahham, S. S., Hassan, L. E. A., Khalilpour, S., & Majid, A. M. S. A. (2016). Cat’s whiskers (Orthosiphon stamineus) tea modulates arthritis pathogenesis via the angiogenesis and inflammatory cascade. BMC complementary and alternative medicine, 16(1), 480.

Tete, S., Tripodi, D., Rosati, M., Conti, F., Maccauro, G., Saggini, A.& Theoharides, T. C. (2012). IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation. International journal of immunopathology and pharmacology, 25(1), 31-38. https://doi.org/10.1177/039463201202500105.

Wu, D., Wu, T., Liu, Q., & Yang, Z. (2020). The SARS-CoV-2 outbreak: what we know. International Journal of Infectious Diseases, 94, 44-48.. https://doi.org/10.1016/j.ijid.2020.03.004.

Ye, Q., Wang, B., & Mao, J. (2020). The pathogenesis and treatment of the Cytokine Storm'in COVID-19. Journal of infection, 80(6), 607-613. https://doi.org/10.1016/j.jinf.2020.03.037.