Cytokine Storm Management in Severe COVID-19: Exploring Four Effective Medicinal Plants as Potential Interventions

Document Type : Review Article

Authors

1 Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Department of pharmaceutical nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

3 Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran

4 Department of Phytopharmaceuticals (Traditional Pharmacy), Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

5 Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

6 Scientific Association of Indigenous Knowledge, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

COVID-19, caused by the SARS-CoV-2 virus, has emerged as a global health threat. Due to coronovirus mutations and genetic variations, effective treatments remain elusive. Currently, the primary strategy for disease management revolves around coronovirus vaccines, representing the sole avenue for disease control. A prominent factor in the pathogenesis of COVID-19 is the severe inflammation triggered by a phenomenon known as cytokine storm. This review delves into the pivotal role of interleukin-6 (IL-6) in orchestrating the cytokine storm and explores the intricate network of signaling pathways and inhibitors, including phytochemicals. Numerous clinical trials have explored the potential of anti-cytokine agents and medicinal plants with cytokine-modulating attributes in COVID-19 patients. According to various studies investigating the effects of medicinal plants on COVID-19, four specific plants—Silybum marianum L., Tanacetum parthenium L., Curcuma longa L., and Zingiber officinale Rosc.—have exhibited significant anti-IL-6 signaling properties. However, further rigorous clinical data are needed to establish their prophylactic or therapeutic efficacy. Overall, both in-vivo and clinical studies suggest that the aforementioned medicinal plants, endowed with proven anti-inflammatory and immune-modulatory properties, particularly through IL-6 reduction, could make valuable contributions to the management of COVID-19.

Highlights

Samira Sadat Abolmaali (Google Scholar)

Ali Mohammad Tamaddon (Google Scholar)

Keywords


1.    Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health. 2020 Mar;25(3):278-280. doi: 10.1111/tmi.13383. Epub 2020 Feb 16. PMID: 32052514; PMCID: PMC7169770.
2.    Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology. 2018 Feb;23(2):130-137. doi: 10.1111/resp.13196. Epub 2017 Oct 20. PMID: 29052924; PMCID: PMC7169239.
3.    Samadi M, Shirvani H, Rahmati-Ahmadabad S. A study of possible role of exercise and some antioxidant supplements against coronavirus disease 2019 (COVID-19): A cytokines related perspective. Apunts Sports Medicine. 2020 July-September;55(207):115–7. doi: 10.1016/j.apunsm.2020.06.003. Epub 2020 Jul 11. PMCID: PMC7837324.
4.    Beltrán-García J, Osca-Verdegal R, Pallardó FV, Ferreres J, Rodríguez M, Mulet S, Sanchis-Gomar F, Carbonell N, García-Giménez JL. Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression. Antioxidants (Basel). 2020 Sep 29;9(10):936. doi: 10.3390/antiox9100936. PMID: 33003552; PMCID: PMC7599810.
5.    Quirch M, Lee J, Rehman S. Hazards of the Cytokine Storm and Cytokine-Targeted Therapy in Patients With COVID-19: Review. J Med Internet Res. 2020 Aug 13;22(8):e20193. doi: 10.2196/20193. PMID: 32707537; PMCID: PMC7428145.
6.    Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents. 2020 Mar;55(3):105924. doi: 10.1016/j.ijantimicag.2020.105924. Epub 2020 Feb 17. PMID: 32081636; PMCID: PMC7127800.
7.    Acter T, Uddin N, Das J, Akhter A, Choudhury TR, Kim S. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: A global health emergency. Sci Total Environ. 2020 Aug 15;730:138996. doi: 10.1016/j.scitotenv.2020.138996. Epub 2020 Apr 30. PMID: 32371230; PMCID: PMC7190497.
8.    Alimardani V, Abolmaali SS, Tamaddon AM. Recent Advances on Nanotechnology-Based Strategies for Prevention, Diagnosis, and Treatment of Coronavirus Infections. J Nanomater. 2021;2021.
9.    Mehta N, Mazer-Amirshahi M, Alkindi N, Pourmand A. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am J Emerg Med. 2020 Jul;38(7):1488-1493. doi: 10.1016/j.ajem.2020.04.035. Epub 2020 Apr 15. PMID: 32336586; PMCID: PMC7158837.
10.    Viana J, van Dorp CH, Nunes A, Gomes MC, van Boven M, Kretzschmar ME, Veldhoen M, Rozhnova G. Controlling the pandemic during the SARS-CoV-2 vaccination rollout. Nat Commun. 2021 Jun 16;12(1):3674. doi: 10.1038/s41467-021-23938-8. PMID: 34135335; PMCID: PMC8209021.
11.    Bahrami M, Kamalinejad M, Latifi SA, Seif F, Dadmehr M. Cytokine storm in COVID-19 and parthenolide: Preclinical evidence. Phytother Res. 2020 Oct;34(10):2429-2430. doi: 10.1002/ptr.6776. Epub 2020 Jun 27. PMID: 32472655; PMCID: PMC7300884.
12.    Locht C. Vaccines against COVID-19. Anaesth Crit Care Pain Med. 2020 Dec;39(6):703-705. doi: 10.1016/j.accpm.2020.10.006. Epub 2020 Oct 20. PMID: 33096260; PMCID: PMC7574838.
13.    Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID: PMC7159299.
14.    Dzobo K, Chiririwa H, Dandara C, Dzobo W. Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine. OMICS. 2021 Jan;25(1):13-22. doi: 10.1089/omi.2020.0122. Epub 2020 Aug 26. PMID: 32857671.
15.    Cunningham L, Kimber I, Basketter DA, McFadden JP. Why judiciously timed anti-IL 6 therapy may be of benefit in severe COVID-19 infection. Autoimmun Rev. 2020 Jul;19(7):102563. doi: 10.1016/j.autrev.2020.102563. Epub 2020 May 5. PMID: 32380318; PMCID: PMC7198409.
16.    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011 May;1813(5):878-88. doi: 10.1016/j.bbamcr.2011.01.034. Epub 2011 Feb 4. PMID: 21296109.
17.    Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015 May;16(5):448-57. doi: 10.1038/ni.3153. Erratum in: Nat Immunol. 2017 Oct 18;18(11):1271. PMID: 25898198.
18.    Murray PJ. STAT3-mediated anti-inflammatory signalling. Biochem Soc Trans. 2006 Dec;34(Pt 6):1028-31. doi: 10.1042/BST0341028. PMID: 17073743.
19.    Gholijani N, Abolmaali SS, Kalantar K, Ravanrooy MH. Therapeutic Effect of Carvacrol-loaded Albumin Nanoparticles on Arthritic Rats. Iran J Pharm Res. 2020 Winter;19(1):312-320. doi: 10.22037/ijpr.2019.15494.13131. PMID: 32922489; PMCID: PMC7462511.
20.    Kordzadeh-Kermani E, Khalili H, Karimzadeh I. Pathogenesis, clinical manifestations and complications of coronavirus disease 2019 (COVID-19). Future Microbiol. 2020 Sep;15:1287-1305. doi: 10.2217/fmb-2020-0110. Epub 2020 Aug 27. PMID: 32851877; PMCID: PMC7493723.
21.    Portsmore S, Tran Nguyen TN, Beacham E, Neelakantan P. Combined IL-6 and JAK/STAT inhibition therapy in COVID-19-related sHLH, potential game changer. Br J Haematol. 2020 Aug;190(4):525-528. doi: 10.1111/bjh.16966. Epub 2020 Jul 22. PMID: 32584421; PMCID: PMC7361602.
22.    Crisafulli S, Isgrò V, La Corte L, Atzeni F, Trifirò G. Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks. BioDrugs. 2020 Aug;34(4):415-422. doi: 10.1007/s40259-020-00430-1. PMID: 32557214; PMCID: PMC7299248.
23.    Alsaffar DF. In Silico Molecular Docking Studies of Medicinal Arabic Plant-Based Bioactive Compounds as a Promising Drug Candidate against COVID-19. IJISRT. 2020;5(5):876-96.
24.    Bosch-Barrera J, Martin-Castillo B, Buxó M, Brunet J, Encinar JA, Menendez JA. Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients. J Clin Med. 2020 Jun 7;9(6):1770. doi: 10.3390/jcm9061770. PMID: 32517353; PMCID: PMC7356916.
25.    Shafiee M, Abolmaali S, Abedanzadeh M, Abedi M, Tamaddon A. Synthesis of Pore-Size-Tunable Mesoporous Silica Nanoparticles by Simultaneous Sol-Gel and Radical Polymerization to Enhance Silibinin Dissolution. Iran J Med Sci. 2021 Nov;46(6):475-486. doi: 10.30476/ijms.2020.86173.1595. PMID: 34840388; PMCID: PMC8611219.
26.    Son Y, Lee HJ, Rho JK, Chung SY, Lee CG, Yang K, Kim SH, Lee M, Shin IS, Kim JS. The ameliorative effect of silibinin against radiation-induced lung injury: protection of normal tissue without decreasing therapeutic efficacy in lung cancer. BMC Pulm Med. 2015 Jul 5;15:68. doi: 10.1186/s12890-015-0055-6. PMID: 26143275; PMCID: PMC4499198.
27.    Tian L, Li W, Wang T. Therapeutic effects of silibinin on LPS-induced acute lung injury by inhibiting NLRP3 and NF-κB signaling pathways. Microb Pathog. 2017 Jul;108:104-108. doi: 10.1016/j.micpath.2017.05.011. Epub 2017 May 5. PMID: 28483599.
28.    Musazadeh V, Karimi A, Bagheri N, Jafarzadeh J, Sanaie S, Vajdi M, Karimi M, Niazkar HR. The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms. Biomed Pharmacother. 2022 Oct;154:113593. doi: 10.1016/j.biopha.2022.113593. Epub 2022 Aug 22. PMID: 36027611; PMCID: PMC9393179.
29.    Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 2011 Jan;5(9):103-10. doi: 10.4103/0973-7847.79105. PMID: 22096324; PMCID: PMC3210009.
30.    Wang M, Li Q. Parthenolide could become a promising and stable drug with anti-inflammatory effects. Nat Prod Res. 2015;29(12):1092-101. doi: 10.1080/14786419.2014.981541. Epub 2014 Nov 28. PMID: 25429885.
31.    Abedanzadeh M, Salmanpour M, Farjadian F, Mohammadi S, Tamaddon AM. Curcumin loaded polymeric micelles of variable hydrophobic lengths by RAFT polymerization: Preparation and in-vitro characterization. J Drug Deliv Sci Technol. 2020;58:101793.
32.    Thota SM, Balan V, Sivaramakrishnan V. Natural products as home-based prophylactic and symptom management agents in the setting of COVID-19. Phytother Res. 2020 Dec;34(12):3148-3167. doi: 10.1002/ptr.6794. Epub 2020 Aug 17. PMID: 32881214; PMCID: PMC7461159.
33.    Avasarala S, Zhang F, Liu G, Wang R, London SD, London L. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS One. 2013;8(2):e57285. doi: 10.1371/journal.pone.0057285. Epub 2013 Feb 20. Erratum in: PLoS One. 2015;10(8):e0134982. PMID: 23437361; PMCID: PMC3577717.
34.    Ahmadi S, Mehrabi Z, Zare M, Ghadir S, Masoumi SJ. Efficacy of Nanocurcumin as an Add-On Treatment for Patients Hospitalized with COVID-19: A Double-Blind, Randomized Clinical Trial. Int J Clin Pract. 2023 Jul 28;2023:5734675. doi: 10.1155/2023/5734675. PMID: 37547100; PMCID: PMC10403319.
35.    Nugraha RV, Ridwansyah H, Ghozali M, Khairani AF, Atik N. Traditional Herbal Medicine Candidates as Complementary Treatments for COVID-19: A Review of Their Mechanisms, Pros and Cons. Evid Based Complement Alternat Med. 2020 Oct 10;2020:2560645. doi: 10.1155/2020/2560645. PMID: 33101440; PMCID: PMC7569437.
36.    Silveira D, Prieto-Garcia JM, Boylan F, Estrada O, Fonseca-Bazzo YM, Jamal CM, Magalhães PO, Pereira EO, Tomczyk M, Heinrich M. COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy? Front Pharmacol. 2020 Sep 23;11:581840. doi: 10.3389/fphar.2020.581840. PMID: 33071794; PMCID: PMC7542597.
37.    Vahdat Shariatpanahi Z, Mokhtari M, Taleban FA, Alavi F, Salehi Surmaghi MH, Mehrabi Y, Shahbazi S. Effect of enteral feeding with ginger extract in acute respiratory distress syndrome. J Crit Care. 2013 Apr;28(2):217.e1-6. doi: 10.1016/j.jcrc.2012.04.017. Epub 2012 Aug 9. PMID: 22884532.
38.    Rajagopal K, Byran G, Jupudi S, Vadivelan R. Activity of phytochemical constituents of black pepper, ginger, and garlic against coronavirus (COVID-19): An in silico approach. Int J Res Health Allied Sci. 2020;9(5):43.
39.    Mesri M, Esmaeili Saber SS, Godazi M, Roustaei Shirdel A, Montazer R, Koohestani HR, et al. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med. 2021 Mar 31;18(4):775-781. doi: 10.1515/jcim-2020-0283. PMID: 33787192.