The Use of Plant Steroids in Viral Disease Treatments: Current Status and Future Perspectives

Year 2023, Volume: 82 Issue: 1, 86 - 94, 26.06.2023

Pınar Obakan Yerlikaya , Elif Damla Arısan , Leila Mehdizadehtapeh , Pinar Uysal-onganer , Ajda Gürkan

https://doi.org/10.26650/EurJBiol.2023.1130357

Abstract

Plants have been used for the prevention and treatment of diseases since the early days of humankind and constitute the natural sources of today’s modern medicine. Approximately one-quarter of approved drugs are derived from plants. Plant steroids are a group of biologically active secondary metabolites with a 5α and 5β gonane carbon skeleton. There is immense chemical diversity in plant steroids due to the side chains, oxidation status of the carbons in the tetracyclic core, and methyl groups. Plant steroids are classified into several groups based on their biological functions and structures, also on their mechanism of biosynthesis. All subtypes have been investigated for their anti-cancer, immunomodulatory, antiinflammatory, and anti-viral properties. The novel coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), which carries an RNA genome. An intense effort has been made in terms of effective treatment strategies and vaccine development since it was declared a pandemic. Nucleoside analogs such as favipiravir and remdesivir are used to block RNA-dependent RNA polymerase enzymes. Other strategies including neuraminidase inhibitors, chloroquine, and hydroxychloroquine as immunomodulatory agents, stem cell and cytokine-based therapies are being conducted. One part of the therapies against SARS-CoV-2 is focused on the spike (S) protein of the virus that binds to the host receptor, angiotensin-converting enzyme 2 (ACE2). It has been suggested that SARS-CoV-2 S protein has a free fatty acidbinding pocket, and according to molecular simulations, steroids are ligands that bind to this pocket. Therefore, this review summarizes the plant steroid biological actions as well as their anti-viral potential against SARS-CoV-2 infection.

Keywords

In silico, Plant steroids, anti-viral drug, SARS-CoV-2

References

• 1. Trautwein EA, McKay S. The role of specific components of a plantbased diet in management of dyslipidemia and the impact on cardiovascular risk. Nutrients. 2020; 12(9), 71-91. google scholar
• 1. Trautwein EA, McKay S. The role of specific components of a plantbased diet in management of dyslipidemia and the impact on cardiovascular risk. Nutrients. 2020; 12(9), 71-91. google scholar
• 2. Kreis W, Muller-Uri F. Biochemistry of sterols, cardiac glycosides, brassinosteroids, phytoecdysteroids and steroid saponins. Annu Rev Plant Biol. 2010;304-363. google scholar
• 2. Kreis W, Muller-Uri F. Biochemistry of sterols, cardiac glycosides, brassinosteroids, phytoecdysteroids and steroid saponins. Annu Rev Plant Biol. 2010;304-363. google scholar
• 3. Beg S, Hasan H, Hussain MS et al. Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives. Pharmacogn Rev. 2011;5(10):120-137. google scholar
• 3. Beg S, Hasan H, Hussain MS et al. Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives. Pharmacogn Rev. 2011;5(10):120-137. google scholar
• 4. Gunaherath GMK, Gunatilaka AAL. Plant steroids: occurrence, biological significance and their analysis. Encyc of Anal Chem. 2014;1-26. google scholar
• 4. Gunaherath GMK, Gunatilaka AAL. Plant steroids: occurrence, biological significance and their analysis. Encyc of Anal Chem. 2014;1-26. google scholar
• 5. Li Y, Li J, Zhou K et al. A review on phytochemistry and pharmacology of cortex periplocae. Molecules. 2016;21(12):2702-2718. google scholar
• 5. Li Y, Li J, Zhou K et al. A review on phytochemistry and pharmacology of cortex periplocae. Molecules. 2016;21(12):2702-2718. google scholar
• 6. Bhandari J, Muhammad B, Thapa P et al. Study of phytochemical, anti-microbial, anti-oxidant, and anti-cancer properties of Allium wallichii. BMC Complement Altern Med. 2017;17(1):102. google scholar
• 6. Bhandari J, Muhammad B, Thapa P et al. Study of phytochemical, anti-microbial, anti-oxidant, and anti-cancer properties of Allium wallichii. BMC Complement Altern Med. 2017;17(1):102. google scholar
• 7. Moosavi B, Liu S, Wang N et al. The anti-fungal 0-sitosterol targets the yeast oxysterol-binding protein Osh4. Pest Management Science , 2019; 76(2):4-11. google scholar
• 7. Moosavi B, Liu S, Wang N et al. The anti-fungal 0-sitosterol targets the yeast oxysterol-binding protein Osh4. Pest Management Science , 2019; 76(2):4-11. google scholar
• 8. Yang L, He J. Traditional uses, phytochemistry, pharmacology and toxicological aspects of the genus Hosta (Liliaceae): A comprehensive review. J Ethnopharmacol. 2021; (265):113-123. google scholar
• 8. Yang L, He J. Traditional uses, phytochemistry, pharmacology and toxicological aspects of the genus Hosta (Liliaceae): A comprehensive review. J Ethnopharmacol. 2021; (265):113-123. google scholar
• 9. Grove MD, Spencer GF, Rohwedder WK et al. Brassinolide, a plant growth-promoting steroid isolated from Brassica napus pollen. Nature, 1979;281(5728):216-217. google scholar
• 9. Grove MD, Spencer GF, Rohwedder WK et al. Brassinolide, a plant growth-promoting steroid isolated from Brassica napus pollen. Nature, 1979;281(5728):216-217. google scholar
• 10. Yokota T, Takahashi N. Chemistry, physiology and agricultural application of brassinolide and related steroids. Proceed in Life Sci. 1986;129-138. google scholar
• 10. Yokota T, Takahashi N. Chemistry, physiology and agricultural application of brassinolide and related steroids. Proceed in Life Sci. 1986;129-138. google scholar
• 11. Kour J, Kohli SK, Khanna K et al. Brassinosteroid signaling, crosstalk and, physiological functions in plants under heavy metal stress. Front Plant Sci. 2021;24(12):608-061. google scholar
• 11. Kour J, Kohli SK, Khanna K et al. Brassinosteroid signaling, crosstalk and, physiological functions in plants under heavy metal stress. Front Plant Sci. 2021;24(12):608-061. google scholar
• 12. Khamsuk O, Sonjaroon W, Suwanwong S et al. Effects of 24-epi-brassinolide and the synthetic brassinosteroid mimic on chili pepper under drought. Acta Physiol. Plant. 2018;(40):106-118. google scholar
• 12. Khamsuk O, Sonjaroon W, Suwanwong S et al. Effects of 24-epi-brassinolide and the synthetic brassinosteroid mimic on chili pepper under drought. Acta Physiol. Plant. 2018;(40):106-118. google scholar
• 13. Sondhi N, Bhardwaj R, Kaur S et al. Isolation of 24-epibrassinolide from leaves of Aegle marmelos and evaluation of its antigenotoxicity employing Allium cepa chromosomal aberration assay. Plant Growth Reg. 2007;54(3):217-224. google scholar
• 13. Sondhi N, Bhardwaj R, Kaur S et al. Isolation of 24-epibrassinolide from leaves of Aegle marmelos and evaluation of its antigenotoxicity employing Allium cepa chromosomal aberration assay. Plant Growth Reg. 2007;54(3):217-224. google scholar
• 14. Carange J, Longpre F, Daoust B et al. 24-epibrassinolide, a phytosterol from the brassinosteroid family, protects dopaminergic cells against MPP-induced oxidative stress and apoptosis. J Toxicol. 2011:392859. google scholar
• 14. Carange J, Longpre F, Daoust B et al. 24-epibrassinolide, a phytosterol from the brassinosteroid family, protects dopaminergic cells against MPP-induced oxidative stress and apoptosis. J Toxicol. 2011:392859. google scholar
• 15. Clouse SD, Sasse, JM. Brassinosteroids: Essential regulators of plant growth and development. Ann. Rev. Plant Physiol. Plant Mol. Biol. 1998;(49): 427-451. google scholar
• 15. Clouse SD, Sasse, JM. Brassinosteroids: Essential regulators of plant growth and development. Ann. Rev. Plant Physiol. Plant Mol. Biol. 1998;(49): 427-451. google scholar
• 16. Singh I, Shono M. Physiological and molecular effects of 24-epi-brassinolide, a brassinosteroid on thermotolerance of tomato. Plant Grow Reg. 2005; 47(2-3): 111-119. google scholar
• 16. Singh I, Shono M. Physiological and molecular effects of 24-epi-brassinolide, a brassinosteroid on thermotolerance of tomato. Plant Grow Reg. 2005; 47(2-3): 111-119. google scholar
• 17. Coskun D, Obakan P, Arisan ED et al. Epibrassinolide alters PI3K/ MAPK signaling axis via activating Foxo3a-induced mitochon-dria-mediated apoptosis in colon cancer cells. Exp Cell Res. 2015; 15;338(1):10-21. google scholar
• 17. Coskun D, Obakan P, Arisan ED et al. Epibrassinolide alters PI3K/ MAPK signaling axis via activating Foxo3a-induced mitochon-dria-mediated apoptosis in colon cancer cells. Exp Cell Res. 2015; 15;338(1):10-21. google scholar
• 18. Ramirez JA, Michelini FM, Galagovsky LR, Berra A, Alche LE. Antian-giogenic brassinosteroid compounds. U.S. Patent 2013088400, 17 November 2015. google scholar
• 18. Ramirez JA, Michelini FM, Galagovsky LR, Berra A, Alche LE. Antian-giogenic brassinosteroid compounds. U.S. Patent 2013088400, 17 November 2015. google scholar
• 19. Zhabinskii VN, Khripach NB, Khripach VA. Steroid plant hormones: effects outside plant kingdom. Steroids. 2015;(97):87-97. google scholar
• 19. Zhabinskii VN, Khripach NB, Khripach VA. Steroid plant hormones: effects outside plant kingdom. Steroids. 2015;(97):87-97. google scholar
• 20. Kaur Kohli S, Bhardwaj A, Bhardwaj V, Sharma A, Kalia N, Landi M, et al. Therapeutic potential of brassinosteroids in biomedical and clinical research. Biomolecules. 2020;10(4):572. google scholar
• 20. Kaur Kohli S, Bhardwaj A, Bhardwaj V, Sharma A, Kalia N, Landi M, et al. Therapeutic potential of brassinosteroids in biomedical and clinical research. Biomolecules. 2020;10(4):572. google scholar
• 21. Puschett JB, Agunanne E, Uddin MN. Emerging role of the bufa-dienolides in cardiovascular and kidney diseases. Am J Kidney Dis. 2010;56(2):359-370. google scholar
• 21. Puschett JB, Agunanne E, Uddin MN. Emerging role of the bufa-dienolides in cardiovascular and kidney diseases. Am J Kidney Dis. 2010;56(2):359-370. google scholar
• 22. Tang HJ, Ruan LJ, Tian HY, et al. Novel stereoselective bufadieno-lides reveal new insights into the requirements for Na(+), K(+)-AT-Pase inhibition by cardiotonic steroids. Sci Rep. 2016;6:29155. google scholar
• 22. Tang HJ, Ruan LJ, Tian HY, et al. Novel stereoselective bufadieno-lides reveal new insights into the requirements for Na(+), K(+)-AT-Pase inhibition by cardiotonic steroids. Sci Rep. 2016;6:29155. google scholar
• 23. Gao H, Popescu R, Kopp B, Wang Z. Bufadienolides and their antitumor activity. Nat Prod Rep. 2011;28(5):953-969. google scholar
• 23. Gao H, Popescu R, Kopp B, Wang Z. Bufadienolides and their antitumor activity. Nat Prod Rep. 2011;28(5):953-969. google scholar
• 24. Li H, Cao X, Chen X, et al. Bufadienolides induce apoptosis and autophagy by inhibiting the AKT signaling pathway in melanoma A-375 cells. Mol Med Rep. 2019;20(3):2347-2354. google scholar
• 24. Li H, Cao X, Chen X, et al. Bufadienolides induce apoptosis and autophagy by inhibiting the AKT signaling pathway in melanoma A-375 cells. Mol Med Rep. 2019;20(3):2347-2354. google scholar
• 25. Kaushik U, Aeri V, Mir SR. Cucurbitacins-An insight into medicinal leads from nature. Pharmacogn Rev. 2015;9(17):12-18. google scholar
• 25. Kaushik U, Aeri V, Mir SR. Cucurbitacins-An insight into medicinal leads from nature. Pharmacogn Rev. 2015;9(17):12-18. google scholar
• 26. Oi T, Asanuma K, Matsumine A, et al. STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma. Int J Oncol. 2016; 49(6):2275-2284. google scholar
• 26. Oi T, Asanuma K, Matsumine A, et al. STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma. Int J Oncol. 2016; 49(6):2275-2284. google scholar
• 27. Chen X, Bao J, Guo J, et al. Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anticancer Drugs. 2012; 23(8):777-787. google scholar
• 27. Chen X, Bao J, Guo J, et al. Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anticancer Drugs. 2012; 23(8):777-787. google scholar
• 28. Dinan L. Phytoecdysteroids: biological aspects. Phytochemistry. 2001;57(3):325-339. google scholar
• 28. Dinan L. Phytoecdysteroids: biological aspects. Phytochemistry. 2001;57(3):325-339. google scholar
• 29. Chadin I, Volodin V, Whiting P, Shirshova T, Kolegova N, Dinan L. Ec-dysteroid content and distribution in plants of genus Potamoge-ton, Biochem Syst and Ecol. 2003; 31(4): 407-415. google scholar
• 29. Chadin I, Volodin V, Whiting P, Shirshova T, Kolegova N, Dinan L. Ec-dysteroid content and distribution in plants of genus Potamoge-ton, Biochem Syst and Ecol. 2003; 31(4): 407-415. google scholar
• 30. Lafont R, Dinan L. Practical uses for ecdysteroids in mammals including humans: an update. J Insect Sci. 2003;3:7. google scholar
• 30. Lafont R, Dinan L. Practical uses for ecdysteroids in mammals including humans: an update. J Insect Sci. 2003;3:7. google scholar
• 31. Festucci-Buselli RA, Contim LA, Barbosa LCA, Stuart J, Otoni WC. Biosynthesis and potential functions of the ecdysteroid 20-hy-droxyecdysone-a review. Botany. 2008;86(9): 978-987. google scholar
• 31. Festucci-Buselli RA, Contim LA, Barbosa LCA, Stuart J, Otoni WC. Biosynthesis and potential functions of the ecdysteroid 20-hy-droxyecdysone-a review. Botany. 2008;86(9): 978-987. google scholar
• 32. Shakhmurova GA, Mamadalieva NZ, Zhanibekov AA, Khushbakto-va ZA, Syrov VN. Effect of total ecdysteroid preparation from Silene viridiflora on the immune state of experimental animals under normal and secondary immunodeficiency conditions. Pharm Chem J. 2012;46 (4), 222-224. google scholar
• 32. Shakhmurova GA, Mamadalieva NZ, Zhanibekov AA, Khushbakto-va ZA, Syrov VN. Effect of total ecdysteroid preparation from Silene viridiflora on the immune state of experimental animals under normal and secondary immunodeficiency conditions. Pharm Chem J. 2012;46 (4), 222-224. google scholar
• 33. Ishola, IO, Ochieng, CO, Olayemi SO, Jimoh MO, Lawal SM. Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: Involvement of monoaminergic systems. Pharmacol Biochem Behav. 2014;127, 90-100. google scholar
• 33. Ishola, IO, Ochieng, CO, Olayemi SO, Jimoh MO, Lawal SM. Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: Involvement of monoaminergic systems. Pharmacol Biochem Behav. 2014;127, 90-100. google scholar
• 34. Kregiel D, Berlowska J, Witonska I, et al. Saponin-based, biological-active surfactants from plants. In application and characterization of surfactants. Edited by Reza Najjar InTech. doi: 10.5772/65591, 2017. google scholar
• 34. Kregiel D, Berlowska J, Witonska I, et al. Saponin-based, biological-active surfactants from plants. In application and characterization of surfactants. Edited by Reza Najjar InTech. doi: 10.5772/65591, 2017. google scholar
• 35. Marrelli M, Conforti F, Araniti F, et al. Effects of saponins on lipid metabolism: a review of potential health benefits in the treatment of obesity. Molecules. 2016;21(10),1404. google scholar
• 35. Marrelli M, Conforti F, Araniti F, et al. Effects of saponins on lipid metabolism: a review of potential health benefits in the treatment of obesity. Molecules. 2016;21(10),1404. google scholar
• 36. Du JR, Long FY, Chen C. Research progress on natural triterpenoid saponins in the chemoprevention and chemotherapy of cancer. Enzymes. 2014;(36):95-130. google scholar
• 36. Du JR, Long FY, Chen C. Research progress on natural triterpenoid saponins in the chemoprevention and chemotherapy of cancer. Enzymes. 2014;(36):95-130. google scholar
• 37. Sarkar FH, Li Y, Wang Z, et al. Cellular signaling perturbation by natural products. Cell Signal. 2009;21(11):1541-1547. google scholar
• 37. Sarkar FH, Li Y, Wang Z, et al. Cellular signaling perturbation by natural products. Cell Signal. 2009;21(11):1541-1547. google scholar
• 38. Haridas V, Higuchi M, Jayatilake GS, et al. Avicins: triterpenoid saponins from Acacia victoriae (Bentham) induce apoptosis by mitochondrial perturbation. Proc Natl Acad Sci USA. 2001;98(10):5821-5826. google scholar
• 38. Haridas V, Higuchi M, Jayatilake GS, et al. Avicins: triterpenoid saponins from Acacia victoriae (Bentham) induce apoptosis by mitochondrial perturbation. Proc Natl Acad Sci USA. 2001;98(10):5821-5826. google scholar
• 39. Patlolla JM, Raju J, Swamy MV, et al. Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol Cancer Ther. 2006;5(6):1459-1466. google scholar
• 39. Patlolla JM, Raju J, Swamy MV, et al. Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol Cancer Ther. 2006;5(6):1459-1466. google scholar
• 40. Fukumura M, Ando H, Hirai Y et al. Achyranthoside H methyl ester, a novel oleanolic acid saponin derivative from Achyranthes fau-riei roots, induces apoptosis in human breast cancer MCF-7 and MDA-MB-453 cells via a caspase activation pathway. J Nat Med. 2009;63(2):181-188. google scholar
• 40. Fukumura M, Ando H, Hirai Y et al. Achyranthoside H methyl ester, a novel oleanolic acid saponin derivative from Achyranthes fau-riei roots, induces apoptosis in human breast cancer MCF-7 and MDA-MB-453 cells via a caspase activation pathway. J Nat Med. 2009;63(2):181-188. google scholar
• 41. Ooh KF, Ong HC, Wong FC, et al. High performance liquid chromatography profiling of health-promoting phytochemicals and evaluation of antioxidant, anti-lipoxygenase, iron chelating and anti-glucosidase activities of wetland macrophytes. Pharmacogn Mag. 2014;10(3):443-455. google scholar
• 41. Ooh KF, Ong HC, Wong FC, et al. High performance liquid chromatography profiling of health-promoting phytochemicals and evaluation of antioxidant, anti-lipoxygenase, iron chelating and anti-glucosidase activities of wetland macrophytes. Pharmacogn Mag. 2014;10(3):443-455. google scholar
• 42. Dey P, Kundu A, Chakraborty HJ, et al. Therapeutic value of steroidal alkaloids in cancer: Current trends and future perspectives. Int J Cancer. 2019;145(7):1731-1744. google scholar
• 42. Dey P, Kundu A, Chakraborty HJ, et al. Therapeutic value of steroidal alkaloids in cancer: Current trends and future perspectives. Int J Cancer. 2019;145(7):1731-1744. google scholar
• 43. Dirsch VM, Müller IM, Eichhorst ST, et al. Cephalostatin 1 selectively triggers the release of Smac/DIABLO and subsequent apoptosis that is characterized by an increased density of the mitochondrial matrix. Cancer Res. 2003;63(24):8869-8876. google scholar
• 43. Dirsch VM, Müller IM, Eichhorst ST, et al. Cephalostatin 1 selectively triggers the release of Smac/DIABLO and subsequent apoptosis that is characterized by an increased density of the mitochondrial matrix. Cancer Res. 2003;63(24):8869-8876. google scholar
• 44. Moser BR. Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis. J Nat Prod. 2008;71(3):487-491. google scholar
• 44. Moser BR. Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis. J Nat Prod. 2008;71(3):487-491. google scholar
• 45. Lacour TG, Guo C, Bhandaru S, et al. Interphylal Product Splicing: The First Total Syntheses of Cephalostatin 1, the North Hemisphere of Ritterazine G, and the Highly Active Hybrid Analogue, Ritterostatin GN1N1. J Am Chem Soc. 1998; 120(4), 692-707. google scholar
• 45. Lacour TG, Guo C, Bhandaru S, et al. Interphylal Product Splicing: The First Total Syntheses of Cephalostatin 1, the North Hemisphere of Ritterazine G, and the Highly Active Hybrid Analogue, Ritterostatin GN1N1. J Am Chem Soc. 1998; 120(4), 692-707. google scholar
• 46. Torres MC, das Chagas L Pinto F, et al. Antiophidic solanidane steroidal alkaloids from Solanum campaniforme. J Nat Prod. 2011;74(10):2168-2173. google scholar
• 46. Torres MC, das Chagas L Pinto F, et al. Antiophidic solanidane steroidal alkaloids from Solanum campaniforme. J Nat Prod. 2011;74(10):2168-2173. google scholar
• 47. Wang K, Sasaki T, Li W, et al. Two novel steroidal alkaloid glycosides from the seeds of Lycium barbarum. Chem Biodivers. 2011;8(12):2277-2284. google scholar
• 47. Wang K, Sasaki T, Li W, et al. Two novel steroidal alkaloid glycosides from the seeds of Lycium barbarum. Chem Biodivers. 2011;8(12):2277-2284. google scholar
• 48. Jan NU, Ahmad B, Ali S, et al. Steroidal alkaloids as an emerging therapeutic alternative for investigation of their immunosuppressive and hepatoprotective potential. Front Pharmacol. 2017;(8):114. google scholar
• 48. Jan NU, Ahmad B, Ali S, et al. Steroidal alkaloids as an emerging therapeutic alternative for investigation of their immunosuppressive and hepatoprotective potential. Front Pharmacol. 2017;(8):114. google scholar
• 49. Antony ML, Lee J, Hahm ER, et al. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of p-tubulin. J Biol Chem. 2014;289(3):1852-1865. google scholar
• 49. Antony ML, Lee J, Hahm ER, et al. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of p-tubulin. J Biol Chem. 2014;289(3):1852-1865. google scholar
• 50. Zhang H, Samadi AK, Gallagher RJ, et al. Cytotoxic withanolide constituents of Physalis longifolia. J Nat Prod. 2011;74(12):2532-2544. google scholar
• 50. Zhang H, Samadi AK, Gallagher RJ, et al. Cytotoxic withanolide constituents of Physalis longifolia. J Nat Prod. 2011;74(12):2532-2544. google scholar
• 51. Zhang H, Bazzill J, Gallagher RJ, et al. Antiproliferative withanolides from Datura wrightii. J Nat Prod. 2013;76(3):445-449. google scholar
• 51. Zhang H, Bazzill J, Gallagher RJ, et al. Antiproliferative withanolides from Datura wrightii. J Nat Prod. 2013;76(3):445-449. google scholar
• 52. Grogan PT, Sleder KD, Samadi AK, et al. Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways. Invest New Drugs. 2013;31(3):545-557. google scholar
• 52. Grogan PT, Sleder KD, Samadi AK, et al. Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways. Invest New Drugs. 2013;31(3):545-557. google scholar
• 53. Srigley CT, Haile EA. Quantification of plant sterols/stanols in foods and dietary supplements containing added phytosterols. J Food Comp Anal. 2015;(40):163-176. google scholar
• 53. Srigley CT, Haile EA. Quantification of plant sterols/stanols in foods and dietary supplements containing added phytosterols. J Food Comp Anal. 2015;(40):163-176. google scholar
• 54. Miras-Moreno B, Sabater-Jara AB, Pedreno MA, et al. Bioactivity of phytosterols and their production in plant in vitro cultures. J Agric Food Chem. 2016; 64(38):7049-7058. google scholar
• 54. Miras-Moreno B, Sabater-Jara AB, Pedreno MA, et al. Bioactivity of phytosterols and their production in plant in vitro cultures. J Agric Food Chem. 2016; 64(38):7049-7058. google scholar
• 55. Salehi-Sahlabadi A, Varkaneh HK, Shahdadian F, et al. Effects of Phytosterols supplementation on blood glucose, glycosylated hemoglobin (HbA1c) and insulin levels in humans: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Metab. Disord. 2020;19(1):625-632. google scholar
• 55. Salehi-Sahlabadi A, Varkaneh HK, Shahdadian F, et al. Effects of Phytosterols supplementation on blood glucose, glycosylated hemoglobin (HbA1c) and insulin levels in humans: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Metab. Disord. 2020;19(1):625-632. google scholar
• 56. Moreau RA, Nystrom L, Whitaker BD, et al. Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses. Prog Lipid Res. 2018;(70):35-61. google scholar
• 56. Moreau RA, Nystrom L, Whitaker BD, et al. Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses. Prog Lipid Res. 2018;(70):35-61. google scholar
• 57. Hannan MA, Sohag AAM, Dash R, et al. Phytosterols of marine algae: Insights into the potential health benefits and molecular pharmacology. Phytomedicine. 2020;(69):153201. google scholar
• 57. Hannan MA, Sohag AAM, Dash R, et al. Phytosterols of marine algae: Insights into the potential health benefits and molecular pharmacology. Phytomedicine. 2020;(69):153201. google scholar
• 58. Vezza T, Canet F, de Maranon AM, et al. Phytosterols: Nutritional health players in the management of obesity and its related disorders. Antioxidants (Basel). 2020;9(12):1266. google scholar
• 58. Vezza T, Canet F, de Maranon AM, et al. Phytosterols: Nutritional health players in the management of obesity and its related disorders. Antioxidants (Basel). 2020;9(12):1266. google scholar
• 59. Liao PC, Lai MH, Hsu KP, et al. Identification of p-Sitosterol as in vitro anti-inflammatory constituent in Moringa oleifera. J Agric Food Chem. 2018;66(41):10748-10759. google scholar
• 59. Liao PC, Lai MH, Hsu KP, et al. Identification of p-Sitosterol as in vitro anti-inflammatory constituent in Moringa oleifera. J Agric Food Chem. 2018;66(41):10748-10759. google scholar
• 60. Turnbaugh PJ, Backhed F, Fulton L, et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213-223. google scholar
• 60. Turnbaugh PJ, Backhed F, Fulton L, et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213-223. google scholar
• 61. Martinez I, Perdicaro DJ, Brown AW, et al. Diet-induced alterations of host cholesterol metabolism are likely to affect the gut microbiota composition in hamsters. Appl Environ Microbiol. 2013;79(2):516-524. google scholar
• 61. Martinez I, Perdicaro DJ, Brown AW, et al. Diet-induced alterations of host cholesterol metabolism are likely to affect the gut microbiota composition in hamsters. Appl Environ Microbiol. 2013;79(2):516-524. google scholar
• 62. Castilla V, Ramirez J, Coto CE. Plant and animal steroids a new hope to search for antiviral agents. Curr Med Chem. 2010;17(18):1858-1873. google scholar
• 62. Castilla V, Ramirez J, Coto CE. Plant and animal steroids a new hope to search for antiviral agents. Curr Med Chem. 2010;17(18):1858-1873. google scholar
• 63. Denaro M, Smeriglio A, Barreca D, et al. Antiviral activity of plants and their isolated bioactive compounds: An update. Phytother Res. 2020;34(4):742-768. google scholar
• 63. Denaro M, Smeriglio A, Barreca D, et al. Antiviral activity of plants and their isolated bioactive compounds: An update. Phytother Res. 2020;34(4):742-768. google scholar
• 64. Alkhatib A, Tsang C, Tiss A, et al. Functional foods and lifestyle approaches for diabetes prevention and management. Nutrients. 2017;9(12):1310. google scholar
• 64. Alkhatib A, Tsang C, Tiss A, et al. Functional foods and lifestyle approaches for diabetes prevention and management. Nutrients. 2017;9(12):1310. google scholar
• 65. Parvez MK, Alam P, Arbab AH, et al. Analysis of antioxidative and antiviral biomarkers p—amyrin, p-sitosterol, lupeol, ursolic acid in Guiera senegalensis leaves extract by validated HPTLC methods. Saudi Pharm. J. 2018;26(5):685-693. google scholar
• 65. Parvez MK, Alam P, Arbab AH, et al. Analysis of antioxidative and antiviral biomarkers p—amyrin, p-sitosterol, lupeol, ursolic acid in Guiera senegalensis leaves extract by validated HPTLC methods. Saudi Pharm. J. 2018;26(5):685-693. google scholar
• 66. Zhou BX, Li J, Liang XL, et al. p-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling. Acta Pharmacol Sin. 2020;41(9):1178-1196. google scholar
• 66. Zhou BX, Li J, Liang XL, et al. p-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling. Acta Pharmacol Sin. 2020;41(9):1178-1196. google scholar
• 67. Yuan M, Jiang Z, Bi G, et al. Pattern-recognition receptors are required for NLR-mediated plant immunity. Nature. 2021;592(7852):105-109. google scholar
• 67. Yuan M, Jiang Z, Bi G, et al. Pattern-recognition receptors are required for NLR-mediated plant immunity. Nature. 2021;592(7852):105-109. google scholar
• 68. Calil IP, Fontes EPB. Plant immunity against viruses: antiviral immune receptors in focus. Ann Bot. 2017;119(5):711-723. google scholar
• 68. Calil IP, Fontes EPB. Plant immunity against viruses: antiviral immune receptors in focus. Ann Bot. 2017;119(5):711-723. google scholar
• 69. Wachsman MB, Lopez EM, Ramirez JA, et al. Antiviral effect of brassinosteroids against herpes virus and arenaviruses. Antivir Chem Chemother. 2000;11(1):71-77. google scholar
• 69. Wachsman MB, Lopez EM, Ramirez JA, et al. Antiviral effect of brassinosteroids against herpes virus and arenaviruses. Antivir Chem Chemother. 2000;11(1):71-77. google scholar
• 70. Nakashita H, Yasuda M, Nitta T, et al. Brassinosteroid functions in a broad range of disease resistance in tobacco and rice. Plant J. 2003; 33(5):887-898. google scholar
• 70. Nakashita H, Yasuda M, Nitta T, et al. Brassinosteroid functions in a broad range of disease resistance in tobacco and rice. Plant J. 2003; 33(5):887-898. google scholar
• 71. Yang H, Gou X, He K, et al. BAK1 and BKK1 in Arabidopsis thaliana confer reduced susceptibility to turnip crinkle virus. Eur J Plant Pathol. 2010; 127(1),149-156. google scholar
• 71. Yang H, Gou X, He K, et al. BAK1 and BKK1 in Arabidopsis thaliana confer reduced susceptibility to turnip crinkle virus. Eur J Plant Pathol. 2010; 127(1),149-156. google scholar
• 72. Zhang DW, Deng XG, Fu FQ, et al. Induction of plant virus defense response by brassinosteroids and brassinosteroid signaling in Ara-bidopsis thaliana. Planta. 2015; 241(4):875- 885. google scholar
• 72. Zhang DW, Deng XG, Fu FQ, et al. Induction of plant virus defense response by brassinosteroids and brassinosteroid signaling in Ara-bidopsis thaliana. Planta. 2015; 241(4):875- 885. google scholar
• 73. Shamsabadipour S, Ghanadian M, Saeedi H, et al. Triterpenes and steroids from Euphorbia denticulata Lam. with anti-herpes symplex virus activity. Iran J Pharm Res. 2013;12(4):759-767. google scholar
• 73. Shamsabadipour S, Ghanadian M, Saeedi H, et al. Triterpenes and steroids from Euphorbia denticulata Lam. with anti-herpes symplex virus activity. Iran J Pharm Res. 2013;12(4):759-767. google scholar
• 74. Supratman U, Fujita T, Akiyama K, et al. Insecticidal compounds from Kalanchoe daigremontiana x tubiflora. Phytochemistry. 2001;58(2):311-314. google scholar
• 74. Supratman U, Fujita T, Akiyama K, et al. Insecticidal compounds from Kalanchoe daigremontiana x tubiflora. Phytochemistry. 2001;58(2):311-314. google scholar
• 75. Munakarmi S, Chand L, Shin HB, et al. Anticancer effects of Poncirus fructus on hepatocellular carcinoma through regulation of apoptosis, migration, and invasion. Oncol Rep. 2020;44(6):2537-2546. google scholar
• 75. Munakarmi S, Chand L, Shin HB, et al. Anticancer effects of Poncirus fructus on hepatocellular carcinoma through regulation of apoptosis, migration, and invasion. Oncol Rep. 2020;44(6):2537-2546. google scholar
• 76. Liu Y, Yang H, Guo Q, et al. Cucurbitacin E Inhibits Huh7 Hepatoma Carcinoma Cell Proliferation and Metastasis via Suppressing MAPKs and JAK/STAT3 Pathways. Molecules. 2020;25(3):560. google scholar
• 76. Liu Y, Yang H, Guo Q, et al. Cucurbitacin E Inhibits Huh7 Hepatoma Carcinoma Cell Proliferation and Metastasis via Suppressing MAPKs and JAK/STAT3 Pathways. Molecules. 2020;25(3):560. google scholar
• 77. Troost B, Mulder LM, Diosa-Toro M, et al. Tomatidine, a natural steroidal alkaloid shows antiviral activity towards chikungunya virus in vitro. Sci Rep. 2020;10(1):6364. google scholar
• 77. Troost B, Mulder LM, Diosa-Toro M, et al. Tomatidine, a natural steroidal alkaloid shows antiviral activity towards chikungunya virus in vitro. Sci Rep. 2020;10(1):6364. google scholar
• 78. Wang P, Bai J, Liu X, et al. Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease. Vet Res. 2020;51(1):136. google scholar
• 78. Wang P, Bai J, Liu X, et al. Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease. Vet Res. 2020;51(1):136. google scholar
• 79. Brian DA, Baric RS. Coronavirus genome structure and replication. Curr Top Microbiol Immunol. 2005;(287):1-30. google scholar
• 79. Brian DA, Baric RS. Coronavirus genome structure and replication. Curr Top Microbiol Immunol. 2005;(287):1-30. google scholar
• 80. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;(1282):1-23. google scholar
• 80. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;(1282):1-23. google scholar
• 81. Mahmood N, Nasir SB, Hefferon K. Plant-Based Drugs and Vaccines for COVID-19. Vaccines (Basel). 2020;9(1):15. google scholar
• 81. Mahmood N, Nasir SB, Hefferon K. Plant-Based Drugs and Vaccines for COVID-19. Vaccines (Basel). 2020;9(1):15. google scholar
• 82. Dent SD, Xia D, Wastling JM, et al. The proteome of the infectious bronchitis virus Beau-R virion. J Gen Virol. 2015;96(12):3499-3506. google scholar
• 82. Dent SD, Xia D, Wastling JM, et al. The proteome of the infectious bronchitis virus Beau-R virion. J Gen Virol. 2015;96(12):3499-3506. google scholar
• 83. Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-269. google scholar
• 83. Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-269. google scholar
• 84. Tang X, Wu C, Li X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7(6):1012-1023. google scholar
• 84. Tang X, Wu C, Li X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7(6):1012-1023. google scholar
• 85. Corman VM, Muth D, Niemeyer D, et al. Hosts and Sources of Endemic Human Coronaviruses. Adv Virus Res. 2018;(100):163-188. google scholar
• 85. Corman VM, Muth D, Niemeyer D, et al. Hosts and Sources of Endemic Human Coronaviruses. Adv Virus Res. 2018;(100):163-188. google scholar
• 86. van Paassen J, Vos JS, Hoekstra EM, et al. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care. 2020;24(1):696. google scholar
• 86. van Paassen J, Vos JS, Hoekstra EM, et al. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care. 2020;24(1):696. google scholar
• 87. Fischer R, Buyel JF. Molecular farming-The slope of enlightenment. Biotechnol. Adv. 2020;(40):107519. google scholar
• 87. Fischer R, Buyel JF. Molecular farming-The slope of enlightenment. Biotechnol. Adv. 2020;(40):107519. google scholar
• 88. Capell T, Twyman RM, Armario-Najera V, et al. Potential applications of plant biotechnology against SARS-CoV-2. Trends Plant Sci. 2020 25(7):635-643. google scholar
• 88. Capell T, Twyman RM, Armario-Najera V, et al. Potential applications of plant biotechnology against SARS-CoV-2. Trends Plant Sci. 2020 25(7):635-643. google scholar
• 89. Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020; 581(7807):221-224. google scholar
• 89. Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020; 581(7807):221-224. google scholar
• 90. Bhuiyan FR, Howlader S, Raihan T, et al. Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic. Front Med (Lausanne). 2020;(7):444. google scholar
• 90. Bhuiyan FR, Howlader S, Raihan T, et al. Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic. Front Med (Lausanne). 2020;(7):444. google scholar
• 91. Fernandez-Oliva A, Ortega-Gonzalez P, Risco C. Targeting host lipid flows: Exploring new antiviral and antibiotic strategies. Cell Microbiol. 2019;21(3):e12996. google scholar
• 91. Fernandez-Oliva A, Ortega-Gonzalez P, Risco C. Targeting host lipid flows: Exploring new antiviral and antibiotic strategies. Cell Microbiol. 2019;21(3):e12996. google scholar
• 92. Baglivo M, Baronio M, Natalini G, et al. Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity? Acta Biomed. 2020;91(1):161-164. google scholar
• 92. Baglivo M, Baronio M, Natalini G, et al. Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity? Acta Biomed. 2020;91(1):161-164. google scholar
• 93. Li SY, Chen C, Zhang HQ, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005;67(1):18-23 google scholar
• 93. Li SY, Chen C, Zhang HQ, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005;67(1):18-23 google scholar
• 94. Cheng PW, Ng LT, Chiang LC, et al. Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin Exp Pharmacol Physiol. 2006;33(7):612-616. google scholar
• 94. Cheng PW, Ng LT, Chiang LC, et al. Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin Exp Pharmacol Physiol. 2006;33(7):612-616. google scholar
• 95. Yang CW, Lee YZ, Hsu HY, et al. Inhibition of SARS-CoV-2 by highly potent broad-spectrum anti-coronaviral tylophorine-based derivatives. Front Pharmacol. 2020;(11):606097. google scholar
• 95. Yang CW, Lee YZ, Hsu HY, et al. Inhibition of SARS-CoV-2 by highly potent broad-spectrum anti-coronaviral tylophorine-based derivatives. Front Pharmacol. 2020;(11):606097. google scholar
• 96. Puttaswamy H, Gowtham HG, Ojha MD, et al. In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis. Sci Rep. 2020;10(1):20584. google scholar
• 96. Puttaswamy H, Gowtham HG, Ojha MD, et al. In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis. Sci Rep. 2020;10(1):20584. google scholar
• 97. Shoemark DK, Colenso CK, Toelzer C, et al. Molecular simulations suggest vitamins, retinoids and steroids as ligands of the free fatty acid pocket of the SARS-CoV-2 spike protein. Angew Chem Int Ed Engl. 2021; 60(13):7098-8010. google scholar
• 97. Shoemark DK, Colenso CK, Toelzer C, et al. Molecular simulations suggest vitamins, retinoids and steroids as ligands of the free fatty acid pocket of the SARS-CoV-2 spike protein. Angew Chem Int Ed Engl. 2021; 60(13):7098-8010. google scholar
• 98. Alka H, Akhilesh A, Archana S, et al. Cucurbitacin: As a candidate against cytokine storm in severe COVID-19 infection. Int J Res Pharm Sci. 2020;11(1): 928-930. google scholar
• 98. Alka H, Akhilesh A, Archana S, et al. Cucurbitacin: As a candidate against cytokine storm in severe COVID-19 infection. Int J Res Pharm Sci. 2020;11(1): 928-930. google scholar
• 99. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):327-331. google scholar
• 99. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):327-331. google scholar
• 100. Qiao J, Xu LH, He J, et al. Cucurbitacin E exhibits anti-inflammatory effect in RAW 264.7 cells via suppression of NF-kB nuclear translocation. Inflamm Res. 2013;62(5):461-469. google scholar
• 100. Qiao J, Xu LH, He J, et al. Cucurbitacin E exhibits anti-inflammatory effect in RAW 264.7 cells via suppression of NF-kB nuclear translocation. Inflamm Res. 2013;62(5):461-469. google scholar
• 101. Escandell JM, Recio MC, Manez S, et al. Cucurbitacin R reduces the inflammation and bone damage associated with adjuvant arthritis in lewis rats by suppression of tumor necrosis factor-alpha in T lymphocytes and macrophages. J Pharmacol Exp Ther. 2007;320(2):581-590. google scholar
• 101. Escandell JM, Recio MC, Manez S, et al. Cucurbitacin R reduces the inflammation and bone damage associated with adjuvant arthritis in lewis rats by suppression of tumor necrosis factor-alpha in T lymphocytes and macrophages. J Pharmacol Exp Ther. 2007;320(2):581-590. google scholar