Pınar OBAKAN YERLİKAYA, Elif Damla ARISAN, Leila MEHDİZADEHTAPEH, Pinar UYSAL-ONGANER, Ajda GÜRKAN

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

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,

PDF

___

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