Diosgenin as a Novel Therapeutic Natural Product for Various Diseases: An Overview

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Authors

  • Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris - 643001, Tamil Nadu ,IN
  • Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris - 643001, Tamil Nadu ,IN
  • Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris - 643001, Tamil Nadu ,IN
  • Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris - 643001, Tamil Nadu ,IN
  • Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris - 643001, Tamil Nadu ,IN

DOI:

https://doi.org/10.18311/jnr/2023/30378

Keywords:

Biosynthesis, Diosgenin, Phytochemical, Saponin Glycoside, Steroidal Hormone

Abstract

Diosgenin (DG) is a saponin glycoside and an active constituent generally present in medicinal plants like Rhizoma polgonita, Trigonella foenum, Dioscorea villosa and Dioscorea rhizome. It is also the starting material for the biosynthesis of steroidal hormones. DG has also been reported as a multipurpose drug aiding in the treatment of various cardiovascular, neurological diseases as well as as malignancies, osteoporosis, diabetes, and atherosclerosis. The underlying mechanisms of DG contributing towards potential therapeutic ability is to suppress the expression of oncogenic genes, preventing the formation of free radicals and thereby resulting in neuroprotection etc. However, the use of DG is restricted due to its limited pharmacokinetic properties such as poor aqueous solubility, poor bioavailability, and quicker biotransformation into its metabolites. Hence, in this study we have briefed the current therapeutic approaches of DG and its derivatives alongside to its medicinal chemistry and its physicochemical, pharmacological & toxicological properties.

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Published

2023-06-13

How to Cite

Mohammed, S., Narasimha Rao, G., Narendar, C., Bharathi, J., & Justin, A. (2023). Diosgenin as a Novel Therapeutic Natural Product for Various Diseases: An Overview. Journal of Natural Remedies, 23(2), 339–350. https://doi.org/10.18311/jnr/2023/30378

Issue

Section

Short Review
Received 2022-06-03
Accepted 2023-04-24
Published 2023-06-13

 

References

Cai B, Zhang Y, Wang Z, Xu D, Jia Y, Guan Y, Liao A, Liu G, Chun C, Li J. Therapeutic potential of diosgenin and its major derivatives against neurological diseases: Recent advances. Oxid Med Cell Longev. 2020; 3153082. https://doi.org/10.1155/2020/3153082 DOI: https://doi.org/10.1155/2020/3153082

Tohda C, Urano T, Umezaki M, Nemere I, Kuboyama T. Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice. Sci Rep. 2012; 2:535. https://doi.org/10.1038/srep00535 DOI: https://doi.org/10.1038/srep00535

Ondeykal JG, Herath KB, Jayasuriya H, Polishook JD, Bills GF, Dombrowski AW, Mojena M, Koch G, DiSalvo J, DeMartino J, Guan Z, Nanakorn W, Morenberg CM, Balick MJ, Stevenson DW, Slattery M, Borris RP, Singh SB. Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3. Mol Divers. 2005; 9(1-3):123-9. https://doi.org/10.1007/s11030-005-1296-8 DOI: https://doi.org/10.1007/s11030-005-1296-8

Shishodia S, Aggarwal BB. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression. Oncogene. 2006; 25(10):1463-1473. https://doi.org/10.1038/ sj.onc.1209194 DOI: https://doi.org/10.1038/sj.onc.1209194

Li B, Xu P, Wu S, Jiang Z, Huang Z, Li Q, Chen D. Diosgenin attenuates lipopolysaccharide-induced parkinson’s disease by inhibiting the TLR/NF- κB Pathway. J Alzheimers Dis. 2018; 64(3):943-55. https://doi.org/10.3233/JAD-180330 DOI: https://doi.org/10.3233/JAD-180330

Tohda C, Lee Y-A, Goto Y, Nemere I. Diosgenininduced cognitive enhancement in normal mice is mediated by 1,25D3-MARRS. Sci Rep. 2013; 3(1):3395.https://doi.org/10.1038/srep03395 DOI: https://doi.org/10.1038/srep03395

Cheng SM, Ho YJ, Yu SH, Liu YF, Lin YY, Huang CY, Ou HC, Huang HL, Lee SD. Anti-Apop7. totic effects of diosgenin in D-galactose-induced aging brain. Am J Chin Med. 2020; 48(2):391-406. https://doi. org/10.1142/S0192415X20500202 DOI: https://doi.org/10.1142/S0192415X20500202

Wu S, Zhao M, Sun Y, Xie M, Le K, Xu M, Huang C. The potential of Diosgenin in treating psoriasis: Studies from HaCaT keratinocytes and imiquimodinduced murine model. Life Sci. 2020; 241:117115. https://doi.org/10.1016/j.lfs.2019.117115 DOI: https://doi.org/10.1016/j.lfs.2019.117115

Gong G, Qin Y, Huang W. Anti-thrombosis effect of diosgenin extract from Dioscorea zingiberensis C.H. Wright In vitro and In vivo. Phytomedicine. 2011; 18(6):458-463. https://doi.org/10.1016/j.phymed.2010.08.015 DOI: https://doi.org/10.1016/j.phymed.2010.08.015

Chen CT, Wang ZH, Hsu CC, Lin HH and Chen JH. In vivo protective effects of diosgenin against doxorubicin-induced cardiotoxicity. Nutrients. 2015; 7(6):4938-4954. https://doi.org/10.3390/nu7064938 DOI: https://doi.org/10.3390/nu7064938

Manivannan J, Shanthakumar J, Silambarasan T, Balamurugan E, Raja B. Diosgenin, a steroidal saponin, prevents hypertension, cardiac remodeling and oxidative stress in adenine induced chronic renal failure rats. RSC Adv. 2015; 5(25):19337-19344. https:// doi.org/10.1039/C4RA13188F DOI: https://doi.org/10.1039/C4RA13188F

Zhang J, Xie JJ, Zhou SJ, Chen J, Hu Q, Pu JX, Lu JL. 2019 Diosgenin inhibits the expression of NEDD4 in prostate cancer cells. Am J Transl Res. 2019; 11(6): 3461-3471.

Yu H, Liu Y, Niu C, Cheng Y. 2018 Diosgenin increased DDX3 expression in hepatocellular carcinoma. Am J Transl Res. 2018; 10(11): 3590-3599.

Chiang CT, Way TD, Tsai SJ, Lin JK. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett. 2007; 581(30):5735-5742. https://doi.org/10.1016/j.febslet.2007.11.021 DOI: https://doi.org/10.1016/j.febslet.2007.11.021

Kim DH, Hong BN, Le HT, Hong HN, Lim CW, Park KH, Kim TW, Kang TH. Small molecular weight PEGylation of diosgenin in an In vivo animal study for diabetic auditory impairment treatment. Bioorg Med Chem Lett. 2012; 22(14):4609-4612. https://doi. org/10.1016/j.bmcl.2012.05.094 DOI: https://doi.org/10.1016/j.bmcl.2012.05.094

Yi T, Fan LL, Chen HL, Zhu GY, Suen HM, Tang YN, Zhu L, Chu C, Zhao ZZ, Chen HB. 2014 Comparative analysis of diosgenin in Dioscorea species and related medicinal plants by UPLC-DAD-MS. BMC Biochem. 2014; 15:19. https://doi.org/10.1186/1471-2091- 15-19 DOI: https://doi.org/10.1186/1471-2091-15-19

Al-Habori M, Raman A, Lawrence MJ, Skett P. In vitro effect of fenugreek extracts on intestinal sodium-dependent glucose uptake and hepatic glycogen phosphorylase A. Int J Exp Diabetes Res. 2001; 2(2):91-9. https://doi.org/10.1155/EDR.2001.91 DOI: https://doi.org/10.1155/EDR.2001.91

Ur Rahman S, Adhikari A, Ismail M, Raza Shah M, Khurram M, Shahid M, Ali F, Haseeb A, Akbar F, Iriti M. Beneficial effects of Trillium govanianum rhizomes in pain and inflammation. Molecules. 2016; 21(8):1095. https://doi.org/10.3390/molecules21081095 DOI: https://doi.org/10.3390/molecules21081095

Rothrock JW, Hammes P, Mcaleer WJ. Isolation of diosgenin by acid hydrolysis of saponin. Ind Eng Chem. 1957; 49:186-188. https://doi.org/10.1021/ ie50566a025 DOI: https://doi.org/10.1021/ie50566a025

Xu M, Huo XK, Tian XG, Dong PP, Wang C, Huang SS, Zhang BJ, Zhang HL, Deng S, Ma XC. 2015 Microbial transformation of diosgenin by Cunninghamella blakesleana AS 3.970 and potential inhibitory effects on P-glycoprotein of its metabolites. RSC Adv. 2015; 5(95):78081-78089. https://doi.org/10.1039/C5RA12253H DOI: https://doi.org/10.1039/C5RA12253H

PubChem. Diosgenin (internet). 2021. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/99474

Indrayanto G, Utami W, Santosa MH, Syahrani A. Diosgenin. In: Brittain HG, editor. Analytical profiles of drug substances and excipients [Internet]. Academic Press; [cited 2021 Dec 7]. 1994; 99-124. Available from: https://www.sciencedirect. com/science/article/pii/S0099542808606012 https://doi.org/10.1016/S0099-5428(08)60601-2 DOI: https://doi.org/10.1016/S0099-5428(08)60601-2

Görög S. Advances in the analysis of steroid hormone drugs in pharmaceuticals and environmental samples (2004-2010). J Pharm Biomed Anal. 2011; 55(4):728- 743. https://doi.org/10.1016/j.jpba.2010.11.011 DOI: https://doi.org/10.1016/j.jpba.2010.11.011

Chen B, Zhou S, Zhan Y, Ke J, Wang K, Liang Q, Hou Y, Zhu P, Ao W, Wei X, Xiao J. Dioscin inhibits the invasion and migration of hepatocellular carcinoma HepG2 cells by reversing TGF-β1-induced epithelial-mesenchymal transition. Molecules. 2019; 24(12):2222. https://doi.org/10.3390/molecules24122222 DOI: https://doi.org/10.3390/molecules24122222

Lim WC, Kim H, Kim YJ, Choi KC, Lee IH, Lee KH, Kim MK, Ko H. Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion. Bioorg Med Chem Lett. 2017; 27(15):3342-3348. https://doi. org/10.1016/j.bmcl.2017.06.014 DOI: https://doi.org/10.1016/j.bmcl.2017.06.014

Tao X, Yin L, Xu L, Peng J. Dioscin: A diverse acting natural compound with therapeutic potential in metabolic diseases, cancer, inflammation and infections. Pharmacol Res. 2018; 137:259-269. https://doi. org/10.1016/j.phrs.2018.09.022 DOI: https://doi.org/10.1016/j.phrs.2018.09.022

Chaudhary S, Chikara SK, Sharma MC, Chaudhary A, Alam Syed B, Chaudhary PS, Mehta A, Patel M, Ghosh A, Iriti M. Elicitation of diosgenin production in Trigonella foenum- graecum (Fenugreek) Seedlings by methyl jasmonate. Int J Mol Sci. 2015;. 16(12):29889-29899. https://doi.org/10.3390/ijms161226208 DOI: https://doi.org/10.3390/ijms161226208

Christ B, Xu C, Xu M, Li FS, Wada N, Mitchell AJ, Han XL, Wen ML, Fujita M, Weng JK. Repeated evolution of cytochrome P450-mediated spiroketal steroid biosynthesis in plants. Nat Commun. 2019; 10:3206. https://doi.org/10.1038/s41467-019-11286-7 DOI: https://doi.org/10.1038/s41467-019-11286-7

Cheng J, Chen J, Liu X, Li X, Zhang W, Dai Z, Lu L, Zhou X, Cai J, Zhang X, Jiang H, Ma Y, et al. The origin and evolution of the diosgenin biosynthetic pathway in yam. Plant Commun. 2021; 2(1):100079. https://doi.org/10.1016/j.xplc.2020.100079 DOI: https://doi.org/10.1016/j.xplc.2020.100079

Manda VK, Avula B, Ali Z, Wong YH, Smillie TJ, Khan IA, Khan SI. Characterization of In vitro ADME properties of diosgenin and dioscin from Dioscorea villosa. Planta Med. 2013; 79(15):1421-1428. https://doi.org/10.1055/s-0033-1350699 DOI: https://doi.org/10.1055/s-0033-1350699

Okawara M, Tokudome Y, Todo H, Sugibayashi K, Hashimoto F. Enhancement of diosgenin distribution in the skin by cyclodextrin complexation following oral administration. Biol Pharm Bull. 2013; 36(1):36- 40. https://doi.org/10.1248/bpb.b12-00467 DOI: https://doi.org/10.1248/bpb.b12-00467

Okawara M, Hashimoto F, Todo H, Sugibayashi K, Tokudome Y. Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, diosgenin, after its oral administration to rats. Int J Pharm. 2014; 472(1-2):257-261. https://doi. org/10.1016/j.ijpharm.2014.06.032 DOI: https://doi.org/10.1016/j.ijpharm.2014.06.032

Singh M, Hamid AA, Maurya AK, Prakash O, Khan F, Kumar A, Aiyelaagbe OO, Negi AS, Bawankule DU. Synthesis of diosgenin analogues as potential anti-inflammatory agents. J Steroid Biochem Mol Biol. 2014; 143:323-333. https://doi.org/10.1016/j. jsbmb.2014.04.006 DOI: https://doi.org/10.1016/j.jsbmb.2014.04.006

Mohamadi N, Sharififar F, Ansari M, Pournamdari M, Rezaei M, Hassanabadi N. Pharmacokinetic profile of diosgenin and trigonelline following intravenous and oral administration of fenugreek seed extract and pure compound in rabbit. J Asian Nat Prod Res. 2021; 23(5):466-477. https://doi.org/10.1080/10286020.2020.1769609 DOI: https://doi.org/10.1080/10286020.2020.1769609

Gao M, Chen L, Yu H, Sun Q, Kou J, Yu B. Diosgenin down-regulates NF-κB p65/p50 and p38MAPK pathways and attenuates acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 2013; 15(2):240-245. https://doi.org/10.1016/j. intimp.2012.11.019 DOI: https://doi.org/10.1016/j.intimp.2012.11.019

Cai B, Seong K-J, Bae S-W, Chun C, Kim W-J, Jung J-Y. A synthetic diosgenin primary amine derivative attenuates LPS-stimulated inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial BV2 cells. Int Immunopharmacol. 2018; 61:204-214. https://doi.org/10.1016/j.intimp.2018.05.021 DOI: https://doi.org/10.1016/j.intimp.2018.05.021

Gouras GK, Olsson TT, Hansson O. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurother J Am Soc Exp Neurother. 2015; 12(1):3-11. https://doi.org/10.1007/s13311-014-0313-y DOI: https://doi.org/10.1007/s13311-014-0313-y

Lecanu L, Rammouz G, McCourty A, Sidahmed EK, Greeson J, Papadopoulos V. Caprospinol reduces amyloid deposits and improves cognitive function in a rat model of Alzheimer’s disease. Neuroscience. 2010; 165(2):427-435. https://doi.org/10.1016/j.neuroscience. 2009.10.033 DOI: https://doi.org/10.1016/j.neuroscience.2009.10.033

Yang X, Tohda C. 2018 Diosgenin restores Aβ-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70). Sci Rep. 2018; 8(1): 11707. https://doi.org/10.1038/s41598-018-30102-8 DOI: https://doi.org/10.1038/s41598-018-30102-8

Huang Y, Huang W, Yang G, Wang R, Ma L. Design and synthesis of novel diosgenin- triazole hybrids targeting inflammation as potential neuroprotective agents. Bioorg Med Chem Lett. 2021; 43:128092. .https://doi.org/10.1016/j.bmcl.2021.128092 DOI: https://doi.org/10.1016/j.bmcl.2021.128092

Koh EK, Yun WB, Kim JE, Song SH, Sung JE, Lee HA, Seo EJ, Jee SW, Bae CJ, Hwang DY. Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection. Lab Anim Res. 2016; 32(2):105-115. https://doi.org/10.5625/lar.2016.32.2.105 DOI: https://doi.org/10.5625/lar.2016.32.2.105

Tohda C, Yang X, Matsui M, Inada Y, Kadomoto E, Nakada S, Watari H, Shibahara N. Diosgenin-richyam extract enhances cognitive function: A placebocontrolled, randomized, double-blind, crossover study of healthy adults. Nutrients. 2017; 9(10):1160. https://doi.org/10.3390/nu9101160 DOI: https://doi.org/10.3390/nu9101160

Zhou LC, Liang YF, Huang Y, Yang GX, Zheng LL, Sun JM, Li Y, Zhu FL, Qian HW, Wang R, Ma L. 2021 Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dualfunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem. 2021; 219:113426. https://doi.org/10.1016/j.ejmech.2021.113426 DOI: https://doi.org/10.1016/j.ejmech.2021.113426

Karimi Askarani H, Iraji A, Rastegari A, Abbas Bukhari SN, Firuzi O, Akbarzadeh T, Saeedi M. Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl- chromenone derivatives with potential use in Alzheimer’s disease. BMC Chem. 2020; 14(1):64. https://doi.org/10.1186/s13065-020-00715-0 DOI: https://doi.org/10.1186/s13065-020-00715-0

Zheng H, Wei Z, Xin G, Ji C, Wen L, Xia Q, Niu H, Huang W. 2016 Preventive effect of a novel diosgenin derivative on arterial and venous thrombosis in vivo. Bioorg Med Chem Lett. 2016; 26(14):3364-3369. https://doi.org/10.1016/j.bmcl.2016.05.032 DOI: https://doi.org/10.1016/j.bmcl.2016.05.032

Xue Y, Lin J, Zhang H, Xiao F, Li W, Huang N. 2021 Anti-cardiovascular effects of diosgenin and its related derivatives. MEDS Clinical Medicine. 2021; 2: 10-14.

Li X, Liu S, Qu L, Chen Y, Yuan C, Qin A, Liang J, Huang Q, Jiang M, Zou W. Dioscin and diosgenin: Insights into their potential protective effects in cardiac diseases. J Ethnopharmacol. 2021; 274:114018. https://doi.org/10.1016/j.jep.2021.114018 DOI: https://doi.org/10.1016/j.jep.2021.114018

Ghosh S, More P, Derle A, Patil AB, Markad P, Asok A, Kumbhar N, Shaikh ML, Ramanamurthy B, Shinde VS, Dhavale DD, Chopade BA. Diosgenin from Dioscorea bulbifera: Novel hit for treatment of type II Diabetes mellitus with inhibitory activity against α-Amylase and α-Glucosidase. PLoS One. 2014; 9(9):e106039. https://doi.org/10.1371/journal. pone.0106039 DOI: https://doi.org/10.1371/journal.pone.0106039

McAnuff MA, Harding WW, Omoruyi FO, Jacobs H, Morrison EY, Asemota HN. Hypoglycemic effects of steroidal sapogenins isolated from Jamaican bitter yam, Dioscorea polygonoides. Food Chem Toxicol. 2005; 43(11):1667-1672. https://doi.org/10.1016/j. fct.2005.05.008 DOI: https://doi.org/10.1016/j.fct.2005.05.008

Fang K, Dong H, Jiang S, Li F, Wang D, Yang D, Gong J, Huang W, Lu F. Diosgenin and 5-methoxypsoralen ameliorate insulin resistance through ER-α/PI3K/ Akt-signaling pathways in HepG2 Cells. Evid Based Complement Alternat Med. 2016; 1-11. https://doi. org/10.1155/2016/7493694 DOI: https://doi.org/10.1155/2016/7493694

Sato K, Fujita S, Iemitsu M. Acute administration of diosgenin or dioscorea improves hyperglycemia with increases muscular steroidogenesis in STZinduced type 1 diabetic rats. J Steroid Biochem Mol Biol. 2014; 143:152-159. https://doi.org/10.1016/j. jsbmb.2014.02.020 DOI: https://doi.org/10.1016/j.jsbmb.2014.02.020

Kiss R, Pesti-Asbóth G, Szarvas MM, Stündl L, Cziáky Z, Hegedűs C, Kovács D, Badale A, Máthé E, Szilvássy Z, Remenyik J. Diosgenin and its fenugreek based biological matrix affect insulin resistance and anabolic hormones in a rat based insulin resistance model. BioMed Res Int. 2019; 1-13. https://doi.org/10.1155/2019/7213913 DOI: https://doi.org/10.1155/2019/7213913

Kalailingam P, Kannaian B, Tamilmani E, Kaliaperumal R. Efficacy of natural diosgenin on cardiovascular risk, insulin secretion, and beta cells in Streptozotocin (STZ)-induced diabetic rats. Phytomedicine. 2014; 21(10):1154-1161. https://doi. org/10.1016/j.phymed.2014.04.005 DOI: https://doi.org/10.1016/j.phymed.2014.04.005

Tharaheswari M, Jayachandra Reddy N, Kumar R, Varshney KC, Kannan M, Sudha Rani S. Trigonelline and diosgenin attenuate ER stress, oxidative stress-mediated damage in pancreas and enhance adipose tissue PPARγ activity in type 2 diabetic rats. Mol Cell Biochem. 2014; 396(1-2):161-174. https://doi.org/10.1007/s11010-014-2152-x DOI: https://doi.org/10.1007/s11010-014-2152-x

Hao S, Xu R, Li D, Zhu Z, Wang T, Liu K. Attenuation of streptozotocin-induced lipid profile anomalies in the heart, brain, and mRNA expression of HMG-CoA reductase by diosgenin in rats. Cell Biochem Biophys. 2015; 72(3):741-749. https://doi.org/10.1007/s12013- 015-0525-8 DOI: https://doi.org/10.1007/s12013-015-0525-8

Sethi G, Shanmugam MK, Warrier S, Merarchi M, Arfuso F, Kumar AP, Bishayee A. Pro-apoptotic and anti-cancer properties of diosgenin: A comprehensive and critical review. Nutrients. 2018; 10(5):645. https://doi.org/10.3390/nu10050645 DOI: https://doi.org/10.3390/nu10050645

Raju J, Patlolla JMR, Swamy MV, Rao CV. Diosgenin, a steroid saponin of Trigonella foenum graecum (Fenugreek), inhibits azoxymethane-induced aberrant crypt foci formation in F344 rats and induces apoptosis in HT-29 human colon cancer cells. Cancer Epidemiol Biomark Prev. 2004; 13(8):1392-1398. https://doi.org/10.1158/1055-9965.1392.13.8 DOI: https://doi.org/10.1158/1055-9965.1392.13.8

Malisetty VS, Patlolla JMR, Raju J, Marcus LA, Choi C-I, Rao CV. Chemoprevention of colon cancer by diosgenin, a steroidal saponin constituent of fenugreek. Cancer Res. 2005; 65(9):580.

Miyoshi N, Nagasawa T, Mabuchi R, Yasui Y, Wakabayashi K, Tanaka T, Ohshima H. Chemoprevention of azoxymethane/dextran sodium sulfate-induced mouse colon carcinogenesis byfreeze-dried yam sanyaku and its constituent diosgenin. Cancer Prev Res (Phila). 2011; 4(6):924-934. https://doi.org/10.1158/1940-6207.CAPR-10-0279 DOI: https://doi.org/10.1158/1940-6207.CAPR-10-0279

Srinivasan S, Koduru S, Kumar R, Venguswamy G, Kyprianou N, Damodaran C. Diosgenin targets Aktmediated prosurvival signaling in human breast cancer cells. Int J Cancer. 2009; 125(4):961-967. https://doi.org/10.1002/ijc.24419 DOI: https://doi.org/10.1002/ijc.24419

Yan LL, Zhang YJ, Gao WY, Man SL, Wang Y. 2009 In vitro and In vivo anticancer activity of steroid saponins of Paris Polyphylla var. yunnanensis. Exp Oncol. 2009; 31(1): 27-32.

Jagadeesan J, Langeswaran K, Gowthamkumar S, Balasubramanian MP. Diosgenin exhibits beneficial efficiency on human mammary carcinoma cell line MCF-7 and against N- Nitroso-N-Methylurea (NMU) induced experimental mammary carcinoma. Biomed Prev Nutr. 2013; 3(4):381-388. https://doi.org/10.1016/j.bionut.2013.06.009 DOI: https://doi.org/10.1016/j.bionut.2013.06.009

Das S, Dey KK, Dey G, Pal I, Majumder A, MaitiChoudhury S, kundu SC, Mandal M. Antineoplastic and apoptotic potential of traditional medicines thymoquinone and diosgenin in squamous cell carcinoma. PLoS One. 2012; 7(10):e46641. https://doi.org/10.1371/journal.pone.0046641 DOI: https://doi.org/10.1371/journal.pone.0046641

Sánchez-Sánchez L, Hernández-Linares MG, Escobar ML, López-Muñoz H, Zenteno E, Fernández-Herrera MA, Guerrero-Luna G, Carrasco-Carballo A, Sandoval-Ramírez J. Antiproliferative, cytotoxic, and apoptotic activity of steroidal oximes in cervicouterine cell lines. Molecules. 2016; 21(11):1533. https:// doi.org/10.3390/molecules21111533 DOI: https://doi.org/10.3390/molecules21111533

Masood-ur-Rahman, Mohammad Y, Fazili KM, Bhat KA Ara T. Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents. Steroids. 2017; 118:1-8. https://doi. org/10.1016/j.steroids.2016.11.003 DOI: https://doi.org/10.1016/j.steroids.2016.11.003

Liu C, Xie F, Zhao GD, Wang DF, Lou HX, Liu ZP. Synthetic studies towards 1α- hydroxysolasodine from diosgenin and the unexpected tetrahydrofuran ring opening in the Birch reduction process. Steroids. 2015; 104:214-219. https://doi.org/10.1016/j.steroids. 2015.10.006 DOI: https://doi.org/10.1016/j.steroids.2015.10.006

Hamid AA, Kaushal T, Ashraf R, Singh A, Chand Gupta A, Prakash O, Sarkar J, Chanda D, Bawankule DU, Khan F, Shanker K, Aiyelaagbe OO, Negi AS. (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxyheptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids. 2017; 119:43-52. https://doi.org/10.1016/j.steroids.2017.01.001 DOI: https://doi.org/10.1016/j.steroids.2017.01.001

Ghosh S, More P, Derle A, Kitture R, Kale T, Gorain M, Avasthi A, Markad P, Kundu GC, Kale S, Dhavale DD, Bellare J, Chopade BA. Diosgenin functionalized iron oxide nanoparticles as novel nanomaterial against breast cancer. J Nanosci Nanotechnol. 2015; 15(12):9464-9472. https://doi.org/10.1166/jnn.2015.11704 DOI: https://doi.org/10.1166/jnn.2015.11704

Yang GX, Huang Y, Zheng LL, Zhang L, Su L, Wu YH, Li J, Zhou LC, Huang J, Tang Y, Wang , Ma L. Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer’s disease agents. Eur J Med Chem. 2020; 187:111913. https:// doi.org/10.1016/j.ejmech.2019.111913 DOI: https://doi.org/10.1016/j.ejmech.2019.111913

Xin G, Wang Y, Guo X, Huang B, Du D, He S, Zhang R, Xing Z, Zhao H, Chen Q, Huang W, He Y. Synthesis of diosgenin-ibuprofen derivatives and their activities against insulin- dependant Diabetes mellitus. 2013. https://doi.org/10.1248/cpb.c12-01024 DOI: https://doi.org/10.1248/cpb.c12-01024

Myszka H, Sokołowska P, Cieślińska A, Nowacki A, Jaśkiewicz M, Kamysz W, Liberek B. Diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside: synthesis, derivatives and antimicrobial activity. Beilstein J Org Chem. 2017; 13(1):2310-2315. https://doi. org/10.3762/bjoc.13.227 DOI: https://doi.org/10.3762/bjoc.13.227

Cai D, Qi J, Yang Y, Zhang W, Zhou F, Jia X, Guo W, Huang X, Gao F, Chen H, Li T, Li G, Wang P, Zhang Y, Lei H. Design, synthesis and biological evaluation of diosgenin- amino acid derivatives with dual functions of neuroprotection and angiogenesis. Mol Basel Switz. 2019; 24(22):4025. https://doi.org/10.3390/ molecules24224025 DOI: https://doi.org/10.3390/molecules24224025

Ma L, Zhang J, Wang X, Yang J, Guo L, Wang X, Song B, Dong W, Wang W. Design and synthesis of diosgenin derivatives as apoptosis inducers through mitochondria-related pathways. Eur J Med Chem. 2021; 217:113361. https://doi.org/10.1016/j. ejmech.2021.113361 DOI: https://doi.org/10.1016/j.ejmech.2021.113361

Zhang J, Wang X, Yang J, Guo L, Wang X, Song B, Dong W, Wang W. 2020 Novel diosgenin derivatives containing 1,3,4-oxadiazole/thiadiazole moieties as potential antitumor agents: Design, synthesis and cytotoxic evaluation. Eur J Med Chem. 2020; 186:111897. https://doi.org/10.1016/j.ejmech.2019.111897 DOI: https://doi.org/10.1016/j.ejmech.2019.111897

Michalak O, Krzeczyński P, Cieślak M, Cmoch P, Cybulski M, Królewska-Golińska K, Kaźmierczak- Barańska J, Trzaskowski B, Ostrowska K. Synthesis and anti-tumour, immunomodulating activity of diosgenin and tigogenin conjugates. J Steroid Biochem Mol Biol. 2020; 198:105573. https://doi.org/10.1016/j.jsbmb.2019.105573 DOI: https://doi.org/10.1016/j.jsbmb.2019.105573

Shen Y, Wen L, Zhang R, Wei Z, Shi N, Xiong Q, Xia Q, Xing Z, Zeng Z, Niu H, Huang W. Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury throughmitochondrial protection and PI3Kγ/Akt inhibition. Br J Pharmacol. 2018; 175(10):1621-1636. https://doi.org/10.1111/bph.14169 DOI: https://doi.org/10.1111/bph.14169

Cayen MN, Ferdinandi ES, Greselin E, Dvornik D. Studies on the disposition of diosgenin in rats, dogs, monkeys and man. Atherosclerosis. 1979; 33(1):71-87. https://doi.org/10.1016/0021-9150(79)90199-055. 78. Qin Y, Wu X, Huang W, Gong G, Li D, He Y and Zhao Y. Acute toxicity and sub-chronic toxicity of steroidal saponins from Dioscorea zingiberensis C.H.Wright in rodents. J Ethnopharmacol. 2009; 126(3):543-550. https://doi.org/10.1016/j.jep.2009.08.047 DOI: https://doi.org/10.1016/0021-9150(79)90199-0

Qin Y, Wu X, Huang W, Gong G, Li D, He Y, Zhao Y. Acute toxicity and sub-chronic toxicity of steroidal saponins from Dioscorea zingiberensis C.H.Wright in rodents. J Ethnopharmacol. 2009; 126(3):543-550. https://doi.org/10.1016/j.jep.2009.08.047 DOI: https://doi.org/10.1016/j.jep.2009.08.047

Lima CM, Lima AK, Melo MG, Serafini MR, Oliveira DL, de Almeida EB, Barreto RS, Nogueira PC, Moraes VR, Oliveira ER, de Albuquerque RL Jr, Quintans- Júnior LJ, Araújo AA. Bioassay-guided evaluation of Dioscorea villosa - an acute and subchronic toxicity, antinociceptive and anti-inflammatory approach. BMC Complement Altern Med. 2013; 13(1):195. https://doi.org/10.1186/1472-6882-13-195 DOI: https://doi.org/10.1186/1472-6882-13-195

Wojcikowski K, Wohlmuth H, Johnson DW, Gobe G. Dioscorea villosa (wild yam) induces chronic kidney injury via pro-fibrotic pathways. Food Chem Toxicol. 2008; 46(9):3122-3131. https://doi.org/10.1016/j.fct.2008.06.090 DOI: https://doi.org/10.1016/j.fct.2008.06.090

Cruz MS, Navoni JA, da Costa Xavier LA, Madalena Rocha Silva Teles M, Barbosa-Filho JM, Almeida- Lima J, de Oliveira Rocha HA, do Amaral VS. Diosgenin induces genotoxic and mutagenic effects on HepG2 cells. Food Chem Toxicol. 2018; 120:98-103. https://doi.org/10.1016/j.fct.2018.07.011 DOI: https://doi.org/10.1016/j.fct.2018.07.011