Withanolides as Prospective Drug Candidates: Production and Therapeutic Applications–A Review

Abstract

Withanolides are a group of steroidal lactones predominantly present in the genus ‘Withania’. These compounds exhibit cytotoxic, neurological, immunomodulatory, and anti-inflammatory activities. Structural diversity leads to various kinds of withanolides with different biological functionality. There is an increasing market demand for withanolides as they exhibit great therapeutic potential and can be explored for developing novel drug entities. Withanolides are primarily produced from plants that are more prone to diseases and are on the verge of endangerment. From the plant sources, the yield of withanolides is meagre (0.5 – 2%), which cannot meet the market demand, and the production cost is very high. This leads to the exploration of an alternative sustainable source for withanolide production. Endophytic fungi can produce host plant metabolites and can be investigated as an alternative source for withanolides production. Endophytic fungi can be isolated from the host plant species producing withanolides and cultured further for production. Studying the genes of the withanolidesʼ biosynthetic pathway (their upregulation or downregulation), media optimisation, co-culture, and various elicitors may enhance withanolides production. In silico approaches like molecular docking and quantitative structure–activity relationship studies may also aid in understanding the mechanism of action of withanolides on a specific target to cure a disease. Nanotechnology techniques help in designing the formulation of withanolides so that they can cross the blood-brain barrier and improve therapeutic effectiveness. This article highlights the biochemistry, biosynthetic pathway, mode of action, therapeutic potential of withanolides, and exploration of endophytic fungi as an alternative source to produce withanolides cost-effectively.

Keywords

withanolides - therapeutic potential and effectiveness - production enhancement - Withania somnifera - Solanaceae - endophytic fungi

Publication History

Received: 18 December 2024

Accepted after revision: 02 July 2025

Accepted Manuscript online:
18 July 2025

Article published online:
12 August 2025

• References

• 1 Tewari D, Chander V, Dhyani A, Sahu S, Gupta P, Patni P, Kalick LS, Bishayee A. Withania somnifera (L.) dunal: Phytochemistry, structure-activity relationship, and anticancer potential. Phytomedicine 2022; 98: 153949
• 2 Chao CH, Chou KJ, Wen ZH, Wang GH, Wu YC, Dai CF, Sheu JH. Paraminabeolides a−f, cytotoxic and anti-inflammatory marine withanolides from the soft coral Paraminabea acronocephala . J Nat Prod 2011; 74: 1132-1141
• 3 Huang CY, Ahmed AF, Su JH, Sung PJ, Hwang TL, Chiang PL, Dai CF, Liaw CC, Sheu JH. Bioactive new withanolides from the cultured soft coral Sinularia brassica . Bioorg Med Chem Lett 2017; 27: 3267-3271
• 4 Ksebati MB, Schmitz FJ. Minabeolides: A group of withanolides from a soft coral, Minabea sp. J Org Chem 1988; 53: 3926-3929
• 5 Kumar S, Bouic PJ, Rosenkranz B. Investigation of CYP2B6, 3A4 and β-esterase interactions of Withania somnifera (L.) dunal in human liver microsomes and HepG2 cells. J Ethnopharmacol 2021; 270: 113766
• 6 Kaul MK, Kumar A, Ahuja A, Mir BA, Suri KA, Qazi GN. Production dynamics of Withaferin A in Withania somnifera (L.) dunal complex. Nat Prod Res 2009; 23: 1304-1311
• 7 Lavie D, Glotter E, Shvo Y. Constituents of Withania somnifera Dun. III. The side chain of Withaferin A*^,1 . J Org Chem 1965; 30: 1774-1778
• 8 Kupchan SM, Doskotch RW, Bollinger P, McPhail AT, Sim GA, Renauld JS. The isolation and structural elucidation of a novel steroidal tumor inhibitor from Acnistus arborescens ^{1, 2} . J Am Chem Soc 1965; 87: 5805-5806
• 9 Fakhri S, Iranpanah A, Gravandi MM, Moradi SZ, Ranjbari M, Majnooni MB, Echeverria J, Qi Y, Wang M, Liao P, Farzaei MH, Xiao J. Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration. Phytomedicine 2021; 91: 153664
• 10 Welcome MO. Neuroinflammation in CNS diseases: Molecular mechanisms and the therapeutic potential of plant derived bioactive molecules. PharmaNutrition 2020; 11: 100176
• 11 Wu Y, Chen M, Jiang J. Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling. Mitochondrion 2019; 49: 35-45
• 12 Yan M, Huo Y, Yin S, Hu H. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 2018; 17: 274-283
• 13 Hamada K, Wang P, Xia Y, Yan N, Takahashi S, Krausz KW, Hao H, Yan T, Gonzalez FJ. Withaferin A alleviates ethanol-induced liver injury by inhibiting hepatic lipogenesis. Food Chem Toxicol 2022; 160: 112807
• 14 Singh A, Raza A, Amin S, Damodaran C, Sharma AK. Recent advances in the chemistry and therapeutic evaluation of naturally occurring and synthetic withanolides. Molecules 2022; 27: 886
• 15 Chhipa AS, Borse SP, Baksi R, Lalotra S, Nivsarkar M. Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications. Pathol Res Pract 2019; 215: 152643
• 16 Jayaprakasam B, Nair MG. Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves. Tetrahedron 2003; 59: 841-849
• 17 Pandey MK, Gupta SC, Karelia D, Gilhooley PJ, Shakibaei M, Aggarwal BB. Dietary nutraceuticals as backbone for bone health. Biotechnol Adv 2018; 36: 1633-1648
• 18 Fazil MHUT, Chirumamilla CS, Perez-Novo C, Wong BHS, Kumar S, Sze SK, Berghe WV, Verma NK. The steroidal lactone withaferin A impedes T-cell motility by inhibiting the kinase ZAP70 and subsequent kinome signaling. J Biol Chem 2021; 297: 101377
• 19 Mehta M, Gohil D, Khattry N, Kumar R, Sandur S, Sharma D, Checker R, Agarwal B, Jha D, Majumdar A, Gota V. Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway. Int Immunopharmacol 2020; 84: 106575
• 20 Wang J, Zhang H, Kaul A, Li K, Priyandoko D, Kaul SC, Wadhwa R. Effect of ashwagandha withanolides on muscle cell differentiation. Biomolecules 2021; 11: 1454
• 21 Chavda VP, Patel AB, Vihol D, Vaghasiya DD, Ahmed KMSB, Trivedi KU, Dave DJ. Herbal remedies, nutraceuticals, and dietary supplements for COVID-19 management: An update. Clin Complement Med Pharmacol 2022; 2: 100021
• 22 Lee SR, Lee BS, Yu JS, Kang H, Yoo MJ, Yi SA, Han JW, Kim S, Kim JK, Kim JC, Kim KH. Identification of anti-adipogenic withanolides from the roots of Indian ginseng (Withania somnifera). J Ginseng Res 2022; 46: 357-366
• 23 Li T, Wei Z, Kuang H. UPLC-orbitrap-MS-based metabolic profiling of HaCaT cells exposed to withanolides extracted from Datura metel.L: Insights from an untargeted metabolomics. J Pharm Biomed Anal 2021; 199: 113979
• 24 Chen CM, Chung YP, Liu CH, Huang KT, Guan SS, Chiang CK, Wu CT, Liu SH. Withaferin A protects against endoplasmic reticulum stress-associated apoptosis, inflammation, and fibrosis in the kidney of a mouse model of unilateral ureteral obstruction. Phytomedicine 2020; 79: 153352
• 25 Acharya P, Huded P, Bettadahalli S, Zarei M, Uppin V, Venugopal N, Talahalli RR. Withaferin-A down-regulate enterohepatic circulation of bile acids: An insight from a hyperlipidemic rat model. J Agric Food Res 2020; 2: 100035
• 26 Pires N, Gota V, Gulia A, Hingorani L, Agarwal M, Puri A. Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial. J Ayurveda Integr Med 2020; 11: 68-72
• 27 Hassannia B, Logie E, Vandenabeele P, Vanden Berghe T, Vanden Berghe W. Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug. Biochem Pharmacol 2020; 173: 113602
• 28 Nasimi Doost Azgomi R, Nazemiyeh H, Sadeghi Bazargani H, Fazljou SMB, Nejatbakhsh F, Moini Jazani A, Ahmadi AsrBadr Y, Zomorrodi A. Comparative evaluation of the effects of Withania somnifera with pentoxifylline on the sperm parameters in idiopathic male infertility: A triple-blind randomised clinical trial. Andrologia 2018; 50: e13041
• 29 Vaidya VG, Naik NN, Ganu G, Parmar V, Jagtap S, Saste G, Bhatt A, Mulay V, Girme A, Modi SJ, Hingorani L. Clinical pharmacokinetic evaluation of Withania somnifera (L.) Dunal root extract in healthy human volunteers: A non-randomized, single dose study utilizing UHPLC-MS/MS analysis. J Ethnopharmacol 2024; 322: 117603
• 30 White PT, Subramanian C, Motiwala HF, Cohen MS. Natural Withanolides in the Treatment of Chronic Diseases. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Anti-inflammatory Nutraceuticals and Chronic Diseases. Adv Exp Med Biol 2016; 928: 329-373
• 31 Patra JK, Das G, Lee S, Kang SS, Shin HS. Selected commercial plants: A review of extraction and isolation of bioactive compounds and their pharmacological market value. Trends Food Sci Technol 2018; 82: 89-109
• 32 Sayed N, Khurana A, Godugu C. Pharmaceutical perspective on the translational hurdles of phytoconstituents and strategies to overcome. J Drug Deliv Sci Technol 2019; 53: 101201
• 33 Laraia L, Robke L, Waldmann H. Bioactive compound collections: From design to target identification. Chem 2018; 4: 705-730
• 34 Chaurasiya ND, Sangwan NS, Sabir F, Misra L, Sangwan RS. Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal). Plant Cell Rep 2012; 31: 1889-1897
• 35 Liu Y. In silico evaluation of pharmacokinetics and acute toxicity of withanolides in ashawagandha. Phytochem Lett 2022; 47: 130-135
• 36 Wu J, Zhao J, Zhang T, Gu Y, Khan IA, Zou Z, Xu Q. Naturally occurring physalins from the genus Physalis: A review. Phytochemistry 2021; 191: 112925
• 37 Alali FQ, Amrine CSM, El-Elimat T, Alkofahi A, Tawaha K, Gharaibah M, Swanson SM, Falkinham JO, Cabeza M, Sanchez A, Figueroa M, Oberlies NH. Bioactive withanolides from Withania obtusifolia . Phytochem Lett 2014; 9: 96-101
• 38 Knoch E, Sugawara S, Mori T, Poulsen C, Fukushima A, Harholt J, Fujimoto Y, Umemoto N, Saito K. Third DWF1 paralog in Solanaceae, sterol Δ 24 -isomerase, branches withanolide biosynthesis from the general phytosterol pathway. Proc Natl Acad Sci 2018; 115
• 39 Saggam A, Tillu G, Dixit S, Chavan-Gautam P, Borse S, Joshi K, Patwardhan B. Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer. J Ethnopharmacol 2020; 255: 112759
• 40 De B. Steroidal compounds from in vitro regenerated shoots of D. metel . Fitoterapia 2003; 74: 14-17
• 41 Brahmachari G, Withaferin A. Chapter 57. In: Brahmachari G. (ed.) Total Synthesis of Bioactive Natural Products. Amsterdam, Netherlands: Elsevier Inc.; 2019: 301-307
• 42 Wang Z, Hui C. Contemporary advancements in the semi-synthesis of bioactive terpenoids and steroids. Org Biomol Chem 2021; 19: 3791-3812
• 43 Majhi S, Das D. Chemical derivatization of natural products: Semisynthesis and pharmacological aspects–A decade update. Tetrahedron 2021; 78: 131801
• 44 Serwetnyk MA, Blagg BSJ. The disruption of protein−protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition. Acta Pharm Sin B 2021; 11: 1446-1468
• 45 Sehrawat A, Samanta SK, Hahm ER, Croix CS, Watkins S, Singh SV. Withaferin A-mediated apoptosis in breast cancer cells is associated with alterations in mitochondrial dynamics. Mitochondrion 2019; 47: 282-293
• 46 Singh G, Dhar YV, Asif MH, Misra P. Exploring the functional significance of sterol glycosyltransferase enzymes. Prog Lipid Res 2018; 69: 1-10
• 47 Madhu S, Komala M, Pandian P. Isolation and identification of Withaferin A (Steroidal Lactone) from Withania somnifera (Ashwagandha). Drug Inven Today 2019; 11: 595-600
• 48 Zahiruddin S, Basist P, Parveen A, Parveen R, Khan W, Ahmad S. Ashwagandha in brain disorders: A review of recent developments. J Ethnopharmacol 2020; 257: 112876
• 49 Dar NJ, Ahmad M. Neurodegenerative diseases and Withania somnifera (L.): An update. J Ethnopharmacol 2020; 256: 112769
• 50 Singh N, Yadav SS, Rao AS, Nandal A, Kumar S, Ganaie SA, Narasihman B. Review on anticancerous therapeutic potential of Withania somnifera (L.) Dunal. J Ethnopharmacol 2021; 270: 113704
• 51 Khan R, Shahzad S, Choudhary MI, Khan SA, Ahmad A. Communities of endophytic fungi in medicinal plant Withania somnifera . Pak J Bot 2010; 42: 1281-1287
• 52 Nile SH, Nile A, Gansukh E, Baskar V, Kai G. Subcritical water extraction of withanosides and withanolides from ashwagandha (Withania somnifera L) and their biological activities. Food Chem Toxicol 2019; 132: 110659
• 53 Kumar A, Konar A, Garg S, Kaul SC, Wadhwa R. Experimental evidence and mechanism of action of some popular neuro-nutraceutical herbs. Neurochem Int 2021; 149: 105124
• 54 Alvarez-Rivera G, Bueno M, Ballesteros-Vivas D, Mendiola JA, Ibanez E. Pressurized Liquid Extraction. Chapter 13. In: Colin F. Poole. ed. In Handbooks in Separation Science, Liquid-Phase Extraction. Amsterdam, Netherlands: Elsevier; 2020: 375-398
• 55 Yang BY, Xia YG, Pan J, Liu Y, Wang QH, Kuang HX. Phytochemistry and biosynthesis of δ-lactone withanolides. Phytochem Rev 2016; 15: 771-797
• 56 Agarwal AV, Gupta P, Singh D, Dhar YV, Chandra D, Trivedi PK. Comprehensive assessment of the genes involved in withanolide biosynthesis from Withania somnifera: chemotype-specific and elicitor-responsive expression. Funct Integr Genomics 2017; 17: 477-490
• 57 Zhang J, Gu M, Ren C, Xu X, Kong L, Li Z, Han C. Natural withanolide-based lysine-specific demethylase 1 inhibitors for antitumor metastasis activity. Phytochem Lett 2022; 49: 93-98
• 58 Mbah NE, Lyssiotis CA. Metabolic regulation of ferroptosis in the tumor microenvironment. J Biol Chem 2022; 298: 101617
• 59 Jha NK, Arfin S, Jha SK, Kar R, Dey A, Gundamaraju R, Ashraf GM, Gupta PK, Dhanasekaran S, Abomughaid MM, Das SS, Singh SK, Dua K, Roychoudhury S, Kumar D, Ruokolainen J, Ojha S, Kesari KK. Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling. Semin Cancer Biol 2022; 86: 1086-1104
• 60 Shehzad A, Islam SU, Shahzad R, Khan S, Lee YS. Extracellular vesicles in cancer diagnostics and therapeutics. Pharmacol Ther 2021; 223: 107806
• 61 Yang Z, Zhang Q, Yu L, Zhu J, Cao Y, Gao X. The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer. J Ethnopharmacol 2021; 264: 113249
• 62 Phull MS, Jadav SS, Gundla R, Mainkar PS. A perspective on medicinal chemistry approaches towards adenomatous polyposis coli and Wnt signal based colorectal cancer inhibitors. Eur J Med Chem 2021; 212: 113149
• 63 Yao MY, Liu T, Zhang L, Wang MJ, Yang Y, Gao J. Role of ferroptosis in neurological diseases. Neurosci Lett 2021; 747: 135614
• 64 Choi BY, Kim BW. Withaferin-A inhibits colon cancer cell growth by blocking STAT3 transcriptional activity. J Cancer Prev 2015; 20: 185-192
• 65 Zúñiga R, Concha G, Cayo A, Cikutovic-Molina R, Arevalo B, Gonzalez W, Catalan MA, Zuniga L. Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3. Biomed Pharmacother 2020; 129: 110383
• 66 Costa TEMM, Raghavendra NM, Penido C. Natural heat shock protein 90 inhibitors in cancer and inflammation. Eur J Med Chem 2020; 189: 112063
• 67 Khatoon E, Banik K, Harsha C, Sailo BL, Thakur KK, Khwairakpam AD, Vikkurthi R, Devi TB, Gupta SC, Kunnumakkara AB. Phytochemicals in cancer cell chemosensitization: Current knowledge and future perspectives. Semin Cancer Biol 2022; 80: 306-339
• 68 Liu W, Wang G, Palovcak A, Li Y, Hao S, Liu ZJ, Landgraf R, Yuan F, Zhang Y. Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation. DNA Repair (Amst) 2019; 77: 10-17
• 69 Checker R, Bhilwade HN, Nandha SR, Patwardhan RS, Sharma D, Sandur SK. Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis. Toxicol Appl Pharmacol 2023; 461: 116389
• 70 Zottel A, Jovčevska I, Šamec N, Komel R. Cytoskeletal proteins as glioblastoma biomarkers and targets for therapy: A systematic review. Crit Rev Oncol Hematol 2021; 160: 103283
• 71 Zulhendri F, Perera CO, Tandean S, Abdulah R, Herman H, Christoper A, Chandrasekaran K, Putra A, Lesmana R. The potential use of propolis as a primary or an adjunctive therapy in respiratory tract-related diseases and disorders: A systematic scoping review. Biomed Pharmacother 2022; 146: 112595
• 72 Kumar R, Nayak D, Somasekharan SP. SILAC-based quantitative MS approach reveals Withaferin A regulated proteins in prostate cancer. J Proteomics 2021; 247: 104334
• 73 Ambrose JM, Veeraraghavan VP, Kullappan M, Velmurugan D, Vennila R, Rupert S, Dorairaj S, Surapaneni KM. Molecular modeling studies of the effects of withaferin A and its derivatives against oncoproteins associated with breast cancer stem cell activity. Process Biochem 2021; 111: 186-199
• 74 Deshpande SH, Muhsinah AB, Bagewadi ZK, Ankad GM, Mahnashi MH, Yaraguppi DA, Shaikh IA, Khan AA, Hegde HV, Roy S. In Silico study on the interactions, molecular docking, dynamics and simulation of potential compounds from Withania somnifera (L.) dunal root against cancer by targeting KAT6A. Molecules 2023; 28: 1117
• 75 Tomar V, Das N, Chauhan H, Roy P, Sircar D. Closed polybag foliar methyl-jasmonate treatment: New technology for rapid enhancement of bioactive withanolide biosynthesis in field-grown plants of Withania somnifera . Ind Crops Prod 2021; 162: 113262
• 76 Dubey S, Kallubai M, Subramanyam R. Improving the inhibition of β-amyloid aggregation by withanolide and withanoside derivatives. Int J Biol Macromol 2021; 173: 56-65
• 77 Ashrafian H, Zadeh EH, Khan RH. Review on Alzheimerʼs disease: Inhibition of amyloid beta and tau tangle formation. Int J Biol Macromol 2021; 167: 382-394
• 78 Singh H, Bharadvaja N. Treasuring the computational approach in medicinal plant research. Prog Biophys Mol Biol 2021; 164: 19-32
• 79 Sinha AK, Dahiya K, Kumar G. Identification of Withanolide G as a potential inhibitor of Rho-associated kinase-2 catalytic domain to confer neuroprotection in ischemic stroke. Lett Drug Des Discov 2023; 20: 845-853
• 80 Özenver N, Efferth T. Phytochemical inhibitors of the NLRP3 inflammasome for the treatment of inflammatory diseases. Pharmacol Res 2021; 170: 105710
• 81 Shapla UM, Raihan J, Islam A, Alam F, Solayman N, Gan SH, Hossen S, Khalil I. Propolis: The future therapy against Helicobacter pylori-mediated gastrointestinal diseases. J Appl Biomed 2018; 16: 81-99
• 82 Adebayo SA, Amoo SO. South African botanical resources: A gold mine of natural pro-inflammatory enzyme inhibitors?. South African J Bot 2019; 123: 214-227
• 83 Ali A, Mir GJ, Ayaz A, Maqbool I, Ahmad SB, Mushtaq S, Khan A, Mir TM, Rehman MU. In silico analysis and molecular docking studies of natural compounds of Withania somnifera against bovine NLRP9. J Mol Model 2023; 29: 171
• 84 Sarkar PK, Das Mukhopadhyay C. Mechanistic insights from the review and evaluation of ayurvedic herbal medicines for the prevention and management of COVID-19 patients. J Herb Med 2022; 32: 100554
• 85 Kalra RS, Kumar V, Dhanjal JK, Garg S, Li X, Kaul SC, Sundar D, Wadhwa R. COVID19-inhibitory activity of withanolides involves targeting of the host cell surface receptor ACE2: insights from computational and biochemical assays. J Biomol Struct Dyn 2022; 40: 7885-7898
• 86 Dubey AK, Chaudhry SK, Singh HB, Gupta VK, Kaushik A. Perspectives on nano-nutraceuticals to manage pre and post COVID-19 infections. Biotechnol Rep (Amst) 2022; 33: e00712
• 87 Gheshlaghi SZ, Nakhaei E, Ebrahimi A, Jafari M, Shahraki A, Rezazadeh S, Saberinasab E, Nowroozi A, Hosseini SS. Analysis of medicinal and therapeutic potential of Withania somnifera derivatives against COVID-19. J Biomol Struct Dyn 2023; 41: 6883-6893
• 88 Singh P, Gupta A, Qayoom I, Singh S, Kumar A. Orthobiologics with phytobioactive cues: A paradigm in bone regeneration. Biomed Pharmacother 2020; 130: 110754
• 89 Brown SA, Axenfeld E, Stonesifer EG, Hutson W, Hanish S, Raufman JP, Urrunaga NH. Current and prospective therapies for acute liver failure. Dis Mon 2018; 64: 493-522
• 90 Bekhit AA, El-Agroudy E, Helmy A, Ibrahim TM, Shavandi A, Bekhit AEDA. Leishmania treatment and prevention: Natural and synthesized drugs. Eur J Med Chem 2018; 160: 229-244
• 91 Sengupta P, Agarwal A, Pogrebetskaya M, Roychoudhury S, Durairajanayagam D, Henkel R. Role of Withania somnifera (Ashwagandha) in the management of male infertility. Reprod Biomed Online 2018; 36: 311-326
• 92 Murugan R, Subramaniyan S, Priya S, Ragavendran C, Arasu MV, Al-Dhabi NA, Choi KC, Guru A, Arockiaraj J. Bacterial clearance and anti-inflammatory effect of Withaferin A against human pathogen of Staphylococcus aureus in infected zebrafish. Aquat Toxicol 2023; 260: 106578
• 93 Oyewusi HA, Wu YS, Safi SZ, Wahab RA, Hatta MHM, Batumalaie K. Molecular dynamics simulations reveal the inhibitory mechanism of Withanolide A against α-glucosidase and α-amylase. J Biomol Struct Dyn 2023; 41: 6203-6218
• 94 Lee DH, Park SH, Lee E, Seo HD, Ahn J, Jang YJ, Ha TY, Im SS, Jung CH. Withaferin A exerts an anti-obesity effect by increasing energy expenditure through thermogenic gene expression in high-fat diet-fed obese mice. Phytomedicine 2021; 82: 153457
• 95 Raut NA, Dhore PW, Saoji SD, Kokare DM. Chapter 9 – Selected bioactive natural products for diabetes mellitus. Studies in Natural Products Chemistry 2016; 48: 287-322
• 96 Saoji SD, Rarokar NR, Dhore PW, Dube SO, Gurav NS, Gurav SS, Raut NA. Phospholipid based colloidal nanocarriers for enhanced solubility and therapeutic efficacy of withanolides. J Drug Deliv Sci Technol 2022; 70: 103251
• 97 Herck SV, Hassannia B, Louage B, Compostizo RP, Coen RD, Berghe WV, Berghe TV, De Geest BG. Water-soluble withaferin A polymer prodrugs via a drug-functionalized RAFT CTA approach. Eur Polym J 2019; 110: 313-318
• 98 Abeesh P, Vishnu WK, Guruvayoorappan C. Preparation and characterization of withaferin A loaded pegylated nanoliposomal formulation with high loading efficacy: In vitro and in vivo anti-tumour study. Mater Sci Eng C Mater Biol Appl 2021; 128: 112335
• 99 Srivastava A, Rathore S, Munshi A, Ramesh R. Organically derived exosomes as carriers of anticancer drugs and imaging agents for cancer treatment. Semin Cancer Biol 2022; 86: 80-100
• 100 Wang Q, Qin X, Fang J, Sun X. Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies. Acta Pharm Sin B 2021; 11: 1158-1174
• 101 Jaggarapu MMCS, Rachamalla HK, Nimmu NV, Banerjee R. NGRKC16-lipopeptide assisted liposomal-withaferin delivery for efficient killing of CD13 receptor-expressing pancreatic cancer and angiogenic endothelial cells. J Drug Deliv Sci Technol 2020; 58: 101798
• 102 Wang X, Liu S, Guan Y, Ding J, Ma C, Xie Z. Vaginal drug delivery approaches for localized management of cervical cancer. Adv Drug Deliv Rev 2021; 174: 114-126
• 103 Raveesha HR, Nayana S, Vasudha DR, Begum JPS, Pratibha S, Ravikumara CR, Dhananjaya N. The electrochemical behavior, antifungal and cytotoxic activities of phytofabricated MgO nanoparticles using Withania somnifera leaf extract. J Sci Adv Mater Devices 2019; 4: 57-65
• 104 Abomosallam M, Hendam BM, Abdallah AA, Refaat R, El-Hak HNG. Neuroprotective effect of Withania somnifera leaves extract nanoemulsion against penconazole-induced neurotoxicity in albino rats via modulating TGF-β1/Smad2 signaling pathway. Inflammopharmacology 2024; 32: 1903-1928
• 105 Gurav S, Wanjari M, Bhole R, Raut N, Prasad S, Saoji S, Chikhale R, Khanal P, Pant A, Ayyanar M, Gurav N. Ethnological validation of Ashwagandha (Withania somnifera L. Dunal) ghrita as ʼVajikarana Rasayanaʼ: In-silico, in-vitro and in-vivo approach. J Ethnopharmacol 2023; 304: 116064
• 106 Usapkar P, Saoji S, Jagtap P, Ayyanar M, Kalaskar M, Gurav N, Nadaf S, Prasad S, Laloo D, Khan MS, Chikhale R, Gurav S. QbD-guided phospholipid-tagged nanonized boswellic acid naturosomal delivery for effective rheumatoid arthritis treatment. Int J Pharm X 2024; 7: 100257
• 107 Saoji SD, Raut NA, Dhore PW, Borkar CD, Popielarczyk M, Dave VS. Preparation and evaluation of phospholipid-based complex of standardized Centella extract (SCE) for the enhanced delivery of phytoconstituents. AAPS J 2016; 18: 102-114
• 108 Saoji SD, Dave VS, Dhore PW, Bobde YS, Mack C, Gupta D, Raut NA. The role of phospholipid as a solubility- and permeability-enhancing excipient for the improved delivery of the bioactive phytoconstituents of Bacopa monnieri . Eur J Pharm Sci 2017; 108: 23-35
• 109 Aswani P, Tijith K, George T, Jisha MS. Characterization of bioactive metabolites of endophytic Fusarium solani isolated from Withania somnifera . J Biol Act Prod Nat 2017; 7: 411-426
• 110 Namdeo AG, Ingawale DK. Ashwagandha: Advances in plant biotechnological approaches for propagation and production of bioactive compounds. J Ethnopharmacol 2021; 271: 113709
• 111 Rana S, Bhat WW, Dhar N, Pandith SA, Razdan S, Vishwakarma R, Lattoo SK. Molecular characterization of two A-type P450 s, WsCYP98A and WsCYP76A from Withania somnifera (L.) Dunal: expression analysis and withanolide accumulation in response to exogenous elicitations. BMC Biotechnol 2014; 14: 89
• 112 Thakur M, Bhattacharya S, Khosla PK, Paul S. Improving production of plant secondary metabolites through biotic and abiotic elicitation. J Appl Res Med Aromat Plants 2019; 12: 1-12
• 113 Singh R, Singh DP, Gupta P, Jain P, Sanchita G, Mishra T, Kumar A, Dhawan SS, Shirke PA. Nanoparticles alter the withanolide biosynthesis and carbohydrate metabolism in Withania somnifera (Dunal). Ind Crops Prod 2019; 127: 94-109
• 114 Thorat SA, Poojari P, Kaniyassery A, Kiran KR, Satyamoorthy K, Mahato KK, Muthusamy A. Red laser-mediated alterations in seed germination, growth, pigments and withanolide content of Ashwagandha [Withania somnifera (L.) Dunal]. J Photochem Photobiol B 2021; 216: 112144
• 115 Varghese S, Akshaya CS, Jisha MS. Unravelling the bioprospects of mycoendophytes residing in Withania somnifera for productive pharmaceutical applications. Biocatal Agric Biotechnol 2021; 37: 102172
• 116 Mishra A, Singh SP, Mahfooz S, Bhattacharya A, Mishra N, Shirke PA, Nautiyal CS. Bacterial endophytes modulates the withanolide biosynthetic pathway and physiological performance in Withania somnifera under biotic stress. Microbiol Res 2018; 212 – 213: 17-28
• 117 Ahlawat S, Saxena P, Ali A, Khan S, Abdin MZ. Comparative study of withanolide production and the related transcriptional responses of biosynthetic genes in fungi elicited cell suspension culture of Withania somnifera in shake flask and bioreactor. Plant Physiol Biochem 2017; 114: 19-28
• 118 Johny L, Cahill DM, Adholeya A. AMF enhance secondary metabolite production in ashwagandha, licorice, and marigold in a fungi-host specific manner. Rhizosphere 2021; 17: 100314
• 119 Sivanandhan G, Selvaraj N, Ganapathi A, Lim YP. Up-regulation of Squalene synthase in hairy root culture of Withania somnifera (L.) Dunal yields higher quantities of withanolides. Ind Crops Prod 2020; 154: 112706
• 120 Sharma A, Rana S, Rather GA, Mishra P, Dhar MK, Latoo SK. Characterization and overexpression of sterol Δ22-desaturase, a key enzyme modulates the biosyntheses of stigmasterol and withanolides in Withania somnifera (L.) Dunal. Plant Sci 2020; 301: 110642
• 121 Zhang X, Lin K, Li Y. Highlights to phytosterols accumulation and equilibrium in plants: Biosynthetic pathway and feedback regulation. Plant Physiol Biochem 2020; 155: 637-649
• 122 Tiwari P, Khare T, Shriram V, Bae H, Kumar V. Plant synthetic biology for producing potent phyto-antimicrobials to combat antimicrobial resistance. Biotechnol Adv 2021; 48: 107729
• 123 Bomzan DP, Shilpashree HB, Anjali P, Kumar SR, Nagegowda DA. Virus-induced gene silencing for functional genomics in Withania somnifera, an important Indian medicinal plant. Methods Mol Biol 2020; 2172 Chapter 11. In: Courdavault V, Besseau S (eds) Virus-induced Gene Silencing in Plants. Methods Mol Biol, New York, Springer Protocols 139–154
• 124 Madina BR, Sharma LK, Chaturvedi P, Sangwan RS, Tuli R. Purification and characterization of a novel glucosyltransferase specific to 27β-hydroxy steroidal lactones from Withania somnifera and its role in stress responses. Biochem Biophys Acta – Proteins Proteom 2007; 1774: 1199-1207
• 125 Sharma L, Maurya B, Rai SP. An overview of biotechnological interventions and abiotic elicitors on biomass and withanolide biosynthesis in Withania somnifera (L.) Dunal. Ind Crops Prod 2023; 193: 116238
• 126 Alwadi HM, Baka ZAM. Microorganisms asssociated with Withania somnifera leaves. Microbiol Res 2001; 156: 303-309
• 127 Kalariya KA, Shahi D, Saran PL, Meena RP, Gajbhiye N, Choyal P, Roy S. Effects of nodding broomrape parasitism on growth, physio-biochemical changes and yield loss of Withania somnifera (Linn.) Dunal plant. Vegetos 2024; 37: 900-910
• 128 Vasundhara M, Kumar A, Reddy MS. Molecular approaches to screen bioactive compounds from endophytic fungi. Front Microbiol 2016; 7: 1774
• 129 Tenguria RK, Khan FN. Biodiversity of endophytic fungi in Withania somnifera leaves of Panchmarhi Biosphere Reserve, Madhya Pradesh. J Innov Pharm Boil Sci 2015; 2: 222-228
• 130 Yadav G, Meena M. Bioprospecting of endophytes in medicinal plants of Thar Desert: An attractive resource for biopharmaceuticals. Biotechnol Reports 2021; 30: e00629
• 131 Hassane AM, Taha TM, Awad MF, Mohamed H, Melebari M. Radical scavenging potency, HPLC profiling and phylogenetic analysis of endophytic fungi isolated from selected medicinal plants of Saudi Arabia. Electron J Biotechnol 2022; 58: 37-45
• 132 Moharram AM, Zohri AA, Seddek NH. L-Asparaginase production by endophytic fungi isolated from Withania Somnifera in Egypt. Int J Multidiscip Res 2016; 2: 30-40
• 133 Sathiyabama M, Parthasarathy R. Withanolide production by fungal endophyte isolated from Withania somnifera . Nat Prod Res 2018; 32: 1573-1577
• 134 Gupta A, Vasundhara M. Withanolides production by the endophytic fungus Penicillium oxalicum associated with Withania somnifera (L.) Dunal. World J Microbiol Biotechnol 2024; 40: 215
• 135 Soni SK, Singh R, Ngpoore NK, Niranjan A, Singh P, Mishra A, Tiwari S. Isolation and characterization of endophytic fungi having plant growth promotion traits that biosynthesizes bacosides and withanolides under in vitro conditions. Braz J Microbiol 2021; 52: 1791-1805
• 136 Ganeshan S, Kim SH, Vujanovic V. Scaling-up production of plant endophytes in bioreactors: Concepts, challenges and perspectives. Bioresour Bioprocess 2021; 8: 63
• 137 Abdi G, Tendulkar R, Thatte C, Mishra S, Desai B, Surve S, Chaudhari A, Patil N, Jain M, Tarighat MA. Scaling Up Natureʼs Chemistry: A Guide to Industrial Production of Valuable Metabolites. Chapter 15. In: Singh V (ed.). Advances in Metabolomics. Singapore: Springer Nature Singapore; 2024: 331-375
• 138 Wang G, Chu J, Noorman H, Xia J, Tang W, Zhuang Y, Zhang S. Prelude to rational scale-up of penicillin production: A scale-down study. Appl Microbiol Biotechnol 2014; 98: 2359-2369
• 139 Waheed R, Farooq AZ, Asma L. Regulatory Considerations for Microbiome-Based Therapeutics. Chapter 21. In: Khurshid M, Akash MSH (eds). Human Microbiome. Singapore: Springer Nature Singapore; 2024: 657-689
• 140 Ahmad Z, Shareen, Ganie IB, Firdaus F, Ramakrishnan M, Shahzad A, Ding Y. Enhancing withanolide production in the Withania Species: Advances in in vitro culture and synthetic biology approaches. Plants 2024; 13: 2171