Table Info

Table 1.

Various in vitro and in vivo studies of formononetin might ameliorate Alzheimer’s disease

Sr. no	Model	Dose	Effect	Reference
1.	HBEMC cell model	1–20 µM	Decreased the VCAM and ICAM Decreased the percentage of NF-κB Increased the Nrf-2 level Ameliorated the adhesion of THP-1 protein	[20]
2.	APP/PS1 mouse model	10 mg/kg	Increased swimming length Decreased latency and APP synthesis Increased the production of Aβ Increased LRP1 and ApoJ levels Decreased RAGE and NF-κB p65 Increased IL-6 and TNF-α level Decreased mRNA and protein levels	[21]
3.	Cell culture model	0.1–100 µM	Increased living cell Decreased the cell death rate, LDH release, and caspase-3 activity Increased cell viability in the cell culture and the level of sAβPPα Increased α-secretase Increased levels of ADAM10 in cells N2a-AβPP cells were treated and increased both ADAM10 and mRNA level	[22]

VCAM: vascular cell adhesion molecule; ICAM: intercellular adhesion molecule; NF-κB: nuclear factor kappa B; Nrf-2: nuclear factor erythroid 2-related factor 2; APP: amyloid precursor protein; Aβ: amyloid-beta; RAGE: receptor for advanced glycation end products; IL: interleukin; TNF: tumor necrosis factor

Declarations

Author contributions

MK: Writing—original draft, Investigation. SS and Avikramjeet S: Writing—review & editing, Investigation. Anish S: Conceptualization, Writing—original draft, Writing—review & editing, Investigation.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

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Consent to publication

Not applicable.

Availability of data and materials

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Funding

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Copyright

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References

Davenport F, Gallacher J, Kourtzi Z, Koychev I, Matthews PM, Oxtoby NP, et al. Neurodegenerative disease of the brain: a survey of interdisciplinary approaches. J R Soc Interface. 2023;20:20220406. [DOI] [PubMed] [PMC]

Ramachandran AK, Das S, Joseph A, Shenoy GG, Alex AT, Mudgal J. Neurodegenerative Pathways in Alzheimer’s Disease: A Review. Curr Neuropharmacol. 2021;19:679–92. [DOI] [PubMed] [PMC]

Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9:71. [DOI] [PubMed] [PMC]

Janoutová J, Kovalová M, Machaczka O, Ambroz P, Zatloukalová A, Němček K, et al. Risk Factors for Alzheimer’s Disease: An Epidemiological Study. Curr Alzheimer Res. 2021;18:372–9. [DOI] [PubMed]

2024 Alzheimer’s disease facts and figures. Alzheimers Dement. 2024;20:3708–821. [DOI] [PubMed] [PMC]

Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer’s disease: amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol. 2009;87:181–94. [DOI] [PubMed]

Khan S, Barve KH, Kumar MS. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr Neuropharmacol. 2020;18:1106–25. [DOI] [PubMed] [PMC]

McNaull BB, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimer’s disease – a mini-review. Gerontology. 2010;56:3–14. [DOI] [PubMed]

Deane R, Sagare A, Zlokovic BV. The role of the cell surface LRP and soluble LRP in blood-brain barrier Aβ clearance in Alzheimer’s disease. Curr Pharm Des. 2008;14:1601–5. [DOI] [PubMed] [PMC]

10.

Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25:988–1000. [DOI] [PubMed] [PMC]

11.

Cheng JJ, Wung BS, Chao YJ, Wang DL. Cyclic strain enhances adhesion of monocytes to endothelial cells by increasing intercellular adhesion molecule-1 expression. Hypertension. 1996;28:386–91. [DOI] [PubMed]

12.

Shah U, Shah A, Patel S, Patel A, Patel M, Solanki N, et al. Atorvastatin’s Reduction of Alzheimer’s Disease and Possible Alteration of Cognitive Function in Midlife as well as its Treatment. CNS Neurol Disord Drug Targets. 2023;22:1462–71. [DOI] [PubMed]

13.

Shah H, Patel A, Parikh V, Nagani A, Bhimani B, Shah U, et al. The β-Secretase Enzyme BACE1: A Biochemical Enigma for Alzheimer’s Disease. CNS Neurol Disord Drug Targets. 2020;19:184–94. [DOI] [PubMed]

14.

Křížová L, Dadáková K, Kašparovská J, Kašparovský T. Isoflavones. Molecules. 2019;24:1076. [DOI] [PubMed] [PMC]

15.

Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al. Formononetin: A Review of Its Anticancer Potentials and Mechanisms. Front Pharmacol. 2019;10:820. [DOI] [PubMed] [PMC]

16.

Aliya S, Alhammadi M, Park U, Tiwari JN, Lee JH, Han YK, et al. The potential role of formononetin in cancer treatment: An updated review. Biomed Pharmacother. 2023;168:115811. [DOI] [PubMed]

17.

Singh L, Kaur H, Chandra Arya G, Bhatti R. Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen. Chem Biol Drug Des. 2024;103:e14353. [DOI] [PubMed]

18.

Yu L, Zhang Y, Chen Q, He Y, Zhou H, Wan H, et al. Formononetin protects against inflammation associated with cerebral ischemia-reperfusion injury in rats by targeting the JAK2/STAT3 signaling pathway. Biomed Pharmacother. 2022;149:112836. [DOI] [PubMed]

19.

Machado Dutra J, Espitia PJP, Andrade Batista R. Formononetin: Biological effects and uses – A review. Food Chem. 2021;359:129975. [DOI] [PubMed]

20.

Fan M, Li Z, Hu M, Zhao H, Wang T, Jia Y, et al. Formononetin attenuates Aβ_25-35-induced adhesion molecules in HBMECs via Nrf2 activation. Brain Res Bull. 2022;183:162–71. [DOI] [PubMed]

21.

Fei HX, Zhang YB, Liu T, Zhang XJ, Wu SL. Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer’s disease. Biosci Biotechnol Biochem. 2018;82:57–64. [DOI] [PubMed]

22.

Sun M, Zhou T, Zhou L, Chen Q, Yu Y, Yang H, et al. Formononetin protects neurons against hypoxia-induced cytotoxicity through upregulation of ADAM10 and sAβPPα. J Alzheimers Dis. 2012;28:795–808. [DOI] [PubMed]

23.

Hu P, Suriguga, Zhao M, Chen S, Wu X, Wan Q. Transcriptional regulation mechanism of flavonoids biosynthesis gene during fruit development in astragalus membranaceus. Front Genet. 2022;13:972990. [DOI] [PubMed] [PMC]

24.

Li Y, Wang J, Li L, Song W, Li M, Hua X, et al. Natural products of pentacyclic triterpenoids: from discovery to heterologous biosynthesis. Nat Prod Rep. 2023;40:1303–53. [DOI] [PubMed]

25.

Wang S, Li J, Huang H, Gao W, Zhuang C, Li B, et al. Anti-hepatitis B virus activities of astragaloside IV isolated from Radix Astragali. Biol Pharm Bull. 2009;32:132–5. [DOI] [PubMed]

26.

Li S, Qi Y, Ren D, Qu D, Sun Y. The Structure Features and Improving Effects of Polysaccharide from Astragalus membranaceus on Antibiotic-Associated Diarrhea. Antibiotics (Basel). 2020;9:8. [DOI] [PubMed] [PMC]

27.

Liu P, Zhao H, Luo Y. Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic. Aging Dis. 2017;8:868–86. [DOI] [PubMed] [PMC]

28.

Peng Y, Deng X, Yang SS, Nie W, Tang YD. Progress in Mechanism of Astragalus membranaceus and Its Chemical Constituents on Multiple Sclerosis. Chin J Integr Med. 2023;29:89–95. [DOI] [PubMed]

29.

Cheng Y, Lin L, Huang P, Zhang J, Pan X. Efficacy, safety, and response predictors of Astragalus in patients with mild to moderate Alzheimer’s disease: A study protocol of an assessor-blind, statistician-blind open-label randomized controlled trial. Contemp Clin Trials Commun. 2024;41:101339. [DOI] [PubMed] [PMC]

30.

Dong M, Li J, Yang D, Li M, Wei J. Biosynthesis and Pharmacological Activities of Flavonoids, Triterpene Saponins and Polysaccharides Derived from Astragalus membranaceus. Molecules. 2023;28:5018. [DOI] [PubMed] [PMC]

31.

Singh A, Singh L. Acyclic sesquiterpenes nerolidol and farnesol: mechanistic insights into their neuroprotective potential. Pharmacol Rep. 2025;77:31–42. [DOI] [PubMed]

32.

Kaczmarczyk-Sedlak I, Wojnar W, Zych M, Ozimina-Kamińska E, Taranowicz J, Siwek A. Effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis. Evid Based Complement Alternat Med. 2013;2013:457052. [DOI] [PubMed] [PMC]

33.

Singh A, Kabra A, Singh L. Role of Formononetin (Isoflavone) in Parkinson’s Disease. Lett Appl NanoBiosci. 2025;14:72. [DOI]

34.

Tian J, Wang XQ, Tian Z. Focusing on Formononetin: Recent Perspectives for its Neuroprotective Potentials. Front Pharmacol. 2022;13:905898. [DOI] [PubMed] [PMC]

35.

Li G, Yang M, Hao X, Li C, Gao Y, Tao J. Acute toxicity of sodium formononetin-3'-sulphonate (Sul-F) in Sprague-Dawley rats and Beagle dogs. Regul Toxicol Pharmacol. 2015;73:629–33. [DOI] [PubMed]

36.

Pingale TD, Gupta GL. Acute and sub-acute toxicity study reveals no dentrimental effect of formononetin in mice upon repeated i.p. dosing. Toxicol Mech Methods. 2023;33:688–97. [DOI] [PubMed]

37.

Singh SP, Wahajuddin, Tewari D, Pradhan T, Jain GK. PAMPA permeability, plasma protein binding, blood partition, pharmacokinetics and metabolism of formononetin, a methoxylated isoflavone. Food Chem Toxicol. 2011;49:1056–62. [DOI] [PubMed]

38.

Luo LY, Fan MX, Zhao HY, Li MX, Wu X, Gao WY. Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco-2 Cell Models. J Agric Food Chem. 2018;66:2917–24. [DOI] [PubMed]

39.

Kim JH, Kang DW, Cho SJ, Cho HY. Parent-Metabolite Pharmacokinetic Modeling of Formononetin and Its Active Metabolites in Rats after Oral Administration of Formononetin Formulations. Pharmaceutics. 2023;15:45. [DOI] [PubMed] [PMC]

40.

Gao J, Liu ZJ, Chen T, Zhao D. Pharmaceutical properties of calycosin, the major bioactive isoflavonoid in the dry root extract of Radix astragali. Pharm Biol. 2014;52:1217–22. [DOI] [PubMed]

41.

Yan SD, Bierhaus A, Nawroth PP, Stern DM. RAGE and Alzheimer’s disease: a progression factor for amyloid-β-induced cellular perturbation? J Alzheimers Dis. 2009;16:833–43. [DOI] [PubMed] [PMC]

42.

Dalal D, Singh L, Singh A. Mechanistic insight unrevealing the potential of Diadzein in ameliorating the Alzheimer’s disease. Front Health Inf. 2024;13:7898–906. [DOI]