Ginkgo (Ginkgo biloba L.) is one of the most distinctive plants, characterized by excellent resistance to various environmental conditions. It is used as an ornamental plant and is recognized as a medicinal plant in both traditional and Western medicine. Its bioactive potential is associated with the presence of flavonoids and terpene trilactones, but many other compounds may also have synergistic effects. Flavonoid dimers-biflavonoids-are important constituents of ginkgophytopharmaceuticals. Currently, the presence of 13 biflavonoids has been reported in ginkgo, of which amentoflavone, bilobetin, sciadopitysin, ginkgetin and isoginkgetin are the most common. Their role in plants remains unknown, but their bioactivity and potential role in the management of human health are better investigated. In this review, we have provided an overview of the chemistry, diversity and biological factors that influence the presence of biflavonoids in ginkgo, as well as their bioactive and health-related properties. We have focused on their antioxidant, anticancer, antiviral, antibacterial, antifungal and anti-inflammatory activities as well as their potential role in the treatment of cardiovascular, metabolic and neurodegenerative diseases. We also highlighted their potential toxicity and pointed out further research directions.

Department for Biology Faculty of Science University of Sarajevo Zmaja od Bosne 33 35 71000 Sarajevo Bosnia and Herzegovina

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 165 00 Prague Czech Republic

Department of Food Technology University North Trga Dr Žarka Dolinara 1 48000 Koprivnica Croatia

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Leistner E., Drewke C. Ginkgo biloba and ginkgotoxin. J. Nat. Prod. 2010;73:86–92. doi: 10.1021/np9005019. PubMed DOI

He B., Gu Y., Xu M., Wang J., Cao F., Xu L.A. Transcriptome analysis of Ginkgo biloba kernels. Front. Plant Sci. 2015;6:819. doi: 10.3389/fpls.2015.00819. PubMed DOI PMC

Šmarda P., Veselý P., Šmerda J., Bureš P., Knápek O., Chytrá M. Polyploidy in a ‘living fossil’ Ginkgo biloba. New Phytol. 2016;212:11–14. doi: 10.1111/nph.14062. PubMed DOI

Gong W., Chen C., Dobeš C., Fu C.X., Koch M.A. Phylogeography of a living fossil: Pleistocene glaciations forced Ginkgo biloba L.(Ginkgoaceae) into two refuge areas in China with limited subsequent postglacial expansion. Mol. Phylogenetics Evol. 2008;48:1094–1105. doi: 10.1016/j.ympev.2008.05.003. PubMed DOI

Tang C.Q., Yang Y., Ohsawa M., Yi S.-R., Momohara A., Su W.-H., Wang H.-C., Zhang Z.-Y., Peng M.-C., Wu Z.-L. Evidence for the persistence of wild Ginkgo biloba (Ginkgoaceae) populations in the Dalou Mountains, southwestern China. Am. J. Bot. 2012;99:1408–1414. doi: 10.3732/ajb.1200168. PubMed DOI

Bainian S., Liang X., Sanping X., Shenghui D., Yongdong W., Hui J., Turner S. Quantitative analysis of paleoatmospheric CO2 level based on stomatal characters of fossil Ginkgo from Jurassic to Cretaceous in China. Acta Geol. Sin. 2007;81:931–939. doi: 10.1111/j.1755-6724.2007.tb01016.x. DOI

Royer D.L., Hickey L.J., Wing S.L. Ecological conservatism in the “living fossil″ Ginkgo. Paleobiology. 2003;29:84–104. doi: 10.1666/0094-8373(2003)029<0084:ECITLF>2.0.CO;2. DOI

Guan R., Zhao Y., Zhang H., Fan G., Liu X., Zhou W., Shi C., Wang J., Liu W., Liang X., et al. Draft genome of the living fossil Ginkgo biloba. Gigascience. 2016;5:49. doi: 10.1186/s13742-016-0154-1. PubMed DOI PMC

Nagata T., Hasebe M., Toriba T., Taneda H., Crane P.R. Sex conversion in Ginkgo biloba (Ginkgoaceae) J. Jpn. Bot. 2016;91:120–127.

Parliment T.H. Characterization of the putrid aroma compounds of Ginkgo biloba fruits. In Fruit Flavors: Biogenesis, Characterization, and Authentication; Rouseff, R., Leahy, M., Eds. Am. Chem. Soc. Symp. Ser. 1995;596:276–279.

Murakami M., Abe M., Kakumoto Y., Kawano H., Fukasawa H., Saha M., Takada H. Evaluation of ginkgo as a biomonitor of airborne polycyclic aromatic hydrocarbons. Atmos. Environ. 2012;54:9–17. doi: 10.1016/j.atmosenv.2012.02.014. DOI

Aziz T.A., Hussain S.A., Mahwi T.O., Ahmed Z.A., Rahman H.S., Rasedee A. The efficacy and safety of Ginkgo biloba extract as an adjuvant in type 2 diabetes mellitus patients ineffectively managed with metformin: A double-blind, randomized, placebo-controlled trial. Drug Des. Devel. Ther. 2018;12:735–742. doi: 10.2147/DDDT.S157113. PubMed DOI PMC

Goh L.M., Barlow P.J. Antioxidant capacity in Ginkgo biloba. Food Res. Int. 2002;35:815–820. doi: 10.1016/S0963-9969(02)00084-4. DOI

Noor-E-Tabassum Das R., Lami M.S., Chakraborty A.J., Mitra S., Tallei T.E., Idroes R., Mohamed A.A.-R., Hossain J., Dhama K., Mostafa-Hedeab G., et al. Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications. Evid.-Based Complement. Altern. Med. 2022;2022:8288818. doi: 10.1155/2022/8288818. PubMed DOI PMC

Barbalho S.M., Direito R., Laurindo L.F., Marton L.T., Guiguer E.L., Goulart R.d.A., Tofano R.J., Carvalho A.C.A., Flato U.A.P., Capelluppi Tofano V.A., et al. Ginkgo biloba in the Aging Process: A Narrative Review. Antioxidants. 2022;11:525. doi: 10.3390/antiox11030525. PubMed DOI PMC

McKenna D.J., Jones K., Hughes K. Efficacy, safety, and use of Ginkgo biloba in clinical and preclinical applications. Altern. Ther. Health Med. 2001;7:88–90. PubMed

Jacobs B.P., Browner W.S. Ginkgo biloba: A living fossil. Am. J. Med. 2000;108:341–342. doi: 10.1016/S0002-9343(00)00290-4. PubMed DOI

Liu L., Wang Y., Zhang J., Wang S. Advances in the chemical constituents and chemical analysis of Ginkgo biloba leaf, extract, and phytopharmaceuticals. J. Pharm. Biomed. Anal. 2021;193:113704. doi: 10.1016/j.jpba.2020.113704. PubMed DOI

He X., Yang F., Huang X. Proceedings of Chemistry, Pharmacology, Pharmacokinetics and Synthesis of Biflavonoids. Molecules. 2021;26:6088. doi: 10.3390/molecules26196088. PubMed DOI PMC

Ražná K., Hrubík P. Cultural Extension of Ginkgo biloba L. in Slovakia. Agrobiodiversity Improv. Nutr. Health Life Qual. 2021;5:258–279. doi: 10.15414/ainhlq.2021.0025. DOI

Del Tredici P. Ginkgos and people: A thousand years of interaction. Arnoldia. 1991;51:2–15.

Barlow P.W., Kurczyńska E.U. The anatomy of the chi-chi of Ginkgo biloba suggests a mode of elongation growth that is an alternative to growth driven by an apical meristem. J. Plant Res. 2007;120:269–280. doi: 10.1007/s10265-006-0050-3. PubMed DOI

Singh B., Kaur P., Gopichand, Singh R.D., Ahuja P.S. Biology and chemistry of Ginkgo biloba. Fitoterapia. 2008;79:401–418. doi: 10.1016/j.fitote.2008.05.007. PubMed DOI

Cheng J.-T., Guo C., Cui W.-J., Zhang Q., Wang S.-H., Zhao Q.-H., Liu D.-W., Zhang J., Chen S., Chen C., et al. Isolation of two rare N-glycosides from Ginkgo biloba and their anti-inflammatory activities. Sci. Rep. 2020;10:5994. doi: 10.1038/s41598-020-62884-1. PubMed DOI PMC

Boateng I.D. A critical review of current technologies used to reduce ginkgotoxin, ginkgotoxin-5′-glucoside, ginkgolic acid, allergic glycoprotein, and cyanide in Ginkgo biloba L. seed. Food Chem. 2022;382:132408. doi: 10.1016/j.foodchem.2022.132408. PubMed DOI

Šamec D., Karalija E., Šola I., Vujčić Bok V., Salopek-Sondi B. The Role of Polyphenols in Abiotic Stress Response: The Influence of Molecular Structure. Plants. 2021;10:118. doi: 10.3390/plants10010118. PubMed DOI PMC

Nabavi S.M., Šamec D., Tomczyk M., Milella L., Russo D., Habtemariam S., Suntar I., Rastrelli L., Daglia M., Xiao J., et al. Flavonoid Biosynthetic Pathways in Plants: Versatile Targets for Metabolic Engineering. Biotechnol. Adv. 2020;38:107316. doi: 10.1016/j.biotechadv.2018.11.005. PubMed DOI

Ahmed T., Javed S., Javed S., Tariq A., Šamec D., Tejada S., Nabavi S.F., Braidy N., Nabavi S.M. Resveratrol and Alzheimer’s Disease: Mechanistic Insights. Mol. Neurobiol. 2017;54:2622–2635. doi: 10.1007/s12035-016-9839-9. PubMed DOI

Nabavi S.F., Khan H., D’onofrio G., Šamec D., Shirooie S., Dehpour A.R., Castilla S.A., Habtemariam S., Sobarzo-Sanchez E. Apigenin as Neuroprotective Agent: Of mice and men. Pharmacol. Res. 2018;128:359–365. doi: 10.1016/j.phrs.2017.10.008. PubMed DOI

Budzynska B., Faggio C., Kruk- Slomka M., Šamec D., Nabavi S.F., Sureda A., Devi K.P., Nabavi S.M. Rutin as neuroprotective agent: From bench to bedside. Curr. Med. Chem. 2019;26:5152–5164. doi: 10.2174/0929867324666171003114154. PubMed DOI

Arafah A., Rehman M.U., Mir T.M., Wali A.F., Ali R., Qamar W., Khan R., Ahmad A., Aga S.S., Alqahtani S., et al. Multi-Therapeutic Potential of Naringenin (4′,5,7-Trihydroxyflavonone): Experimental Evidence and Mechanisms. Plants. 2020;9:1784. doi: 10.3390/plants9121784. PubMed DOI PMC

Šudomová M., Berchová-Bímová K., Mazurakova A., Šamec D., Kubatka P., Hassan S.T.S. Flavonoids Target Human Herpesviruses That Infect the Nervous System: Mechanisms of Action and Therapeutic Insights. Viruses. 2022;14:592. doi: 10.3390/v14030592. PubMed DOI PMC

Wang L.-T., Fan X.-H., Jian Y., Dong M.-Z., Yang Q., Meng D., Fu Y.-J. A sensitive and selective multiple reaction monitoring mass spectrometry method for simultaneous quantification of flavonol glycoside, terpene lactones, and biflavonoids in Ginkgo biloba leaves. J. Pharm. Biomed. Anal. 2019;170:335–340. doi: 10.1016/j.jpba.2019.03.058. PubMed DOI

Ma G.-L., Xiong J., Yang G.-X., Pan L.-L., Hu C.-L., Wang W., Fan H., Zhao Q.-H., Zhang H.-Y., Hu J.-F. Biginkgosides A–I, Unexpected Minor Dimeric Flavonol Diglycosidic Truxinate and Truxillate Esters from Ginkgo biloba Leaves and Their Antineuroinflammatory and Neuroprotective Activities. J. Nat. Prod. 2016;79:1354–1364. doi: 10.1021/acs.jnatprod.6b00061. PubMed DOI

DeForest J.C., Du L., Joyner P.M. 4′,4′′′,7,7′′-Tetra-O-methylcupressuflavone Inhibits Seed Germination of Lactuca sativa. J. Nat. Prod. 2014;77:1093–1096. doi: 10.1021/np4010739. PubMed DOI

Šamec D., Pierz V., Srividya N., Wüst M., Lange B.M. Assessing chemical diversity in Psilotum nudum (L.) Beauv., a Pantropical whisk fern that has lost many of its fern-like characters. Front. Plant Sci. 2019;10:868. doi: 10.3389/fpls.2019.00868. PubMed DOI PMC

Gontijo V.S., dos Santos M.H., Viegas C. Biological and Chemical Aspects of Natural Biflavonoids from Plants: A Brief Review. Mini Rev. Med. Chem. 2017;17:834–862. doi: 10.2174/1389557517666161104130026. PubMed DOI

Wollenweber E., Kraut L., Mues R. External Accumulation of Biflavonoids on Gymnosperm Leaves. Z. Nat. C. 1998;53:946–950. doi: 10.1515/znc-1998-11-1202. DOI

Lin L.-Z., Chen P., Ozcan M., Harnly J.M. Chromatographic Profiles and Identification of New Phenolic Components of Ginkgo biloba Leaves and Selected Products. J. Agric. Food Chem. 2008;56:6671–6679. doi: 10.1021/jf800488x. PubMed DOI PMC

Beck S., Stengel J. Mass spectrometric imaging of flavonoid glycosides and biflavonoids in Ginkgo biloba L. Phytochemistry. 2016;130:201–206. doi: 10.1016/j.phytochem.2016.05.005. PubMed DOI

Kaur P., Chaudhary A., Singh B., Gopichand Simultaneous quantification of flavonoids and biflavonoids in Ginkgo biloba using RP-HPTLC densitometry method. JPC-J. Planar Chromat. –Mod. TLC. 2011;24:507–512. doi: 10.1556/JPC.24.2011.6.10. DOI

Wang L.-T., Yang Q., Cui Q., Fan X.-H., Dong M.-Z., Gao M.-Z., Lv M.-J., An J.-Y., Meng D., Zhao X.-H., et al. Recyclable menthol-based deep eutectic solvent micellar system for extracting phytochemicals from Ginkgo biloba leaves. J. Clean. Prod. 2019;244:118648. doi: 10.1016/j.jclepro.2019.118648. DOI

Lei J., Jiang Y., Luo X., Zheng Y., Zhu L., Sun C., Linghu L., Qin C., Gang W. Ultrasonic-Assisted Ionic Liquid Extraction of Four Biflavonoids from Ginkgo biloba L. ChemistrySelect. 2021;6:3297–3307. doi: 10.1002/slct.202004605. DOI

Pandey R., Chandra P., Arya K.R., Kuma B. Development and validation of an ultra high performance liquid chromatography electrospray ionization tandem mass spectrometry method for the simultaneous determination of selected flavonoids in Ginkgo biloba. J. Sep. Sci. 2014;37:3610–3618. doi: 10.1002/jssc.201400853. PubMed DOI

Li M., Li B., Xia Z.-M., Tian Y., Zhang D., Rui W.-J., Dong J.-X., Xiao F.-J. Anticancer Effects of Five Biflavonoids from Ginkgo Biloba L. Male Flowers In Vitro. Molecules. 2019;24:1496. doi: 10.3390/molecules24081496. PubMed DOI PMC

Shen N., Liu Y., Cui Y., Xin H. Large-scale targetedly isolation of biflavonoids with high purity from industrial waste Ginkgo biloba exocarp using two-dimensional chromatography coupled with macroporous adsorption resin enrichment. Ind. Crops Prod. 2022;175:114264. doi: 10.1016/j.indcrop.2021.114264. PubMed DOI

Zhou G., Yao X., Tang Y., Yang N., Pang H., Mo X., Zhu S., Su S., Qian D., Jin C., et al. Two new nonacosanetriols from Ginkgo biloba sarcotesta. Chem. Phys. Lipids. 2012;165:731–736. doi: 10.1016/j.chemphyslip.2012.08.003. PubMed DOI

Chen X., Zhong W., Shu C., Yang H., Li E. Comparative analysis of chemical constituents and bioactivities of the extracts from leaves, seed coats and embryoids of Ginkgo biloba L. Nat. Prod. Res. 2021;35:5498–5501. doi: 10.1080/14786419.2020.1788020. PubMed DOI

Lu Z., Zhu L., Lu J., Shen N., Wang L., Liu S., Wang Q., Yu W., Kato-Noguchi H., Li W., et al. Rejuvenation increases leaf biomass and flavonoid accumulation in Ginkgo biloba. Hortic. Res. 2022;9 doi: 10.1093/hr/uhab018. in press . PubMed DOI PMC

Guo Y., Gao C., Wang M., Fu F., El-Kassaby Y.A., Wang T., Wang G. Metabolome and transcriptome analyses reveal flavonoids biosynthesis differences in Ginkgo biloba associated with environmental conditions. Ind. Crops Prod. 2020;158:112963. doi: 10.1016/j.indcrop.2020.112963. DOI

Wu Y., Guo J., Zhou Q., Xin Y., Wang G., Xu L.-a. De novo transcriptome analysis revealed genes involved in flavonoid biosynthesis, transport and regulation in Ginkgo biloba. Ind. Crops Prod. 2018;124:226–235. doi: 10.1016/j.indcrop.2018.07.060. DOI

Wang G., Cao F., Chang L., Guo X., Wang J. Temperature has more effects than soil moisture on biosynthesis of flavonoids in Ginkgo (Ginkgo biloba L.) leaves. New For. 2014;45:797–812. doi: 10.1007/s11056-014-9437-5. DOI

Xu Y., Wang G., Cao F., Zhu C., Wang G., El-Kassaby Y.A. Light intensity affects the growth and flavonol biosynthesis of Ginkgo (Ginkgo biloba L.) New For. 2014;45:765–776. doi: 10.1007/s11056-014-9435-7. DOI

Zhao B., Wang L., Pang S., Jia Z., Wang L., Li W., Jin B. UV-B promotes flavonoid synthesis in Ginkgo biloba leaves. Ind. Crops Prod. 2020;151:112483. doi: 10.1016/j.indcrop.2020.112483. DOI

Xu N., Liu S., Lu Z., Pang S., Wang L., Wang L., Li W. Gene Expression Profiles and Flavonoid Accumulation during Salt Stress in Ginkgo biloba Seedlings. Plants. 2020;9:1162. doi: 10.3390/plants9091162. PubMed DOI PMC

Martínez-Solís I., Acero N., Bosch-Morell F., Castillo E., González-Rosende M.E., Muñoz-Mingarro D., Ortega T., Sanahuja M.A., Villagrasa V. Neuroprotective Potential of Ginkgo biloba in Retinal Diseases. Planta Med. 2019;85:1292–1303. doi: 10.1055/a-0947-5712. PubMed DOI

De Souza G.A., de Marqui S.V., Matias J.N., Elen Landgraf Guiguer E.L., Barbalho S.M. Effects of Ginkgo biloba on Diseases Related to Oxidative Stress. Planta Med. 2020;86:376–386. PubMed

Bedir E., Tatli I.I., Khan R.A., Zhao J., Takamatsu S., Walker L.A., Goldman P., Khan I.A. Biologically Active Secondary Metabolites from Ginkgo biloba. J. Agric. Food Chem. 2002;50:3150–3155. doi: 10.1021/jf011682s. PubMed DOI

Bajpai V.K., Park I., Lee J., Shukla S., Nile S.H., Chun H.S., Khan I., Oh S.-Y., Huh Y.S., Na M.K., et al. Antioxidant and antimicrobial efficacy of a biflavonoid, amentoflavone from Nandina domestica in vitro and in minced chicken meat and apple juice food models. Food Chem. 2019;271:239–247. doi: 10.1016/j.foodchem.2018.07.159. PubMed DOI

Li Y.-L., Chen X., Niu S.-Q., Zhou H.-Y., Li Q.-S. Protective Antioxidant Effects of Amentoflavone and Total Flavonoids from Hedyotis diffusa on H2O2-Induced HL-O2 Cells through ASK1/p38 MAPK Pathway. Chem. Biodivers. 2020;17:e2000251. doi: 10.1002/cbdv.202000251. PubMed DOI

Li X., Ouyang X., Cai R., Chen D. 3′,8″-Dimerization Enhances the Antioxidant Capacity of Flavonoids: Evidence from Acacetin and Isoginkgetin. Molecules. 2019;24:2039. doi: 10.3390/molecules24112039. PubMed DOI PMC

Yu S., Yan H., Zhang L., Shan M., Chen P., Ding A., Li S.F.Y. A Review on the Phytochemistry, Pharmacology, and Pharmacokinetics of Amentoflavone, a Naturally-Occurring Biflavonoid. Molecules. 2017;22:299. doi: 10.3390/molecules22020299. PubMed DOI PMC

Gan L., Ma J., You G., Mai J., Wang Z., Yang R., Xie C., Fei J., Tang L., Zhao J., et al. Glucuronidation and its effect on the bioactivity of amentoflavone, a biflavonoid from Ginkgo biloba leaves. J. Pharm. Pharmacol. 2020;72:1840–1853. doi: 10.1111/jphp.13247. PubMed DOI

Ahmed H.H., El-Abhar H.S., Hassanin E.A.K., Abdelkader N.F., Shalaby M. B Ginkgo biloba L. leaf extract offers multiple mechanisms in bridling N -methylnitrosourea–mediated experimental colorectal cancer. Biomed. Pharmacother. 2017;95:387–393. doi: 10.1016/j.biopha.2017.08.103. PubMed DOI

Silva A.M., Silva S.C., Soares J.P., Martins-Gomes C., Teixeira J.P., Leal F., Gaivão I. Ginkgo biloba L. Leaf Extract Protects HepG2 Cells Against Paraquat-Induced Oxidative DNA Damage. Plants. 2019;8:556. doi: 10.3390/plants8120556. PubMed DOI PMC

Slika H., Mansour H., Wehbe N., Nasser S.A., Iratni R., Nasrallah G., Shaito A., Ghaddar T., Kobeissy F., Eid A.H. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed. Pharmacother. 2022;146:112442. doi: 10.1016/j.biopha.2021.112442. PubMed DOI

Menezes J.C.J.M.D.S., Diederich M.F. Bioactivity of natural biflavonoids in metabolism-related disease and cancer therapies. Pharmacol. Res. 2021;167:105525. doi: 10.1016/j.phrs.2021.105525. PubMed DOI

Park Y., Woo S.H., Seo S.-K., Kim H., Noh W.C., Lee J.K., Kwon B.-M., Min K.N., Choe T.B., Park I.-C. Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor. Oncol. Lett. 2017;14:5027–5033. doi: 10.3892/ol.2017.6742. PubMed DOI PMC

You O.H., Kim S.-H., Kim B., Sohn E.J., Lee H.-J., Shim B.-S., Yun M., Kwon B.-M., Kim S.-H. Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells. Bioorganic Med. Chem. Lett. 2013;23:2692–2695. doi: 10.1016/j.bmcl.2013.02.080. PubMed DOI

Liu Q., Chen L., Yin W., Nie Y., Zeng P., Yang X. Anti-tumor effect of ginkgetin on human hepatocellular carcinoma cell lines by inducing cell cycle arrest and promoting cell apoptosis. Cell Cycle. 2022;21:74–85. doi: 10.1080/15384101.2021.1995684. PubMed DOI PMC

Pan L.-L., Wu W.-J., Zheng G.-F., Han X.-Y., He J.-S., Cai Z. Ginkgetin inhibits proliferation of human leukemia cells via the TNF-α signaling pathway. Z. Nat. C. 2017;72:441–447. doi: 10.1515/znc-2016-0210. PubMed DOI

Chiang C.-H., Yeh C.-Y., Chung J.G., Chiang I.-T., Hsu F.-T. Amentoflavone Induces Apoptosis and Reduces Expression of Anti-apoptotic and Metastasis-associated Proteins in Bladder Cancer. Anticancer Res. 2019;39:3641–3649. doi: 10.21873/anticanres.13512. PubMed DOI

Liu H., Yue Q., He S. Amentoflavone suppresses tumor growth in ovarian cancer by modulating Skp2. Life Sci. 2017;189:96–105. doi: 10.1016/j.lfs.2017.09.026. PubMed DOI

Lee S., Kim H., Kang J.W., Kim J.H., Lee D.H., Kim M.-S., Yang Y., Woo E.-R., Kim Y.M., Hong J., et al. The Biflavonoid Amentoflavone Induces Apoptosis via Suppressing E7 Expression, Cell Cycle Arrest at Sub-G1 Phase, and Mitochondria-Emanated Intrinsic Pathways in Human Cervical Cancer Cells. J. Med. Food. 2011;14:7–8. doi: 10.1089/jmf.2010.1428. PubMed DOI

Adnan M., Rasul A., Hussain G., Shah M.A., Zahoor M.K., Anwar H., Sarfraz I., Riaz A., Manzoor M., Adem S., et al. Ginkgetin: A natural biflavone with versatile pharmacological activities. Food Chem. Toxicol. 2020;145:111642. doi: 10.1016/j.fct.2020.111642. PubMed DOI

Bhadresha K., Upadhyay V., Kumar S.P., Pandya P., Jain N., Rawal R.M. Computational investigation of ginkgetin and theaflavin as potential inhibitors of heat shock protein 90 (Hsp90) J. Biomol. Struct. Dyn. 2021;25:1–7. doi: 10.1080/07391102.2021.1993344. PubMed DOI

Lou J.-S., Zhao L.-P., Huang Z.-H., Chen X.-Y., Xu J.-T., TAI W.C.-S., Tsim K.W.K., Chen Y.-T., Xie T. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine. 2021;80:153370. doi: 10.1016/j.phymed.2020.153370. PubMed DOI

Hu W.-H., Chan G.K.-L., Duan R., Wang H.-Y., Kong X.-P., Dong T.T.-X., Tsim K.W.-K. Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer. Cancers. 2019;11:1828. doi: 10.3390/cancers11121828. PubMed DOI PMC

Xiong X., Tang N., Lai X., Zhang J., Wen W., Li X., Li A., Wu Y., Liu Z. Insights Into Amentoflavone: A Natural Multifunctional Biflavonoid. Front. Pharmacol. 2021;12:768708. doi: 10.3389/fphar.2021.768708. PubMed DOI PMC

Choi S.-K., Oh H.-M., Lee S.-K., Jeong D.G., Ryu S.E., Son K.-H., Han D.C., Sung N.-D., Nam-In Baek N.-I., Kwon B.-M. Biflavonoids inhibited phosphatase of regenerating liver-3 (PRL-3) Nat. Prod. Res. 2006;20:341–346. doi: 10.1080/14786410500463312. PubMed DOI

Lin Y.-M., Flavin M.T., Schure R., Chen F.-C., Sidwell R., Barnard D.I., Huffmann J.H., Kern E.R. Antiviral Activities of Biflavonoids. Planta Med. 1999;65:120–125. doi: 10.1055/s-1999-13971. PubMed DOI

Singh A.V. Potential of amentoflavone with antiviral properties in COVID-19 treatment. Asian Biomed. 2021;15:153–159. doi: 10.2478/abm-2021-0020. PubMed DOI PMC

Hossain R., Islam M.T., Ray P., Jain D., Saikat A.S.M., Nahar L., Calina D. Amentoflavone, New Hope against SARS-CoV-2: An Outlook through its Scientific Records and an in silico Study. Pharm. Res. 2021;13:149–157. doi: 10.5530/pres.13.3.7. DOI

Li F., Song X., Su G., Wang Y., Wang Z., Jia J., Qing S., Huang L., Wang Y., Zheng K., et al. Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection. Viruses. 2019;11:466. doi: 10.3390/v11050466. PubMed DOI PMC

Miki K., Nagai T., Suzuki K., Tsujimura R., Koyama K., Kinoshita K., Furuhata K., Yamada H., Takahashi K. Anti-Influenza Virus Activity of Biflavonoids. Bioorg. Med. Chem. Lett. 2007;17:772–775. doi: 10.1016/j.bmcl.2006.10.075. PubMed DOI

Haruyama T., Nagata K. Anti-Influenza Virus Activity of Ginkgo Biloba Leaf Extracts. J. Nat. Med. 2013;67:636–642. doi: 10.1007/s11418-012-0725-0. PubMed DOI

Xiong Y., Zhu G.-H., Wang H.-N., Hu Q., Chen L.-L., Guan X.-Q., Li H.-L., Chen H.-Z., Tang H., Ge G.-B. Discovery of Naturally Occurring Inhibitors against SARS-CoV-2 3CLpro from Ginkgo Biloba Leaves via Large-Scale Screening. Fitoterapia. 2021;152:104909. doi: 10.1016/j.fitote.2021.104909. PubMed DOI PMC

Ražná K., Sawinska Z., Ivanišová E., Vukovic N., Terentjeva M., Stričík M., Kowalczewski P.Ł., Hlavačková L., Rovná K., Žiarovská J., et al. Properties of Ginkgo biloba L.: Antioxidant Characterization, Antimicrobial Activities, and Genomic MicroRNA Based Marker Fingerprints. Int. J. Mol. Sci. 2020;21:3087. doi: 10.3390/ijms21093087. PubMed DOI PMC

Hwang J.H., Choi H., Woo E.-R., Lee D.G. Antibacterial Effect of Amentoflavone and Its Synergistic Effect with Antibiotics. J. Microbiol. Biotechnol. 2013;23:953–958. doi: 10.4014/jmb.1302.02045. PubMed DOI

Lee J., Kim M., Jeong S.E., Yoon Park H., Jeon C.O., Park W. Amentoflavone, a novel cyanobacterial killing agent from Selaginella tamariscina. J. Hazard. Mater. 2019;384:121312. doi: 10.1016/j.jhazmat.2019.121312. PubMed DOI

Shen X., Niu X., Li G., Deng X., Wang J. Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo. Appl. Environ. Microbiol. 2018;84:e01804-18. doi: 10.1128/AEM.01804-18. PubMed DOI PMC

Li G., Wang G., Wang S., Deng Y. Ginkgetin in vitro and in vivo reduces Streptococcus suis virulence by inhibiting suilysin activity. J. Appl. Microbiol. 2019;127:1556–1563. doi: 10.1111/jam.14365. PubMed DOI

Bagla V.P., McGaw L.J., Elgorashi E.E., Eloff J.N. Antimicrobial activity, toxicity and selectivity index of two biflavonoids and a flavone isolated from Podocarpus henkelii (Podocarpaceae) leaves. BMC Complement. Alter. Med. 2014;14:383. doi: 10.1186/1472-6882-14-383. PubMed DOI PMC

Krauze-Baranowska M., Wiwart M. Antifungal Activity of Biflavones from Taxus baccata and Ginkgo biloba. Z. Nat. C. 2003;58:65–69. doi: 10.1515/znc-2003-1-212. PubMed DOI

Jung H.J., Park K., Lee I.-S., Kim H.S., Yeo S.H., Woo E.R., Lee D.G. S-Phase Accumulation of Candida albicans by Anticandidal Effect of Amentoflavone Isolated from Selaginella tamariscina. Biol. Pharm. Bull. 2007;30:1969–1971. doi: 10.1248/bpb.30.1969. PubMed DOI

Hwang I.S., Lee J., Jin H.G., Woo E.-R., Lee D.G. Amentoflavone Stimulates Mitochondrial Dysfunction and Induces Apoptotic Cell Death in Candida albicans. Mycopathologia. 2012;173:207–218. doi: 10.1007/s11046-011-9503-x. PubMed DOI

Kim H.P., Park H., Son K.H., Chang H.W., Kang S.S. Biochemical pharmacology of biflavonoids: Implications for anti-inflammatory action. Arch. Pharm. Res. 2008;31:265. doi: 10.1007/s12272-001-1151-3. PubMed DOI

Zhou H.-F., Xie C., Jian R., Kang J., Li Y., Zhuang C.-L., Yang F., Zhang L.-L., Lai L., Wu T., et al. Biflavonoids from Caper (Capparis spinosa L.) Fruits and Their Effects in Inhibiting NF-kappa B Activation. J. Agric. Food Chem. 2011;59:3060–3065. doi: 10.1021/jf105017j. PubMed DOI

Kim H.P., Mani I., Iversen L., Ziboh V.A. Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and Iipoxygenase from guinea-pigs. Prostaglandins Lukot. Essent. Fatty Acids. 1998;58:17–24. doi: 10.1016/S0952-3278(98)90125-9. PubMed DOI

Li M., Li B., Hou Y., Tian Y., Chen L., Liu S., Zhang N., Dong J. Anti-inflammatory effects of chemical components from Ginkgo biloba L. male flowers on lipopolysaccharide-stimulated RAW264.7 macrophages. Phytoter. Res. 2019;33:989–997. doi: 10.1002/ptr.6292. PubMed DOI

Liu P.-K., Weng Z.-M., Ge G.-B., Li H.-L., Ding L.-L., Dai Z.-R., Hou X.-D., Leng Y.-H., Yu Y., Hou J. Biflavones from Ginkgo biloba as novel pancreatic lipase inhibitors: Inhibition potentials and mechanism. Int. J. Biol. Macromol. 2018;118:2216–2223. doi: 10.1016/j.ijbiomac.2018.07.085. PubMed DOI

Wang L.-T., Huang H., Chang Y.-H., Wang Y.-Q., Jian-DongWang J.-D., Cai Z.-H., Efferth T., Fu Y.-J. Biflavonoids from Ginkgo biloba leaves as a novel anti-atherosclerotic candidate: Inhibition potency and mechanistic analysis. Phytomedicine. 2022:154053. doi: 10.1016/j.phymed.2022.154053. in press . PubMed DOI

Dell’Agli M., Galli G.V., Bosisio E. Inhibition of cGMP-Phosphodiesterase-5 By Biflavones of Ginkgo biloba. Planta Med. 2006;72:468–470. doi: 10.1055/s-2005-916236. PubMed DOI

Kubota Y., Umegaki K., Tanaka N., Mizuno H., Nakamura K., Kunitomo M., Shinozuka K. Safety of Dietary Supplements: Chronotropic and Inotropic Effects on Isolated Rat Atria. Biol. Pharm. Bull. 2002;25:197–200. doi: 10.1248/bpb.25.197. PubMed DOI

Li W., Li D., Qin Y., Sun C., Wang Y., Gao L., Ling-Hu L., Zhang F., Cai W., Zhu L., et al. Cardioprotective effects of Amentoflavone by suppression of apoptosis and inflammation on an in vitro and vivo model of myocardial ischemia-reperfusion injury. Int. Immunopharmacol. 2021;101:108296. doi: 10.1016/j.intimp.2021.108296. PubMed DOI

Qin L., Zhao Y., Zhang B., Li Y. Amentoflavone improves cardiovascular dysfunction and metabolic abnormalities in high fructose and fat diet-fed rats. Food Funct. 2018;9:243–252. doi: 10.1039/C7FO01095H. PubMed DOI

Zhuang J.-L., Liu Y.-Y., Li Z.-Z., Zhuang Q.-Z., Tang W.-Z., Xiong Y., Huang X.-Z. Amentoflavone prevents ox-LDL-induced lipid accumulation by suppressing the PPARγ/CD36 signal pathway. Toxicol. Appl. Pharmacol. 2021;431:115733. doi: 10.1016/j.taap.2021.115733. PubMed DOI

Uddin S., Kabir T., Tewari D., Mathew B., Aleya L. Emerging Signal Regulating Potential of Small Molecule Biflavonoids to Combat Neuropathological Insults of Alzheimer Disease. Sci. Total Environ. 2020;700:134836. doi: 10.1016/j.scitotenv.2019.134836. PubMed DOI

Kang S.S., Lee J.Y., Choi Y.K., Song S.S., Kim J.S., Jeon S.J., Han Y.N., Son K.H., Han B.H. Neuroprotective effects of naturally occurring biflavonoids. Bioorganic Med. Chem. Lett. 2005;15:3588–3591. doi: 10.1016/j.bmcl.2005.05.078. PubMed DOI

Wang Y.-Q., Wang M.-Y., Fu X.-R., Peng-Yu, Gao G.-F., Fan Y.-M., Duan X.-L., Zhao B.-L., Chang Y.Z., Shi Z.-H. Neuroprotective effects of ginkgetin against neuroinjury in Parkinson’s disease model induced by MPTP via chelating iron. Free Radic Res. 2015;49:1069–1080. doi: 10.3109/10715762.2015.1032958. PubMed DOI

Wang Y., Cheng R., Wu X., Miao M. Neuroprotective and neurotrophic effects of ginkgetin and bilobalide on MPTP-induced mice with Parkinson’ disease. Pharmazie. 2021;76:27–33.

Li Y., Meng L., Li B., Huang D., Huang X., Lin C., Li D., Qiu S., Wu Y., Wei Z., et al. Isoginkgetin attenuates endoplasmic reticulum stress-induced autophagy of brain after ischemic reperfusion injury. Bioengineered. :2021. doi: 10.1080/21655979.2021.1997564. in press . PubMed DOI PMC

Varshney M., Kumar B., Rana V.S., Sethiya N.K. An overview on therapeutic and medicinal potential of poly-hydroxy flavone viz. Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone for management of Alzheimer’s and Parkinson’s diseases: A critical analysis on mechanistic insight. Crit. Rev. Food Sci. Nutr. 2021 doi: 10.1080/10408398.2021.1980761. in press . PubMed DOI

Colovic M., Fracasso C., Caccia S. Brain-to-plasma distribution ratio of the biflavone amentoflavone in the mouse. Drug Metab. Lett. 2008;2:90–94. doi: 10.2174/187231208784040988. PubMed DOI

Ishola I.O., Chatterjee M., Tota S., Tadigopulla N., Adeyemi O.O., Palit G., Shukla R. Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice. Pharmacol. Biochem. Behav. 2012;103:322–331. doi: 10.1016/j.pbb.2012.08.017. PubMed DOI

Wang J., Chen X., Bai W., Wang Z., Xiao W., Zhu J. Study on Mechanism of Ginkgo biloba L. Leaves for the Treatment of Neurodegenerative Diseases Based on Network Pharmacology. Neurochem. Res. 2021;46:1881–1894. doi: 10.1007/s11064-021-03315-z. PubMed DOI

Mei N., Guo X., Ren Z., Kobayashi D., Wada K., Guo L. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. J. Environ. Sci. Health. C Environ. Carcinog. Ecotoxicol. Rev. 2017;35:1–28. doi: 10.1080/10590501.2016.1278298. PubMed DOI PMC

Cardoso CR P., de Syllos Cólus I.M., Bernardi C.C., Sannomiya M., Vilegas W., Varanda E.A. Mutagenic activity promoted by amentoflavone and methanolic extract of Byrsonima crassa Niedenzu. Toxicology. 2006;225:55–63. doi: 10.1016/j.tox.2006.05.003. PubMed DOI

Lv X., Zhang J.B., Wang X.X., Hu W.-Z., Shi Y.-S., Liu S.-W., Hao D.-C., Zhang W.-D., Ge G.-B., Hou J., et al. Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases. Chem. Biol. Interact. 2018;284:48–55. doi: 10.1016/j.cbi.2018.02.009. PubMed DOI

Wang X.X., Hou J., Ning J., Pan Y.-q., Hong M., Guo B. Inhibition of sciadopitysin against UDP-glucuronosyltransferases. Acta Pharm. Sin. 2016;51:749–755. PubMed

Li Y.-Y., Lu X.-Y., Sun J.-L., Wang Q.-Q., Zhang Y.-D., Zhang J.-B., Fan X.-H. Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba. Chin. J. Nat. Med. 2019;17:672–681. doi: 10.1016/S1875-5364(19)30081-0. PubMed DOI