{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T03:44:24Z","timestamp":1772250264938,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,13]],"date-time":"2022-11-13T00:00:00Z","timestamp":1668297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81903616"],"award-info":[{"award-number":["81903616"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81903618"],"award-info":[{"award-number":["81903618"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2022A1515010034"],"award-info":[{"award-number":["2022A1515010034"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2021A1515010648"],"award-info":[{"award-number":["2021A1515010648"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Administration of Traditional Chinese Medicine of Guangdong Province, China","award":["20221100"],"award-info":[{"award-number":["20221100"]}]},{"name":"Department of Education of Guangdong Province \u201cInnovative projects with characteristics of ordinary universities\u201d project","award":["2021KTSCX007"],"award-info":[{"award-number":["2021KTSCX007"]}]},{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization","award":["2021B1212040007"],"award-info":[{"award-number":["2021B1212040007"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>Postmenopausal osteoporosis is a significant threat to human health globally. Genistein, a soy-derived isoflavone, is regarded as a promising anti-osteoporosis drug with the effects of promoting osteoblastogenesis and suppressing osteoclastogenesis. However, its oral bioavailability (6.8%) is limited by water solubility, intestinal permeability, and biotransformation. Fortunately, 8-prenelylated genistein (8PG), a derivative of genistein found in Erythrina Variegate, presented excellent predicted oral bioavailability (51.64%) with an improved osteoblastogenesis effect, although its effects on osteoclastogenesis and intestinal biotransformation were still unclear. In this study, an in vitro microbial transformation platform and UPLC-QTOF\/MS analysis method were developed to explore the functional metabolites of 8PG. RANKL-induced RAW264.7 cells were utilized to evaluate the effects of 8PG on osteoclastogenesis. Our results showed that genistein was transformed into dihydrogenistein and 5-hydroxy equol, while 8PG metabolites were undetectable under the same conditions. The 8PG (10\u22126 M) was more potent in inhibiting osteoclastogenesis than genistein (10\u22125 M) and it down-regulated NFATC1, cSRC, MMP-9 and Cathepsin K. It was concluded that 8-prenyl plays an important role in influencing the osteoclast activity and intestinal biotransformation of 8PG, which provides evidence supporting the further development of 8PG as a good anti-osteoporosis agent.<\/jats:p>","DOI":"10.3390\/molecules27227811","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T04:24:10Z","timestamp":1668399850000},"page":"7811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genistein Modified with 8-Prenyl Group Suppresses Osteoclast Activity Directly via Its Prototype but Not Metabolite by Gut Microbiota"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9161-5435","authenticated-orcid":false,"given":"Zuo-Cheng","family":"Qiu","sequence":"first","affiliation":[{"name":"Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"},{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng-Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-Ling","family":"Hu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Jinan University, Guangzhou 510632, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang-Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0635-1931","authenticated-orcid":false,"given":"Zi-Ling","family":"Tang","sequence":"additional","affiliation":[{"name":"Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Jinan University, Guangzhou 510632, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man-Sau","family":"Wong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of the Hong Kong Polytechnic University, Shenzhen 518057, China"},{"name":"Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong 999077, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5570-6233","authenticated-orcid":false,"given":"Jia-Xu","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7501-7112","authenticated-orcid":false,"given":"Hui-Hui","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of the Hong Kong Polytechnic University, Shenzhen 518057, China"},{"name":"Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong 999077, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMcp1513724","article-title":"Clinical Practice. Postmenopausal Osteoporosis","volume":"374","author":"Black","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s40618-017-0761-4","article-title":"The epidemiology of osteoporosis in Italian postmenopausal women according to the National Bone Health Alliance (NBHA) diagnostic criteria: A multicenter cohort study","volume":"41","author":"Cipriani","year":"2018","journal-title":"J. Endocrinol. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s11657-018-0549-y","article-title":"The epidemiology of osteoporosis, associated fragility fractures, and management gap in China","volume":"14","author":"Yu","year":"2019","journal-title":"Arch. Osteoporos."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7081","DOI":"10.1039\/D1FO01124C","article-title":"A novel strategy for exploring food originated anti-adipogenesis substances and mechanism by structural similarity evaluation, ADME prediction, network pharmacology and experimental validation","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/aps.2015.85","article-title":"Aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing NF-\u03baB and NFATc1 activation and DC-STAMP expression","volume":"37","author":"Zeng","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nri2062","article-title":"Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems","volume":"7","author":"Takayanagi","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/S0140-6736(02)08827-X","article-title":"Treatment of postmenopausal osteoporosis","volume":"359","author":"Delmas","year":"2002","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s12272-010-0418-8","article-title":"Formononetin prevents ovariectomy-induced bone loss in rats","volume":"33","author":"Ha","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1080\/13697137.2018.1555582","article-title":"Assessment and hormonal management of osteoporosis","volume":"22","year":"2019","journal-title":"Climacteric"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nrclinonc.2011.110","article-title":"Hormone replacement therapy and the risk of breast cancer","volume":"8","author":"Narod","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/jcp.24158","article-title":"Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling","volume":"228","author":"Ming","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1301\/nr.2003.oct.346-351","article-title":"Genistein appears to prevent early postmenopausal bone loss as effectively as hormone replacement therapy","volume":"61","author":"Cotter","year":"2003","journal-title":"Nutr. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.2174\/187152012803833107","article-title":"Bioavailability and pharmacokinetics of genistein: Mechanistic studies on its ADME","volume":"12","author":"Yang","year":"2012","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF03192335","article-title":"Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity","volume":"27","author":"Coldham","year":"2002","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24221","DOI":"10.18632\/oncotarget.24823","article-title":"8-Prenylgenistein, a prenylated genistein derivative, exerted tissue selective osteoprotective effects in ovariectomized mice","volume":"9","author":"Zhang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/d41586-020-00196-0","article-title":"The complex relationship between drugs and the microbiome","volume":"577","author":"Savage","year":"2020","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/rcm.2897","article-title":"A fragmentation study of isoflavones in negative electrospray ionization by MSn ion trap mass spectrometry and triple quadrupole mass spectrometry","volume":"21","author":"Kang","year":"2007","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1248\/cpb.54.570","article-title":"Four new isoflavonoids from the stem bark of Erythrina variegata","volume":"54","author":"Li","year":"2006","journal-title":"Chem. Pharm. Bull."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1007\/s12272-001-2147-5","article-title":"Osteogenic activities of genistein derivatives were influenced by the presence of prenyl group at ring A","volume":"31","author":"Zhang","year":"2008","journal-title":"Arch. Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/S0031-9422(01)00368-5","article-title":"Cytotoxic Isoflavones from Erythrina Indica","volume":"58","author":"Nkengfack","year":"2001","journal-title":"Phytochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1055\/s-2000-8602","article-title":"Two new isoflavonoids from Erythrina variegata","volume":"66","author":"Tanaka","year":"2000","journal-title":"Planta Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4325","DOI":"10.1039\/D1FO00104C","article-title":"Dissection of the potential pharmacological function of neohesperidin dihydrochalcone\u2014A food additive\u2014By in vivo substances profiling and network pharmacology","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e9205","DOI":"10.1002\/rcm.9205","article-title":"Dissection of the potential anti-diabetes mechanism of salvianolic acid B by metabolite profiling and network pharmacology","volume":"36","author":"Zhang","year":"2022","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1080\/09168451.2018.1444467","article-title":"Flavonoid Metabolism: The Interaction of Metabolites and Gut Microbiota","volume":"82","author":"Murota","year":"2018","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3945\/jn.111.148247","article-title":"Daidzein and Genistein Are Converted to Equol and 5-Hydroxy-Equol by Human Intestinal Slackia Isoflavoniconvertens in Gnotobiotic Rats","volume":"142","author":"Matthies","year":"2012","journal-title":"J. Nutr."},{"key":"ref_26","first-page":"S401","article-title":"Phytoestrogens and the Intestinal Microbiome","volume":"67","year":"2018","journal-title":"Physiol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/00498250110085809","article-title":"Comparative metabolism of genistin by human and rat gut microflora: Detection and identification of the end-products of metabolism","volume":"32","author":"Coldham","year":"2002","journal-title":"Xenobiotica"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.abb.2014.04.002","article-title":"Prenylation Modulates the Bioavailability and Bioaccumulation of Dietary Flavonoids","volume":"559","author":"Terao","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_29","first-page":"741","article-title":"Degradation of flavonoid aglycones by rabbit, rat and human fecal flora","volume":"26","author":"Lina","year":"2003","journal-title":"Biol. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/09168451.2017.1415750","article-title":"Prenylation Enhances the Biological Activity of Dietary Flavonoids by Altering Their Bioavailability","volume":"82","author":"Mukai","year":"2018","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1172\/JCI35711","article-title":"NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism","volume":"118","author":"Aliprantis","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1083\/jcb.151.2.311","article-title":"Decreased c-Src expression enhances osteoblast differentiation and bone formation","volume":"151","author":"Marzia","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1083\/jcb.151.4.879","article-title":"Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones","volume":"151","author":"Engsig","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_34","first-page":"666","article-title":"Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation","volume":"123","author":"Lotinun","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1016\/S0040-4020(03)00579-9","article-title":"Synthesis of lupiwighteone via a para-Claisen\u2013Cope rearrangement","volume":"59","author":"Botting","year":"2003","journal-title":"Tetrahedron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants","volume":"45","author":"Bravo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."}],"updated-by":[{"DOI":"10.3390\/molecules29245818","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,11,13]],"date-time":"2022-11-13T00:00:00Z","timestamp":1668297600000}}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/7811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:09:43Z","timestamp":1754258983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/7811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,13]]},"references-count":40,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27227811"],"URL":"https:\/\/doi.org\/10.3390\/molecules27227811","relation":{"correction":[{"id-type":"doi","id":"10.3390\/molecules29245818","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,13]]}}}