{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:47:18Z","timestamp":1790736438571,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T00:00:00Z","timestamp":1611964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kobayashi Fundation","award":["8-17"],"award-info":[{"award-number":["8-17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Phytoestrogens are herbal polyphenolic compounds that exert various estrogen-like effects in animals and can be taken in easily from a foodstuff in daily life. The fallopian tube lumen, where transportation of the oocyte occurs, is lined with secretory cells and multi-ciliated epithelial cells. Recently, we showed that estrogen induces multi-ciliogenesis in the porcine fallopian tube epithelial cells (FTECs) through the activation of the estrogen receptor beta (ER\u03b2) pathway and simultaneous inhibition of the Notch pathway. Thus, ingested phytoestrogens may induce FTEC ciliogenesis and thereby affect the fecundity. To address this issue, we added isoflavones (genistein, daidzein, or glycitin) and coumestan (coumestrol) to primary culture FTECs under air\u2013liquid interface conditions and assessed the effects of each compound. All phytoestrogens except glycitin induced multi-ciliated cell differentiation, which followed Notch signal downregulation. On the contrary, the differentiation of secretory cells decreased slightly. Furthermore, genistein and daidzein had a slight effect on the proportion of proliferating cells exhibited by Ki67 expression. Ciliated-cell differentiation is inhibited by the ER\u03b2 antagonist, PHTPP. Thus, this study suggests that phytoestrogens can improve the fallopian tube epithelial sheet homeostasis by facilitating the genesis of multi-ciliated cells and this effect depends on the ER\u03b2-mediated pathway.<\/jats:p>","DOI":"10.3390\/molecules26030722","type":"journal-article","created":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T08:56:01Z","timestamp":1611996961000},"page":"722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Natural Herbal Estrogen-Mimetics (Phytoestrogens) Promote the Differentiation of Fallopian Tube Epithelium into Multi-Ciliated Cells via Estrogen Receptor Beta"],"prefix":"10.3390","volume":"26","author":[{"given":"Maobi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7090-2139","authenticated-orcid":false,"given":"Sen","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Iwano","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/humupd\/dml012","article-title":"The reproductive significance of human Fallopian tube cilia","volume":"12","author":"Lyons","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0188105","article-title":"Profiling of proteins secreted in the bovine oviduct reveals diverse functions of this luminal microenvironment","volume":"12","author":"Pillai","year":"2017","journal-title":"PLoS ONE"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1126\/science.1251215","article-title":"Egg transport in the rabbit oviduct: The roles of cilia and muscle","volume":"191","author":"Halbert","year":"1976","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1093\/oxfordjournals.humrep.a138628","article-title":"Endocrinology: Comparative immunohistochemical study of oestrogen and progesterone receptors in the fallopian tube and uterus at different stages of the menstrual cycle and the menopause","volume":"9","author":"Amso","year":"1994","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/aja.1001870109","article-title":"Oviductal epithelium of the baboon: Hormonal control and the immuno-gold localization of oviduct-specific glycoproteins","volume":"187","author":"Verhage","year":"1990","journal-title":"Am. J. Anat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0378-5122(83)90020-8","article-title":"Changes in ciliation and cell height in human tubal epithelium in the fertile and post-fertile years","volume":"5","author":"Donnez","year":"1983","journal-title":"Maturitas"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1210\/er.2018-00087","article-title":"Estrogen receptors: New directions in the new millennium","volume":"39","author":"Hewitt","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15677","DOI":"10.1073\/pnas.95.26.15677","article-title":"Generation and reproductive phenotypes of mice lacking estrogen receptor \u03b2","volume":"95","author":"Krege","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhu, M., Iwano, T., and Takeda, S. (2019). Estrogen and EGFR Pathways Regulate Notch Signaling in Opposing Directions for Multi-Ciliogenesis in the Fallopian Tube. Cells, 8.","DOI":"10.3390\/cells8080933"},{"key":"ref_10","first-page":"1","article-title":"Effects of dietary phytoestrogens on hormones throughout a human lifespan: A review","volume":"12","year":"2020","journal-title":"Nutrients"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ejphar.2014.07.057","article-title":"Phytoestrogens and their effects","volume":"741","author":"Alexander","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2017.00699","article-title":"The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A targeted metabolomics approach","volume":"8","author":"Poschner","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1248\/jhs.47.394","article-title":"Content and composition of isoflavonoids in mature or immature beans and bean sprouts consumed in Japan","volume":"47","author":"Nakamura","year":"2001","journal-title":"J. Heal. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.1021\/jf034427b","article-title":"Phytoestrogens Modulate Binding Response of Estrogen Receptors \u03b1 and \u03b2 to the Estrogen Response Element","volume":"51","author":"Kostelac","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1096\/fj.13-234617","article-title":"Mechanisms enforcing the estrogen receptor \u03b2 selectivity of botanical estrogens","volume":"27","author":"Jiang","year":"2013","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1248\/bpb.24.351","article-title":"Interaction of phytoestrogens with estrogen receptors \u03b1 and\u03b2","volume":"24","author":"Morito","year":"2001","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12935-018-0559-2","article-title":"Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K\/AKT signaling in ovarian cancer","volume":"18","author":"Chan","year":"2018","journal-title":"Cancer Cell Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.foodchem.2015.09.085","article-title":"Understanding genistein in cancer: The \u201cgood\u201d and the \u201cbad\u201d effects: A review","volume":"196","author":"Russo","year":"2016","journal-title":"Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.3389\/fphar.2019.01336","article-title":"Molecular mechanisms of action of genistein in cancer: Recent advances","volume":"10","author":"Tuli","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/biom10091270","article-title":"Fallopian tube basal stem cells reproducing the epithelial sheets in vitro\u2014stem cell of fallopian epithelium","volume":"10","author":"Zhu","year":"2020","journal-title":"Biomolecules"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8989","DOI":"10.1038\/ncomms9989","article-title":"The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids","volume":"6","author":"Kessler","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1093\/jn\/131.10.3168","article-title":"Phytoestrogen concentrations in serum from Japanese men and women over forty years of age","volume":"132","author":"Morton","year":"2002","journal-title":"J. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/sj.jea.7500278","article-title":"Urinary and serum concentrations of seven phytoestrogens in a human reference population subset","volume":"13","author":"Blount","year":"2003","journal-title":"J. Expo. Anal. Environ. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/ptr.5313","article-title":"Soy isoflavone glycitin (4\u2032-hydroxy-6-methoxyisoflavone-7-D-Glucoside) promotes human dermal fibroblast cell proliferation and migration via TGF-\u03b2 signaling","volume":"29","author":"Kim","year":"2015","journal-title":"Phyther. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.reprotox.2017.04.010","article-title":"Genistein crosses the bioartificial oviduct and alters secretion composition","volume":"71","author":"Simintiras","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1095\/biolreprod.108.073171","article-title":"Neonatal exposure to genistein disrupts ability of female mouse reproductive tract to support preimplantation embryo development and implantation","volume":"80","author":"Jefferson","year":"2009","journal-title":"Biol. Reprod."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/3\/722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:17:38Z","timestamp":1760159858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/3\/722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,30]]},"references-count":26,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26030722"],"URL":"https:\/\/doi.org\/10.3390\/molecules26030722","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,30]]}}}