{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:21:39Z","timestamp":1760232099283,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T00:00:00Z","timestamp":1651536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sanming Project of Medicine","award":["SZSM201612083","SZXK2020089","17120720"],"award-info":[{"award-number":["SZSM201612083","SZXK2020089","17120720"]}]},{"name":"Shenzhen Key Medical Discipline","award":["SZSM201612083","SZXK2020089","17120720"],"award-info":[{"award-number":["SZSM201612083","SZXK2020089","17120720"]}]},{"name":"General Research Fund, Research Grants Council, Hong Kong","award":["SZSM201612083","SZXK2020089","17120720"],"award-info":[{"award-number":["SZSM201612083","SZXK2020089","17120720"]}]},{"name":"Department of Obstetrics and Gynaecology, The University of Hong Kong","award":["SZSM201612083","SZXK2020089","17120720"],"award-info":[{"award-number":["SZSM201612083","SZXK2020089","17120720"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current contraceptive methods interfere with folliculogenesis, fertilization, and embryo implantation by physical or hormonal approaches. Although hormonal contraceptive pills are effective in regulating egg formation, they are less effective in preventing embryo implantation. To explore the use of non-hormonal compounds that suppress embryo implantation, we established a high-throughput spheroid-endometrial epithelial cell co-culture assay to screen the Library of Pharmacologically Active Compounds (LOPAC) for compounds that affect trophoblastic spheroid (blastocyst surrogate) attachment onto endometrial epithelial Ishikawa cells. We identified 174 out of 1280 LOPAC that significantly suppressed BeWo spheroid attachment onto endometrial Ishikawa cells. Among the top 20 compounds, we found the one with the lowest cytotoxicity in Ishikawa cells, P11B5, which was later identified as Nemadipine-A. Nemadipine-A at 10 \u00b5M also suppressed BeWo spheroid attachment onto endometrial epithelial RL95-2 cells and primary human endometrial epithelial cells (hEECs) isolated from LH +7\/8-day endometrial biopsies. Mice at 1.5 days post coitum (dpc) treated with a transcervical injection of 100 \u00b5g\/kg Nemadipine-A or 500 \u00b5g\/kg PRI-724 (control, Wnt-inhibitor), but not 10 \u00b5g\/kg Nemadipine-A, suppressed embryo implantation compared with controls. The transcript expressions of endometrial receptivity markers, integrin \u03b1V (ITGAV) and mucin 1 (MUC1), but not \u03b2-catenin (CTNNB1), were significantly decreased at 2.5 dpc in the uterus of treated mice compared with controls. The reduction of embryo implantation by Nemadipine-A was likely mediated through suppressing endometrial receptivity molecules ITGAV and MUC1. Nemadipine-A is a potential novel non-hormonal compound for contraception.<\/jats:p>","DOI":"10.3390\/ijms23095073","type":"journal-article","created":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T08:26:35Z","timestamp":1651566395000},"page":"5073","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Throughput In Vitro Screening Identified Nemadipine as a Novel Suppressor of Embryo Implantation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0731-8930","authenticated-orcid":false,"given":"Xian","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudini Ranshaya","family":"Fernando","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Department of Animal Science, Faculty of Animal Science and Export Agriculture, Uva Wellassa University, Badulla 90000, Sri Lanka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0559-4381","authenticated-orcid":false,"given":"Yin-Lau","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William Shu-Biu","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7688-4557","authenticated-orcid":false,"given":"Ernest Hung-Yu","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond Hang-Wun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-439X","authenticated-orcid":false,"given":"Kai-Fai","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1053\/beog.2000.0121","article-title":"Paracrine regulators of implantation","volume":"14","author":"Pellicer","year":"2000","journal-title":"Best Pract. Research. Clin. Obstet. Gynaecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0950-3552(05)80092-6","article-title":"The implantation window","volume":"6","author":"Harper","year":"1992","journal-title":"Baillieres Clin. Obstet. Gynaecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1093\/molehr\/4.12.1089","article-title":"MUC1 and endometrial receptivity","volume":"4","author":"Meseguer","year":"1998","journal-title":"Mol. Hum. Reprod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1469-7580.2008.01034.x","article-title":"Adhesion molecules in endometrial epithelium: Tissue integrity and embryo implantation","volume":"215","author":"Singh","year":"2009","journal-title":"J. Anat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/humrep\/deab032","article-title":"Podocalyxin is a key negative regulator of human endometrial epithelial receptivity for embryo implantation","volume":"36","author":"Paule","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1093\/humupd\/dml004","article-title":"Endometrial receptivity markers, the journey to successful embryo implantation","volume":"12","author":"Achache","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S0015-0282(99)00604-4","article-title":"Use of integrins to date the endometrium","volume":"73","author":"Lessey","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1210\/jc.2003-030494","article-title":"Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium","volume":"88","author":"Tulac","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3109\/09513599609027987","article-title":"Alteration of E-cadherin, alpha- and beta-catenin mRNA expression in human uterine endometrium during the menstrual cycle","volume":"10","author":"Fujimoto","year":"1996","journal-title":"Gynecol. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12978-015-0034-7","article-title":"Changes in receptivity epithelial cell markers of endometrium after ovarian stimulation treatments: Its role during implantation window","volume":"12","author":"Cruz","year":"2015","journal-title":"Reprod. Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"854056","DOI":"10.1155\/2015\/854056","article-title":"Participation of WNT and \u03b2-Catenin in Physiological and Pathological Endometrial Changes: Association with Angiogenesis","volume":"2015","author":"Kiewisz","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/humrep\/13.suppl_3.247","article-title":"Endometrial integrins and the establishment of uterine receptivity","volume":"13","author":"Lessey","year":"1998","journal-title":"Hum Reprod"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1172\/JCI115835","article-title":"Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle","volume":"90","author":"Lessey","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1023\/A:1015450727580","article-title":"Integrins and implantation in the human","volume":"3","author":"Lessey","year":"2002","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12905-017-0438-3","article-title":"AlphaVBeta3 Integrin expression within uterine endometrium in unexplained infertility: A prospective cohort study","volume":"17","author":"Elnaggar","year":"2017","journal-title":"BMC Womens Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10815-019-01623-6","article-title":"Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window","volume":"37","author":"Xiong","year":"2020","journal-title":"J. Assist. Reprod. Genet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1055\/s-2007-991038","article-title":"Experimental models for investigating implantation of the human embryo","volume":"25","author":"Mardon","year":"2007","journal-title":"Semin. Reprod. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.rbmo.2013.08.002","article-title":"In-vitro model systems for the study of human embryo\u2013endometrium interactions","volume":"27","author":"Weimar","year":"2013","journal-title":"Reprod. Biomed. Online"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111606","DOI":"10.1016\/j.ecoenv.2020.111606","article-title":"The fungicide Mancozeb reduces spheroid attachment onto endometrial epithelial cells through downregulation of estrogen receptor \u03b2 and integrin \u03b23 in Ishikawa cells","volume":"208","author":"Wang","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.2105\/AJPH.2013.301416","article-title":"Shifts in Intended and Unintended Pregnancies in the United States, 2001\u20132008","volume":"104","author":"Finer","year":"2014","journal-title":"Am. J. Public Health"},{"key":"ref_21","first-page":"12","article-title":"Deaths due to unintended pregnancies on the rise.(Global Health Council report)","volume":"32","author":"Krisberg","year":"2002","journal-title":"Nation\u2019s Health (1971)"},{"key":"ref_22","first-page":"722","article-title":"Emergency contraception: Oral and intrauterine options","volume":"46","author":"Black","year":"2017","journal-title":"Aust. Fam. Physician"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0140-6736(10)60101-8","article-title":"Ulipristal acetate versus levonorgestrel for emergency contraception: A randomised non-inferiority trial and meta-analysis","volume":"375","author":"Glasier","year":"2010","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10815-014-0409-7","article-title":"The role of Wnt signaling members in the uterus and embryo during pre-implantation and implantation","volume":"32","author":"Tepekoy","year":"2015","journal-title":"J. Assist. Reprod. Genet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/molehr\/gap009","article-title":"Embryo-uterine cross-talk during implantation: The role of Wnt signaling","volume":"15","author":"Chen","year":"2009","journal-title":"Mol. Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41598-017-00282-w","article-title":"Selective inhibitor of Wnt\/\u03b2-catenin\/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model","volume":"7","author":"Tokunaga","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1016\/j.celrep.2019.04.071","article-title":"Small Heterodimer Partner Controls the Virus-Mediated Antiviral Immune Response by Targeting CREB-Binding Protein in the Nucleus","volume":"27","author":"Kim","year":"2019","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1093\/humrep\/dex328","article-title":"Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model","volume":"32","author":"Li","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.3389\/fmicb.2015.01453","article-title":"Screening of Pharmacologically Active Small Molecule Compounds Identifies Antifungal Agents Against Candida Biofilms","volume":"6","author":"Watamoto","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nm.4184","article-title":"Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen","volume":"22","author":"Xu","year":"2016","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"dmm031906","DOI":"10.1242\/dmm.031906","article-title":"High-throughput screen for compounds that modulate neurite growth of human induced pluripotent stem cell-derived neurons","volume":"11","author":"Sherman","year":"2018","journal-title":"Dis Model Mech"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1128\/AAC.05722-11","article-title":"PD 404,182 is a virocidal small molecule that disrupts hepatitis C virus and human immunodeficiency virus","volume":"56","author":"Chamoun","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1038\/mt.2016.153","article-title":"The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing","volume":"24","author":"Nawrot","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.taap.2017.06.011","article-title":"Behavioral screening of the LOPAC(1280) library in zebrafish embryos","volume":"329","author":"Vliet","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.bcp.2013.09.001","article-title":"Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness","volume":"86","author":"Hirano","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1095\/biolreprod.109.077800","article-title":"Models for study of human embryo implantation: Choice of cell lines?","volume":"82","author":"Hannan","year":"2010","journal-title":"Biol. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/S0015-0282(16)55014-6","article-title":"Characterization of human purified epithelial and stromal cells from endometrium and endometriosis in tissue culture","volume":"57","author":"Matthews","year":"1992","journal-title":"Fertil. Steril."},{"key":"ref_38","first-page":"231","article-title":"The Window of Implantation Is Closed by Estrogen via Insulin-Like Growth Factor 1 Pathway","volume":"18","author":"Kobayashi","year":"2017","journal-title":"J. Reprod. Infertil."},{"key":"ref_39","first-page":"514","article-title":"Advance in L-Type Calcium Channel Structures, Functions and Molecular Modeling","volume":"27","author":"Xu","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1085\/jgp.201812236","article-title":"Calcium-dependent inactivation controls cardiac L-type Ca2+ currents under \u03b2-adrenergic stimulation","volume":"151","author":"Morales","year":"2019","journal-title":"J. Gen. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1002\/mrd.23166","article-title":"Changes in calcium levels in the endometrium throughout pregnancy and the role of calcium on endometrial gene expression at the time of conceptus implantation in pigs","volume":"86","author":"Choi","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/humrep\/deu285","article-title":"Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: A prospective multicenter study","volume":"30","author":"Ebner","year":"2014","journal-title":"Hum. Reprod."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/nm.2771","article-title":"Activation of the epithelial Na+ channel triggers prostaglandin E(2) release and production required for embryo implantation","volume":"18","author":"Ruan","year":"2012","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/humupd\/dmu006","article-title":"Ion channels in the endometrium: Regulation of endometrial receptivity and embryo implantation","volume":"20","author":"Ruan","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fphys.2019.00125","article-title":"Identification of Gene Expression Changes Associated With Uterine Receptivity in Mice","volume":"10","author":"He","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1095\/biolreprod62.5.1285","article-title":"Blockade of the alpha(v)beta(3) integrin adversely affects implantation in the mouse","volume":"62","author":"Illera","year":"2000","journal-title":"Biol. Reprod."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5653","DOI":"10.1016\/j.febslet.2006.09.014","article-title":"Profiling of E-cadherin, \u03b2-catenin and Ca2+ in embryo\u2013uterine interactions at implantation","volume":"580","author":"Jha","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1242\/jcs.105.2.397","article-title":"Modulation of Muc-1 mucin expression in the mouse uterus during the estrus cycle, early pregnancy and placentation","volume":"105","author":"Braga","year":"1993","journal-title":"J. Cell Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1023\/A:1011379725811","article-title":"MUC1, the renaissance molecule","volume":"6","author":"Gendler","year":"2001","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1477-7827-2-4","article-title":"MUC1: A multifunctional cell surface component of reproductive tissue epithelia","volume":"2","author":"Brayman","year":"2004","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1093\/oxfordjournals.humrep.a135762","article-title":"MUC1 in secretory phase endometrium: Expression in precisely dated biopsies and flushings from normal and recurrent miscarriage patients","volume":"10","author":"Hey","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1093\/humrep\/dev223","article-title":"Establishment of a novel human embryonic stem cell-derived trophoblastic spheroid implantation model","volume":"30","author":"Lee","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.fertnstert.2020.01.009","article-title":"Human embryonic stem cell-derived blastocyst-like spheroids resemble human trophectoderm during early implantation process","volume":"114","author":"Yue","year":"2020","journal-title":"Fertil. Steril."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.fertnstert.2012.01.116","article-title":"A high-throughput in vitro model of human embryo attachment","volume":"97","author":"Ho","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_55","first-page":"228","article-title":"Transcervical embryo transfer in mice","volume":"53","author":"Cui","year":"2014","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5073\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:05:43Z","timestamp":1760137543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5073"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,3]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095073"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095073","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,5,3]]}}}