{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:16Z","timestamp":1787028556656,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recurrent pregnancy loss (RPL) of unknown genesis is a complex condition with multifactorial origins, including genetic, hormonal, and immunological factors. However, the specific mechanisms underlying endocervical cell proliferation disorders in women with RPL remain inadequately understood, particularly concerning the role of microbiota and viral infections. The aim of this study was to investigate the mechanisms of endocervical cell proliferation disorders in women with RPL of unknown genesis by examining microbiota, human papillomavirus (HPV) typing, and the expression levels of key molecular biological markers, including p16\/Ki-67, BCL-2, miR-145, and miR-34a. A prospective observational comparative study was executed on women with RPL and healthy pregnant controls with full ethical approval. Samples were collected for HPV typing and immunocytochemical analysis to evaluate the expression of p16, Ki-67, BCL-2, and the anti-oncogenic microRNAs (miR-145 and miR-34a). The expression of mRNA for the progesterone receptor (PGR-A) was also assessed, alongside local immune status markers, including proinflammatory T-lymphocytes (Th17\/Th1) and regulatory CD4+ Tregs. Overexpression of p16, Ki-67, and BCL-2 was observed in 52.5% of women with RPL who had an ASC-US\/LSIL cytogram, with the average double expression of p16\/Ki-67 being three times higher than in the healthy pregnant group. A significant decrease in PGR-A mRNA expression in the endocervix of women with RPL was noted, accompanied by a dysregulated local immune status characterized by an increased prevalence of Th17\/Th1 cells and a reduction in regulatory CD4+ Tregs. Additionally, the expression of miR-145 and miR-34a in the endocervix and endometrium of women with RPL significantly differed from the physiological pregnancy group, particularly in the context of high-risk HPV infection. The findings describe that disorders of endocervical cell proliferation in women with RPL of unknown genesis are associated with overexpression of specific molecular markers, impaired immune regulation, and altered microRNA profiles. These alterations may contribute to the pathophysiology of RPL, highlighting the need for further research into targeted interventions that could improve reproductive outcomes in affected individuals.<\/jats:p>","DOI":"10.3390\/ijms26031326","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T10:57:53Z","timestamp":1738666673000},"page":"1326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploring the Role of Lower Genital Tract Microbiota and Cervical\u2013Endometrial Immune Metabolome in Unknown Genesis of Recurrent Pregnancy Loss"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4822-0956","authenticated-orcid":false,"given":"Sergey A.","family":"Mikhalev","sequence":"first","affiliation":[{"name":"Federal State Autonomous Educational Institution of Higher Education \u201cN.I. Pirogov Russian National Research Medical University\u201d of the Ministry of Health of the Russian Federation, 117997 Moscow, Russia"},{"name":"City Clinical Hospital No. 31 Named After Academician G.M. Savelyeva of the Department of Health, 119415 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-1968","authenticated-orcid":false,"given":"Mark A.","family":"Kurtser","sequence":"additional","affiliation":[{"name":"Federal State Autonomous Educational Institution of Higher Education \u201cN.I. Pirogov Russian National Research Medical University\u201d of the Ministry of Health of the Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor E.","family":"Radzinsky","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Federal State Autonomous Educational Institution of Higher Education \u00abPeoples\u2019 Friendship University of Russia\u00bb, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mekan R.","family":"Orazov","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Federal State Autonomous Educational Institution of Higher Education \u00abPeoples\u2019 Friendship University of Russia\u00bb, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6879-7835","authenticated-orcid":false,"given":"Narasimha M.","family":"Beeraka","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russia"},{"name":"Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu 515721, Andhra Pradesh, India"},{"name":"Department of Studies in Molecular Biology, University of Mysore, Mysore 570006, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2052-914X","authenticated-orcid":false,"given":"Lyudmila M.","family":"Mikhaleva","sequence":"additional","affiliation":[{"name":"Scientific Research Institute of Human Morphology Named After Academician A.P. Avtsyn of the Federal State Budgetary Scientific Institution \u201cRussian Scientific Center of Surgery Named After Academician B.V. Petrovsky\u201d, 125315 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1515\/mr-2022-0030","article-title":"Understanding recurrent pregnancy loss: Recent advances on its etiology, clinical diagnosis, and management","volume":"2","author":"Cao","year":"2022","journal-title":"Med. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103785","DOI":"10.1016\/j.jri.2022.103785","article-title":"Unexplained recurrent pregnancy loss: Novel causes and advanced treatment","volume":"155","author":"Yu","year":"2023","journal-title":"J. Reprod. 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