{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:29:56Z","timestamp":1785461396362,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dicle University Scientific Research Projects Coordination Office","award":["TIP.22.007"],"award-info":[{"award-number":["TIP.22.007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: SARS-CoV-2 infection during pregnancy has been associated with systemic inflammatory responses and placental pathology; however, the molecular mechanisms underlying placental involvement remain incompletely understood. The endocannabinoid system plays a critical role in placental development, immune regulation, and vascular homeostasis. Materials and Methods: Placental tissues were obtained from 20 healthy pregnant women and 20 women with confirmed SARS-CoV-2 infection who had recovered by the time of delivery. Demographic and laboratory parameters were recorded. Histopathological evaluation was performed using hematoxylin and eosin staining. Immunohistochemical analysis of cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) expression was conducted, supported by quantitative digital image analysis using QuPath. Network-based protein\u2013protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore potential molecular mechanisms. Results: COVID-19-positive placentas exhibited prominent histopathological alterations, including increased fibrinoid deposition, syncytial knot formation, vascular congestion, and intervillous inflammatory cell infiltration. Systemic inflammatory and coagulation markers, particularly neutrophil percentage, C-reactive protein, D-dimer, and fibrinogen levels, were significantly elevated in the COVID-19 group. CNR1 and CNR2 expressions were markedly increased across multiple placental compartments, including decidual cells, trophoblastic layers, syncytial knots, and Hofbauer cells. Quantitative digital analysis confirmed significant upregulation of both receptors. Bioinformatic analysis revealed enrichment of endocannabinoid signaling, cAMP-related pathways, and inflammatory mediator regulation of TRP channels. Conclusions: The findings indicate that SARS-CoV-2 infection is associated with coordinated inflammatory, structural, and molecular alterations in the placenta. Upregulation of CB1 and CB2 suggests an active involvement of the endocannabinoid system in placental immune and vascular responses to COVID-19, highlighting its potential relevance for understanding placental pathology associated with maternal viral infections<\/jats:p>","DOI":"10.3390\/diagnostics16050690","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"690","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Altered Endocannabinoid Signaling in Placentas from SARS-CoV-2-Infected Pregnancies"],"prefix":"10.3390","volume":"16","author":[{"given":"\u00d6zge","family":"Kaplan","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet U\u011fur","family":"Karabat","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00fcreyya","family":"\u00d6zdemir Ba\u015faran","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"Yavuz","sequence":"additional","affiliation":[{"name":"Department of Andrology, Gazi Yasargil Education and Research Hospital, Health Science University, 21090 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6384-9146","authenticated-orcid":false,"given":"F\u0131rat","family":"A\u015f\u0131r","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-4022","authenticated-orcid":false,"given":"Tu\u011fcan","family":"Korak","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical Faculty, Kocaeli University, 41380 Kocaeli, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"A\u011fa\u00e7ayak","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engin","family":"Deveci","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Diyarbak\u0131r, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","first-page":"14","article-title":"Diagnosis, Treatment, and Prevention of COVID-19 Infection in Children","volume":"4","author":"Ozdemir","year":"2020","journal-title":"J. Biotechnol. Strateg. Health Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/FM9.0000000000000133","article-title":"Viral Infections During Pregnancy: The Big Challenge Threatening Maternal and Fetal Health","volume":"4","author":"Yu","year":"2022","journal-title":"Matern. Fetal Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bukowska-O\u015bko, I., Popiel, M., and Kowalczyk, P. (2021). The Immunological Role of the Placenta in SARS-CoV-2 Infection-Viral Transmission, Immune Regulation, and Lactoferrin Activity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115799"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1172\/JCI87490","article-title":"Risks associated with viral infections during pregnancy","volume":"127","author":"Racicot","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Husen, M.F., van der Meeren, L.E., Verdijk, R.M., Fraaij, P.L.A., van der Eijk, A.A., Koopmans, M.P.G., Freeman, L., Bogers, H., Trietsch, M.D., and Reiss, I.K.M. (2021). Unique Severe COVID-19 Placental Signature Independent of Severity of Clinical Maternal Symptoms. Viruses, 13.","DOI":"10.3390\/v13081670"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1097\/PAS.0000000000001889","article-title":"Diffuse and Localized SARS-CoV-2 Placentitis: Prevalence and Pathogenesis of an Uncommon Complication of COVID-19 Infection During Pregnancy","volume":"46","author":"Redline","year":"2022","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Auger, N., Ukah, U.V., and Wei, S.Q. (2023). Impact of COVID-19 on risk of severe maternal morbidity. Crit. Care, 27.","DOI":"10.1186\/s13054-023-04584-6"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.placenta.2021.03.007","article-title":"Ferroptosis, trophoblast lipotoxic damage, and adverse pregnancy outcome","volume":"108","author":"Beharier","year":"2021","journal-title":"Placenta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1002\/cbin.11623","article-title":"COVID-19-related coagulopathy: A review of pathophysiology and pharmaceutical management","volume":"45","author":"Shirin","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.placenta.2021.04.002","article-title":"Placental pathology in COVID-19 affected pregnant women: A prospective case-control study","volume":"110","author":"Tasca","year":"2021","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rudenko, K., Roshchina, T., Zazerskaya, I., Kudlay, D., Starshinova, A., and Mitrofanova, L. (2025). Morphological Changes in the Placenta of Patients with COVID-19 During Pregnancy. Diagnostics, 15.","DOI":"10.3390\/diagnostics15243188"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R101","DOI":"10.1530\/REP-12-0508","article-title":"The role of endocannabinoids in pregnancy","volume":"146","author":"Chan","year":"2013","journal-title":"Reproduction"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kalak, P., Kupczyk, P., Szumny, A., G\u0119barowski, T., Jasiak, M., Nied\u017awied\u017a, A., Ni\u017ca\u0144ski, W., and Dzi\u0119cio\u0142, M. (2025). Molecular Mechanisms of the Endocannabinoid System with a Focus on Reproductive Physiology and the Cannabinoid Impact on Fertility. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157095"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"F\u00fcgedi, G., Moln\u00e1r, M., Rig\u00f3, J., Sch\u00f6nl\u00e9ber, J., Kovalszky, I., and Molvarec, A. (2014). Increased placental expression of cannabinoid receptor 1 in preeclampsia: An observational study. BMC Pregnancy Childbirth, 14.","DOI":"10.1186\/s12884-014-0395-x"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1161\/HYPERTENSIONAHA.125.24934","article-title":"Placental Endocannabinoid System: Focus on Preeclampsia and Cannabis Use","volume":"82","author":"Harhangi","year":"2025","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41577-022-00694-4","article-title":"Immunomodulation by endothelial cells\u2014Partnering up with the immune system?","volume":"22","author":"Amersfoort","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100745","DOI":"10.1016\/j.blre.2020.100745","article-title":"Coagulation dysfunction in COVID-19: The interplay between inflammation, viral infection and the coagulation system","volume":"46","author":"Lazzaroni","year":"2021","journal-title":"Blood Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1055\/a-2451-2223","article-title":"The Immunohistochemical and Bioinformatics Analysis of the Placental Expressions of Vascular Cell Adhesion Protein 1 (VCAM-1) and High Mobility Group Box 1 (HMGB1) Proteins in Gestational Diabetic Mothers","volume":"229","author":"Bolluk","year":"2025","journal-title":"Z. Geburtshilfe Neonatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Guler, R., Ozden, E., As\u0131r, F., and Gulsun, B. (2025). High-Dose Shilajit Enhances Xenograft-Mediated Bone Regeneration in a Rat Tibial Defect Model: An In Vivo Experimental Study. Life, 15.","DOI":"10.3390\/life15101528"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.mce.2004.09.007","article-title":"Cannabinoid receptor I activation markedly inhibits human decidualization","volume":"229","author":"Moghadam","year":"2005","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.placenta.2012.10.009","article-title":"Differential expression of endocannabinoid system in normal and preeclamptic placentas","volume":"34","author":"Cella","year":"2013","journal-title":"Placenta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41577-022-00762-9","article-title":"Understanding COVID-19-associated coagulopathy","volume":"22","author":"Conway","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/978-3-319-20825-1_6","article-title":"Endocannabinoids and the immune system in health and disease","volume":"231","author":"Cabral","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e940130","DOI":"10.12659\/MSM.940130","article-title":"Relationship Between D-Dimer Levels and Neutrophil-to-Lymphocyte Ratio (NLR) in Preeclamptic Pregnant Women with COVID-19: A Cohort Study","volume":"29","author":"Tjahyadi","year":"2023","journal-title":"Med. Sci. Monit."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/imm.13378","article-title":"Endocannabinoids in immune regulation and immunopathologies","volume":"164","author":"Rahaman","year":"2021","journal-title":"Immunology"},{"key":"ref_26","first-page":"157","article-title":"Pathological involvement of placenta in COVID-19: A systematic review","volume":"30","author":"Motwani","year":"2022","journal-title":"Infez. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s42047-024-00146-4","article-title":"Histopathological and clinical analysis of COVID-19-infected placentas","volume":"7","author":"Nascimento","year":"2024","journal-title":"Surg. Exp. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102499","DOI":"10.1016\/j.dsx.2022.102499","article-title":"Comparative study of CNR1 and CNR2 cannabinoid receptors expression levels in COVID-19 patients with and without diabetes mellitus: Recommendations for future research targets","volume":"16","author":"Aghamahdi","year":"2022","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Khalil, M., Alliger, K., Weidinger, C., Yerinde, C., Wirtz, S., Becker, C., and Engel, M.A. (2018). Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00174"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41392-023-01464-x","article-title":"TRP (transient receptor potential) ion channel family: Structures, biological functions and therapeutic interventions for diseases","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16887","DOI":"10.1073\/pnas.1010892107","article-title":"Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation","volume":"107","author":"Sun","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1007\/s00018-016-2300-4","article-title":"The CB2 receptor and its role as a regulator of inflammation","volume":"73","author":"Turcotte","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rakotoarivelo, V., Mayer, T.Z., Simard, M., Flamand, N., and Di Marzo, V. (2024). The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules, 29.","DOI":"10.3390\/molecules29143381"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rad, H.S., R\u00f6hl, J., Stylianou, N., Allenby, M.C., Bazaz, S.R., Warkiani, M.E., Guimaraes, F.S.F., Clifton, V.L., and Kulasinghe, A. (2021). The Effects of COVID-19 on the Placenta During Pregnancy. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.743022"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Haspula, D., and Clark, M.A. (2020). Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207693"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/5\/690\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:14:38Z","timestamp":1772115278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/5\/690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["diagnostics16050690"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16050690","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]}}}