{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:06:16Z","timestamp":1792065976916,"version":"4.4.0"},"reference-count":86,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T00:00:00Z","timestamp":1694476800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T00:00:00Z","timestamp":1694476800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82305294"],"award-info":[{"award-number":["82305294"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M733193"],"award-info":[{"award-number":["2023M733193"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Prenatal tobacco exposure (PTE) correlates significantly with a surge in adverse pregnancy outcomes, yet its pathological mechanisms remain partially unexplored. This study aims to meticulously examine the repercussions of PTE on placental immune landscapes, employing a coordinated research methodology encompassing bioinformatics, machine learning and animal studies. Concurrently, it aims to screen biomarkers and potential compounds that could sensitively indicate and mitigate placental immune disorders. In the course of this research, two gene expression omnibus (GEO) microarrays, namely GSE27272 and GSE7434, were included. Gene set enrichment analysis (GSEA) and immune enrichment investigations on differentially expressed genes (DEGs) indicated that PTE might perturb numerous innate or adaptive immune\u2010related biological processes. A cohort of 52 immune\u2010associated DEGs was acquired by cross\u2010referencing the DEGs with gene sets derived from the ImmPort database. A protein\u2013protein interaction (PPI) network was subsequently established, from which 10 hub genes were extracted using the maximal clique centrality (MCC) algorithm (\n                    <jats:italic>JUN, NPY, SST, FLT4, FGF13, HBEGF, NR0B2, AREG, NR1I2, SEMA5B<\/jats:italic>\n                    ). Moreover, we substantiated the elevated affinity of tobacco reproductive toxicants, specifically nicotine and nitrosamine, with hub genes through molecular docking (\n                    <jats:italic>JUN, FGF13<\/jats:italic>\n                    and\n                    <jats:italic>NR1I2<\/jats:italic>\n                    ). This suggested that these genes could potentially serve as crucial loci for tobacco's influence on the placental immune microenvironment. To further elucidate the immune microenvironment landscape, consistent clustering analysis was conducted, yielding three subtypes, where the abundance of follicular helper T cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in subtype A, M2 macrophages (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), neutrophils (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in subtype B and CD8+ T cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), resting NK cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), M2 macrophages (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in subtype C were significantly different from the control group. Additionally, three pivotal modules, designated as red, blue and green, were identified, each bearing a close association with differentially infiltrated immunocytes, as discerned by the weighted gene co\u2010expression network analysis (WGCNA). Functional enrichment analysis was subsequently conducted on these modules. To further probe into the mechanisms by which immune\u2010associated DEGs are implicated in intercellular communication, 20 genes serving as ligands or receptors and connected to differentially infiltrating immunocytes were isolated. Employing a variety of machine learning techniques, including one\u2010way logistic regression, LASSO regression, random forest and artificial neural networks, we screened 11 signature genes from the intersection of immune\u2010associated DEGs and secretory protein\u2010encoding genes derived from the Human Protein Atlas. Notably, CCL18 and IFNA4 emerged as prospective peripheral blood markers capable of identifying PTE\u2010induced immune disorders. These markers demonstrated impressive predictive power, as indicated by the area under the curve (AUC) of 0.713 (0.548\u20130.857) and 0.780 (0.618\u20130.914), respectively. Furthermore, we predicted 34 potential compounds, including cyclosporine, oestrogen and so on, which may engage with hub genes and attenuate immune disorders instigated by PTE. The diagnostic performance of these biomarkers, alongside the interventional effect of cyclosporine, was further corroborated in animal studies via ELISA, Western blot and immunofluorescence assays. In summary, this study identifies a disturbance in the placental immune landscape, a secondary effect of PTE, which may underlie multiple pregnancy complications. Importantly, our research contributes to the noninvasive and timely detection of PTE\u2010induced placental immune disorders, while also offering innovative therapeutic strategies for their treatment.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.17846","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:44:28Z","timestamp":1694565868000},"page":"3026-3052","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Demystifying the impact of prenatal tobacco exposure on the placental immune microenvironment: Avoiding the tragedy of mending the fold after death"],"prefix":"10.1111","volume":"27","author":[{"given":"Xiaoxuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine (TCM) Gynecology Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University  Hangzhou China"},{"name":"Research Institute of Women's Reproductive Health Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuepeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ma","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qujia","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Ding","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University  Hangzhou 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