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Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn\u2010induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D<jats:sub>1<\/jats:sub>, and E2F1) and enhancing negative ones (p27<jats:sup>KIP1<\/jats:sup> and p57<jats:sup>KIP2<\/jats:sup>), leading to cell proliferation dysfunction. Mel inhibited the Mn\u2010dependent changes to these proteins and the cell cycle through nuclear receptor\u2010related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus\u2010expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn\u2010induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.<\/jats:p>","DOI":"10.1002\/tox.24258","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T15:32:25Z","timestamp":1712071945000},"page":"3883-3896","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1"],"prefix":"10.1002","volume":"39","author":[{"given":"Nan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi\u2010Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"},{"name":"Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"},{"name":"Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8024-2066","authenticated-orcid":false,"given":"Bin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, School of Public Health China Medical University  Shenyang PR China"},{"name":"Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education  Shenyang PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV119.009453"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph192013020"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2020.105547"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2021.106468"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40572-022-00384-2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00533"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23922"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.15246"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v28.i22.2437"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32462-2"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2019.103536"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23041971"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2011.00867.x"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2968"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.786226"},{"issue":"12","key":"e_1_2_10_17_1","first-page":"584","article-title":"NURR1 alterations in perinatal stress: a first step towards late\u2010onset diseases? 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