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Netrin\u20101 is an important member of the family of laminin\u2010related secreted proteins, which plays an important role in governing axon elongation. However, it is unknown whether Netrin\u20101 possesses a beneficial role in stroke. Here, we employed the middle cerebral artery occlusion (MCAO)\u00a0model to study the function of Netrin\u20101 in alleviating brain injuries. Our results demonstrate that Netrin\u20101 rescued poststroke neurological deficits and inhibited production of the inflammatory cytokines such as interleukin 6 (IL\u20106)\u00a0and endothelial chemokine (C\u2010X\u2010C motif) ligand 1 (Cxcl1). Importantly, Netrin\u20101 protected against MCAO\u2010induced dysfunction of the blood\u2013brain barrier (BBB)\u00a0in mice and a reduction in the expression of the tight junction (TJ)\u00a0protein occludin. Additionally, we report that Netrin\u20101 could ameliorate oxygen\u2010glucose deprivation\/reoxygenation (OGD\/R)\u2010induced\u00a0injury and prevent aggravation in endothelial monolayer permeability in bEnd.3 human brain microvascular endothelial cells (HBMVECs).\u00a0Mechanistically, Netrin\u20101 ameliorated OGD\/R\u2010induced decrease in occludin and Kruppel\u2010like\u00a0factor 2 (KLF2) in HBMVECs. Notably, silencing of KLF2\u00a0abolished the beneficial effects of Netrin\u20101 in protecting endothelial permeability and occludin expression, suggesting that these effects are mediated by KLF2. In conclusion, our findings suggest that Netrin\u20101 could constitute a novel therapeutic strategy for ischemic stroke.<\/jats:p>","DOI":"10.1002\/jbt.23623","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T02:00:51Z","timestamp":1704247251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Netrin\u20101 protects blood\u2013brain barrier (BBB) integrity after cerebral ischemia\u2010reperfusion by activating the Kruppel\u2010like factor 2 (KLF2)\/occludin pathway"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4814-9807","authenticated-orcid":false,"given":"Yuanxiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital  Fuzhou Fujian Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital  Fuzhou Fujian Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital  Fuzhou Fujian Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanbin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital  Fuzhou Fujian Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital  Fuzhou Fujian Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000004597"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2021.07.027"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010014"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.687246"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-022-03697-8"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-022-00859-0"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2022.10.020"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.5114\/fn.2022.120101"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020412"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-023-03923-x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22331"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/2048004020959574"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-9-239"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2018.08.021"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.01.130"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1590"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.751570"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00700"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2006.09.006"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-022-00495-6"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858415585108"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isatra.2015.06.001"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361-648X\/aac52f"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17091418"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2022.0225"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2019.119491"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.005819"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00095.2018"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14798"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15102"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-011-9584-5"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.12.016"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202194"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13699"},{"key":"e_1_2_9_36_1","first-page":"54","volume":"85","author":"Turpaev K. 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