{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:48:17Z","timestamp":1790758097889,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS099539"],"award-info":[{"award-number":["R01 NS099539"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood\u2013brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPAR\u03b3) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPAR\u03b3 DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPAR\u03b3-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1\u03b2-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPAR\u03b3 activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPAR\u03b3 DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke.<\/jats:p>","DOI":"10.3390\/ijms21030824","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T09:37:09Z","timestamp":1580204229000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db\/db Male Mice via Cerebrovascular PPAR\u03b3 Activation"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7344-7028","authenticated-orcid":false,"given":"Yinghua","family":"Jiang","sequence":"first","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yuan","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadan","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0627-5278","authenticated-orcid":false,"given":"Shuzhen","family":"Guo","sequence":"additional","affiliation":[{"name":"Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanyang","family":"Yu","sequence":"additional","affiliation":[{"name":"Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Center, Department of Neurosurgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1093\/eurheartj\/eht142","article-title":"Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part II","volume":"34","author":"Beckman","year":"2013","journal-title":"Eur. 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