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Engeletin, a natural <jats:italic>Smilax glabra rhizomilax<\/jats:italic> derivative, is reported to possess anti\u2010inflammatory activity. Herein, we examined the mechanism of engeletin\u2010mediated neuroprotection in rats having transient middle cerebral artery occlusion (tMCAO) against cerebral ischemia reperfusion injury. Male SD rats were induced using a 1.5\u2009h tMCAO, following by reperfusion for 22.5\u2009h. Engeletin (15, 30 or 60\u2009mg\/kg) was intravenously administered immediately following 0.5\u2009h of ischemia. Based on our results, engeletin, in a dose\u2010dependent fashion, reduced neurological deficits, infarct size, histopathological alterations, brain edema and inflammatory factors, namely, circulating IL\u20101\u03b2, TNF\u2010\u03b1, IL\u20106 and IFN\u2010\u03b3. Furthermore, engeletin treatment markedly reduced neuronal apoptosis, which, in turn, elevated Bcl\u20102 protein levels, while suppressing Bax and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.bio-equip.com\/showarticle.asp?id=453109360\">Cleaved Caspase\u20103<\/jats:ext-link> protein levels. Meanwhile, engeletin significantly reduces overall expressions of HMGB1, TLR4, and NF\u2010\u03baB and attenuated nuclear transfer of nuclear factor kappa B (NF\u2010\u03baB) p65 in ischemic cortical tissue. In conclusion, engeletin strongly prevents focal cerebral ischemia via suppression of the HMGB1\/TLR4\/NF\u2010\u03baB inflammatory network.<\/jats:p>","DOI":"10.1111\/jcmm.17758","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T06:20:14Z","timestamp":1683094814000},"page":"1653-1663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Engeletin alleviates cerebral ischemia <scp>reperfusion\u2010induced<\/scp> neuroinflammation via the <scp>HMGB1<\/scp>\/<scp>TLR4<\/scp>\/<scp>NF\u2010\u03baB<\/scp> network"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6427-7250","authenticated-orcid":false,"given":"Yangyang","family":"Xu","sequence":"first","affiliation":[{"name":"School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug 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