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Our study demonstrated for the first time that a 6-h delayed post-treatment with amorfrutin B prevented hypoxia\/ischemia-induced neuronal apoptosis in terms of the loss of mitochondrial membrane potential, heterochromatin foci formation, and expression of specific genes and proteins. The expression of all studied apoptosis-related factors was decreased in response to amorfrutin B, both during hypoxia and ischemia, except for the expression of anti-apoptotic BCL2, which was increased. After post-treatment with amorfrutin B, the methylation rate of the pro-apoptotic <jats:italic>Bax<\/jats:italic> gene was inversely correlated with the protein level, which explained the decrease in the BAX\/BCL2 ratio as a result of <jats:italic>Bax<\/jats:italic> hypermethylation. The mechanisms of the protective action of amorfrutin B also involved the inhibition of autophagy, as evidenced by diminished autophagolysosome formation and the loss of neuroprotective properties of amorfrutin B after the silencing of <jats:italic>Becn1<\/jats:italic> and\/or <jats:italic>Atg7<\/jats:italic>. Although post-treatment with amorfrutin B reduced the expression levels of <jats:italic>Becn1<\/jats:italic>, <jats:italic>Nup62<\/jats:italic>, and <jats:italic>Ambra1<\/jats:italic> during hypoxia, it stimulated <jats:italic>Atg5<\/jats:italic> and the protein levels of MAP1LC3B and AMBRA1 during ischemia, supporting the ambiguous role of autophagy in the development of brain pathologies. Furthermore, amorfrutin B affected the expression levels of apoptosis-focused and autophagy-related miRNAs, and many of these miRNAs were oppositely regulated by amorfrutin B and hypoxia\/ischemia. The results strongly support the position of amorfrutin B among the most promising anti-stroke and wide-window therapeutics.<\/jats:p>","DOI":"10.1007\/s12035-022-03087-9","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T04:31:23Z","timestamp":1667449883000},"page":"576-595","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Amorfrutin B Protects Mouse Brain Neurons from Hypoxia\/Ischemia by Inhibiting Apoptosis and Autophagy Processes Through Gene Methylation- and miRNA-Dependent Regulation"],"prefix":"10.1007","volume":"60","author":[{"given":"Karolina","family":"Przepi\u00f3rska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Wnuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordian","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-7031","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Kajta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"issue":"4","key":"3087_CR1","doi-asserted-by":"publisher","first-page":"e03793","DOI":"10.1016\/j.heliyon.2020.e03793","volume":"6","author":"Y Workineh","year":"2020","unstructured":"Workineh Y, Semachew A, Ayalew E, Animaw W, Tirfie M, Birhanu M (2020) Prevalence of perinatal asphyxia in East and Central Africa: systematic review and meta-analysis. 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