{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:36:02Z","timestamp":1785818162720,"version":"3.56.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Diabetes mellitus exacerbates cerebral ischemic injury. However, effective interventions remain limited. Ischemic postconditioning (IPOC) is a potential neuroprotective strategy; however, its efficacy and mechanisms in diabetes remain poorly understood. This study aimed to explore the therapeutic effects and underlying mechanisms of IPOC in diabetes complicated by cerebral ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Tree shrews with diabetes complicated by cerebral ischemia were used as the study subjects and were subjected to a standardized IPOC intervention protocol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results showed that compared with the control group, the cerebral infarction volume of tree shrews in the cerebral ischemia (IS) group and the diabetes complicated with cerebral ischemia (DMIS) group was significantly higher, the neurons were severely damaged, A1 astrocytes were activated, the levels of inflammatory factors interleukin (IL)-1\u03b2 and IL-6 increased, and mitochondrial autophagy was inhibited. In contrast, in the DMIS + IPOC group, cerebral infarction volume was significantly reduced, neuronal damage was improved, activation of A1 astrocytes and release of inflammatory factors were inhibited, and mitochondrial autophagy was increased. Mechanistically, IPOC activated the brain-derived neurotrophic factor (BDNF)\/tropomyosin receptor kinase B (TrkB) pathway and upregulated hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) expression, which further promoted the expression of Bcl-2\/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IPOC coordinates microglial mitochondrial autophagy and astrocyte inflammatory regulation through the BDNF\u2013TrkB\u2013HIF\u20131\u03b1\u2013BNIP3 signaling cascade, providing a new target for precise intervention in diabetes combined with cerebral ischemia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1620004","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T04:13:03Z","timestamp":1758514383000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Ischemic postconditioning ameliorates diabetic cerebral ischemia via activating the brain-derived neurotrophic factor\u2013tropomyosin receptor kinase B\u2013hypoxia-inducible factor 1\u03b1\u2013Bcl-2\/adenovirus E1B 19-kDa-interacting protein 3 pathway to induce microglial mitophagy and suppress A1 astrocyte-mediated neuroinflammation"],"prefix":"10.3389","volume":"16","author":[{"given":"Ling","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2021-007714","article-title":"Multimorbidity and catastrophic health expenditure among patients with diabetes in China: a nationwide population-based study","volume":"7","author":"Fu","year":"2022","journal-title":"BMJ Glob Health"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/09513590.2017.1399698","article-title":"Risk factors of cerebral ischemia in infants born to mothers with gestational diabetes","volume":"33","author":"Shupletsova","year":"2017","journal-title":"Gynecol Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.339490","article-title":"Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy","volume":"17","author":"Fang","year":"2022","journal-title":"Neural Regener Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.jgr.2020.11.004","article-title":"Notoginseng leaf triterpenes ameliorates mitochondrial oxidative injury via the NAMPT-SIRT1\/2\/3 signaling pathways in cerebral ischemic model rats","volume":"47","author":"Xie","year":"2023","journal-title":"J Ginseng Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2024.149201","article-title":"Exogenous leptin alleviates glutamate-excitotoxic injury caused by cerebral ischemia-reperfusion in mice by affecting the expression of glutamate transporters","volume":"1845","author":"Chen","year":"2024","journal-title":"Brain Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5812\/ijpr-156838","article-title":"Bupropion showed neuroprotective impacts against cerebral ischemia\/reperfusion injury by reducing oxidative stress and inflammation","volume":"23","author":"Baba Ahmadi","year":"2025","journal-title":"Iran J Pharm Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26051847","article-title":"Galangin's neuroprotective role: targeting oxidative stress, inflammation, and apoptosis in ischemic stroke in a rat model of permanent middle cerebral artery occlusion","volume":"26","author":"Palachai","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1177\/11795735241301568","article-title":"Enriched environment may improve secondary brain injury after traumatic brain injury by regulating the TLR2\/NF-\u03baB signaling pathway","volume":"16","author":"Wu","year":"2024","journal-title":"J Cent Nerv Syst Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S487628","article-title":"Curcumin-loaded gelatin nanoparticles cross the blood-brain barrier to treat ischemic stroke by attenuating oxidative stress and neuroinflammation","volume":"19","author":"Yang","year":"2024","journal-title":"Int J Nanomedicine"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2174\/156720208785425666","article-title":"Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways","volume":"5","author":"Chong","year":"2008","journal-title":"Curr Neurovasc Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/4722797","article-title":"Panax notoginseng protects against diabetes-associated endothelial dysfunction: comparison between ethanolic extract and total saponin","volume":"2021","author":"Zhang","year":"2021","journal-title":"Oxid Med Cell Longev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"142","DOI":"10.3892\/ijmm.2021.4975","article-title":"Damage to the blood-brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition","volume":"48","author":"Guo","year":"2021","journal-title":"Int J Mol Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2025.123850","article-title":"Analysis of prognostic risk factors in patients with complete revascularization after thrombectomy for acute anterior circulation large vessel occlusion","volume":"197","author":"Yang","year":"2025","journal-title":"World Neurosurg"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.034471","article-title":"Collateral circulation in thrombectomy for stroke after 6 to 24 hours in the DAWN trial","volume":"53","author":"Liebeskind","year":"2022","journal-title":"Stroke"},{"key":"B15","article-title":"Ischemic postconditioning for stroke treatment: current experimental advances and future directions","volume":"3","author":"Chen","year":"2020","journal-title":"Cond Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-022-07349-5","article-title":"Hyperglycemia-induced overexpression of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) compromises the cardioprotective effect of ischemic postconditioning via modulation of the akt\/mst1 pathway signaling","volume":"37","author":"Qiu","year":"2023","journal-title":"Cardiovasc Drugs Ther"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.2354","article-title":"The neuroprotective effect and RNA-sequence analysis of postconditioning on the ischemic stroke with diabetes mellitus tree shrew model","volume":"11","author":"Zhao","year":"2021","journal-title":"Brain Behav"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.124.037859","article-title":"Metabolic syndrome and efficacy of remote ischemic postconditioning in acute moderate ischemic stroke: A post hoc analysis of the RICAMIS trial","volume":"14","author":"Zhang","year":"2025","journal-title":"J Am Heart Assoc"},{"key":"B19","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.brainres.2019.05.011","article-title":"Establishment of brain ischemia model in tree shrew","volume":"1718","author":"Wang","year":"2019","journal-title":"Brain Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/6286571","article-title":"Ischemic postconditioning mitigates retinopathy in tree shrews with diabetic cerebral ischemia","volume":"2020","author":"Zhao","year":"2020","journal-title":"J Diabetes Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105667","article-title":"Impact of diabetes and ischemic stroke on the cerebrovasculature: A female perspective","volume":"167","author":"Wolf","year":"2022","journal-title":"Neurobiol Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/01616412.2018.1424696","article-title":"Remote ischemic postconditioning protects the brain from focal ischemia\/reperfusion injury by inhibiting autophagy through the mTOR\/p70S6K pathway","volume":"40","author":"Chen","year":"2018","journal-title":"Neurol Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00108","article-title":"The central role of aquaporins in the pathophysiology of ischemic stroke","volume":"9","author":"Vella","year":"2015","journal-title":"Front Cell Neurosci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102489","article-title":"Unraveling the protein post-translational modification landscape: Neuroinflammation and neuronal death after stroke","volume":"101","author":"Tao","year":"2024","journal-title":"Ageing Res Rev"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.115.009070","article-title":"Effects of postconditioning on neurogenesis and angiogenesis during the recovery phase after focal cerebral ischemia","volume":"46","author":"Esposito","year":"2015","journal-title":"Stroke"},{"key":"B26","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.neuint.2017.01.006","article-title":"Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia","volume":"107","author":"Fan","year":"2017","journal-title":"Neurochem Int"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.108085","article-title":"Blockage of p38MAPK in astrocytes alleviates brain damage in a mouse model of embolic stroke through the CX43\/AQP4 axis","volume":"33","author":"Chen","year":"2024","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-023-03371-2","article-title":"The effect of simvastatin on the dynamics of NF-\u03baB-regulated neurodegenerative and neuroprotective processes in the acute phase of ischemic stroke","volume":"60","author":"Lietzau","year":"2023","journal-title":"Mol Neurobiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-024-02219-8","article-title":"LncRNA tug1 regulates post-stroke microglial pyroptosis via PINK1\/parkin-mediated mitophagy","volume":"48","author":"Yao","year":"2024","journal-title":"Inflammation"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1515\/biol-2019-0020","article-title":"Effects of ischemic post-conditioning on the expressions of LC3-II and beclin-1 in the hippocampus of rats after cerebral ischemia and reperfusion","volume":"14","author":"Huang","year":"2019","journal-title":"Open Life Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161629","article-title":"Trk receptors: roles in neuronal signal transduction","volume":"72","author":"Huang","year":"2003","journal-title":"Annu Rev Biochem"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms160818544","article-title":"SCM-198 ameliorates cognitive deficits, promotes neuronal survival and enhances CREB\/BDNF\/trkB signaling without affecting A\u03b2 Burden in A\u03b2PP\/PS1 mice","volume":"16","author":"Hong","year":"2015","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s10059-011-0065-z","article-title":"Silencing of BNIP3 results from promoter methylation by DNA methyltransferase 1 induced by the mitogen-activated protein kinase pathway","volume":"31","author":"An","year":"2011","journal-title":"Mol Cells"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00092","article-title":"Endothelial monocyte-activating polypeptide-II induces BNIP3-mediated mitophagy to enhance temozolomide cytotoxicity of glioma stem cells via down-regulating miR-24-3p","volume":"11","author":"Zhang","year":"2018","journal-title":"Front Mol Neurosci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.02.002","article-title":"HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia","volume":"3","author":"Kim","year":"2006","journal-title":"Cell Metab"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: the metabolic requirements of cell proliferation","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2025.149476","article-title":"Paeoniflorin inhibits pyruvate dehydrogenase kinase 3 and promotes BDNF activity by modulating neuronal activity and TNF-\u03b1","volume":"1851","author":"Pinky","year":"2025","journal-title":"Brain Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.3c00191","article-title":"Pyruvate dehydrogenase complex in neonatal hypoxic-ischemic brain injury","volume":"7","author":"Zhou","year":"2023","journal-title":"ACS Pharmacol Transl Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5123-04.2005","article-title":"ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin","volume":"25","author":"Teng","year":"2005","journal-title":"J Neurosci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1620004\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T04:13:04Z","timestamp":1758514384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1620004\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,22]]},"references-count":40,"alternative-id":["10.3389\/fendo.2025.1620004"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1620004","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,22]]},"article-number":"1620004"}}