{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:10:27Z","timestamp":1793333427014,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81960223"],"award-info":[{"award-number":["81960223"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["202301AY070001-163"],"award-info":[{"award-number":["202301AY070001-163"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Applied Basic Research Projects of Yunnan Province","award":["81960223"],"award-info":[{"award-number":["81960223"]}]},{"name":"Applied Basic Research Projects of Yunnan Province","award":["202301AY070001-163"],"award-info":[{"award-number":["202301AY070001-163"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Among all stroke types, ischemic stroke (IS) occurs most frequently, resulting in neuronal death and tissue injury within both the central infarct region and surrounding areas. This study explored the neuroprotective mechanisms of scutellarin, a flavonoid compound, through an integrated strategy that merged in silico analyses (including network pharmacology and molecular docking simulations) with both in vitro and in vivo experimental verification. We identified 1887 IS-related targets and 129 scutellarin targets, with 23 overlapping targets. PPI network analysis revealed five core targets, and molecular docking demonstrated strong binding affinities between scutellarin and these targets. Bioinformatic analyses, including GO functional annotation and KEGG pathway mapping, indicated that the PI3K\/AKT cascade represents the primary signaling mechanism. An in vitro experimental system was developed using PC12 cells under oxygen-glucose deprivation conditions to investigate how scutellarin regulates neuronal cell death via the PI3K\/AKT pathway. Western blot quantification demonstrated that treatment with scutellarin enhanced the expression of p-PI3K, p-AKT, and Bcl-2 proteins, while simultaneously reducing levels of apoptotic markers Bax and cleaved caspase-3. Furthermore, pharmacological intervention with the selective PI3K inhibitor LY294002 attenuated these molecular alterations, resulting in diminished expression of p-PI3K, p-AKT, and Bcl-2, accompanied by elevated levels of Bax and cleaved caspase-3. In a rat model of middle cerebral artery occlusion, scutellarin administration demonstrated comparable neuroprotective effects, maintaining neuronal survival and modulating apoptotic protein expression via PI3K\/AKT pathway activation. Collectively, this study demonstrates the therapeutic potential of scutellarin in cerebral ischemia through PI3K\/AKT pathway modulation, suggesting its possible application in treating ischemic disorders.<\/jats:p>","DOI":"10.3390\/ijms26052175","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T04:28:18Z","timestamp":1740716898000},"page":"2175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Scutellarin Alleviates Neuronal Apoptosis in Ischemic Stroke via Activation of the PI3K\/AKT Signaling Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhaoda","family":"Duan","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"},{"name":"Institute of Biomedical Engineering, Kunming Medical Univesity, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqi","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyao","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuke","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyun","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Kunming Medical Univesity, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119166","DOI":"10.1016\/j.jep.2024.119166","article-title":"Elemene mitigates oxidative stress and neuronal apoptosis induced by cerebral ischemia-reperfusion injury through the regulation of glutathione metabolism","volume":"340","author":"Wu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156305","DOI":"10.1016\/j.phymed.2024.156305","article-title":"Exploring the mechanism of Taohong Siwu Decoction in treating ischemic stroke injury via the circDnajc1\/miR-27a-5p\/C1qc signaling axis","volume":"136","author":"Li","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e12023","DOI":"10.1002\/ccs3.12023","article-title":"Scutellarin alleviates microglia-mediated neuroinflammation and apoptosis after ischemic stroke through the PI3K\/AKT\/GSK3\u03b2 signaling pathway","volume":"18","author":"Duan","year":"2024","journal-title":"J. Cell Commun. Signal"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.neuroscience.2024.11.064","article-title":"Protective effects of PIK3CG knockdown against OGD\/R-induced neuronal damage via inhibition of autophagy through the AMPK\/mTOR pathway","volume":"565","author":"Lv","year":"2024","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107229","DOI":"10.1016\/j.phrs.2024.107229","article-title":"Multi-omics approaches for the understanding of therapeutic mechanism for Huang-Qi-Long-Dan Granule against ischemic stroke","volume":"205","author":"Wu","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107527","DOI":"10.1016\/j.phrs.2024.107527","article-title":"The therapeutic effects of salvianolic acids on ischemic stroke: From molecular mechanisms to clinical applications","volume":"210","author":"Zhao","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.14336\/AD.2022.0311","article-title":"Ancient Chinese Herbal Recipe Huanglian Jie Du Decoction for Ischemic Stroke: An Overview of Current Evidence","volume":"13","author":"Yu","year":"2022","journal-title":"Aging Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Song, X., Gong, Z., Liu, K., Kou, J., Liu, B., and Liu, K. (2020). Baicalin combats glutamate excitotoxicity via protecting glutamine synthetase from ROS-induced 20S proteasomal degradation. Redox Biol., 34.","DOI":"10.1016\/j.redox.2020.101559"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Duan, Z.D., Zheng, L.Y., Jia, Q.Y., Chen, H.L., Xu, D.Y., Yang, Y.J., Qi, Z., Yang, L., and Wu, C.Y. (2024). Effect of scutellarin on BV-2 microglial-mediated apoptosis in PC12 cells via JAK2\/STAT3 signalling pathway. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-64226-x"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.pharmthera.2018.05.006","article-title":"Clinical benefits and pharmacology of scutellarin: A comprehensive review","volume":"190","author":"Wang","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/med.21817","article-title":"Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications","volume":"42","author":"Tuo","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s10495-019-01556-6","article-title":"Apoptosis regulation in the penumbra after ischemic stroke: Expression of pro- and antiapoptotic proteins","volume":"24","author":"Uzdensky","year":"2019","journal-title":"Apoptosis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/nn.2953","article-title":"Stroke research at a crossroad: Asking the brain for directions","volume":"14","author":"Iadecola","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1161\/STROKEAHA.119.026692","article-title":"Effect of Recanalization on Cerebral Edema in Ischemic Stroke Treated With Thrombolysis and\/or Endovascular Therapy","volume":"51","author":"Dixit","year":"2020","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113359","DOI":"10.1016\/j.expneurol.2020.113359","article-title":"Delayed recanalization after MCAO ameliorates ischemic stroke by inhibiting apoptosis via HGF\/c-Met\/STAT3\/Bcl-2 pathway in rats","volume":"330","author":"Tang","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2961079","DOI":"10.1155\/2021\/2961079","article-title":"\u03b3-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress","volume":"2021","author":"Li","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114478","DOI":"10.1016\/j.bbr.2023.114478","article-title":"DUSP10 alleviates ischemic stroke-induced neuronal damage by restricting p38\/JNK pathway","volume":"450","author":"Song","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cai, D., Fraunfelder, M., Fujise, K., and Chen, S.Y. (2023). ADAR1 exacerbates ischemic brain injury via astrocyte-mediated neuron apoptosis. Redox Biol., 67.","DOI":"10.1016\/j.redox.2023.102903"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2356507","DOI":"10.1155\/2022\/2356507","article-title":"Candesartan Reduces Neuronal Apoptosis Caused by Ischemic Stroke via Regulating the FFAR1\/ITGA4 Pathway","volume":"2022","author":"Ding","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1007\/s11033-022-08238-8","article-title":"Myricetin improves apoptosis after ischemic stroke via inhibiting MAPK-ERK pathway","volume":"50","author":"Zhang","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s41401-022-00995-3","article-title":"Oridonin ameliorates caspase-9-mediated brain neuronal apoptosis in mouse with ischemic stroke by inhibiting RIPK3-mediated mitophagy","volume":"44","author":"Li","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s12017-016-8394-x","article-title":"Scutellarin as a Potential Therapeutic Agent for Microglia-Mediated Neuroinflammation in Cerebral Ischemia","volume":"18","author":"Yuan","year":"2016","journal-title":"Neuromol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s12017-019-08582-2","article-title":"Scutellarin Exerts Anti-Inflammatory Effects in Activated Microglia\/Brain Macrophage in Cerebral Ischemia and in Activated BV-2 Microglia Through Regulation of MAPKs Signaling Pathway","volume":"22","author":"Chen","year":"2020","journal-title":"Neuromol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"116306","DOI":"10.1016\/j.jep.2023.116306","article-title":"Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula","volume":"309","author":"Zhao","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ye, J., Li, L., and Hu, Z. (2021). Exploring the Molecular Mechanism of Action of Yinchen Wuling Powder for the Treatment of Hyperlipidemia, Using Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation. Biomed. Res. Int., 2021.","DOI":"10.1155\/2021\/9965906"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, H., Zhang, Y., Li, Y., Wang, Y., Yan, S., Xu, S., Deng, Z., Yang, X., Xie, H., and Li, J. (2021). Bioinformatics and Network Pharmacology Identify the Therapeutic Role and Potential Mechanism of Melatonin in AD and Rosacea. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.756550"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114481","DOI":"10.1016\/j.jep.2021.114481","article-title":"A preparation of Ginkgo biloba L. leaves extract inhibits the apoptosis of hippocampal neurons in post-stroke mice via regulating the expression of Bax\/Bcl-2 and Caspase-3","volume":"280","author":"Li","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1021\/acsnano.7b01926","article-title":"Nanomotor-Enabled pH-Responsive Intracellular Delivery of Caspase-3: Toward Rapid Cell Apoptosis","volume":"11","author":"Campuzano","year":"2017","journal-title":"ACS Nano"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/stem.1503","article-title":"Caspase-3 modulates regenerative response after stroke","volume":"32","author":"Fan","year":"2014","journal-title":"Stem Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"148247","DOI":"10.1016\/j.brainres.2023.148247","article-title":"Tongqiao Huoxue decoction alleviates neurological impairment following ischemic stroke via the PTGS2\/NF-kappa B axis","volume":"1805","author":"Zhou","year":"2023","journal-title":"Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhuang, J., Chen, Z., Cai, P., Wang, R., Yang, Q., Li, L., Yang, H., and Zhu, R. (2020). Targeting MicroRNA-125b Promotes Neurite Outgrowth but Represses Cell Apoptosis and Inflammation via Blocking PTGS2 and CDK5 in a FOXQ1-Dependent Way in Alzheimer Disease. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.587747"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1007\/s12035-023-03548-9","article-title":"EGFR-Activated JAK2\/STAT3 Pathway Confers Neuroprotection in Spinal Cord Ischemia-Reperfusion Injury: Evidence from High-Throughput Sequencing and Experimental Models","volume":"61","author":"Lv","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1161\/STROKEAHA.122.041977","article-title":"Epidermal Growth Factor Receptor Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage in Mice","volume":"54","author":"Nakano","year":"2023","journal-title":"Stroke"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"141375","DOI":"10.1016\/j.chemosphere.2024.141375","article-title":"Role of an interdependent Wnt, GSK3-\u03b2\/\u03b2-catenin and HB-EGF\/EGFR mechanism in arsenic-induced hippocampal neurotoxicity in adult mice","volume":"352","author":"Garg","year":"2024","journal-title":"Chemosphere"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Geng, H., Chen, L., Tang, J., Chen, Y., and Wang, L. (2022). The Role of CCL2\/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073485"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, J., Zhang, L., Xue, S., Yu, C., Li, Y., Li, S., Ye, Q., Duan, X., and Peng, D. (2024). Exploration of the mechanism of Taohong Siwu Decoction for the treatment of ischemic stroke based on CCL2\/CCR2 axis. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1428572"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.bbrc.2019.03.202","article-title":"Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia\/macrophage and suppressing NF-\u03baB activation","volume":"513","author":"Li","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1038\/s41401-022-00913-7","article-title":"Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window","volume":"43","author":"Pan","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Liang, Y., Song, P., Chen, W., Xie, X., Luo, R., Su, J., Zhu, Y., Xu, J., Liu, R., and Zhu, P. (2020). Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.540669"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gu, C., Zhang, Q., Li, Y., Li, R., Feng, J., Chen, W., Ahmed, W., Soufiany, I., Huang, S., and Long, J. (2022). The PI3K\/AKT Pathway-The Potential Key Mechanisms of Traditional Chinese Medicine for Stroke. Front. Med., 9.","DOI":"10.3389\/fmed.2022.900809"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1080\/13880209.2021.1928241","article-title":"Angelica gigas root ameliorates ischaemic stroke-induced brain injury in mice by activating the PI3K\/AKT\/mTOR and MAPK pathways","volume":"59","author":"Lee","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Liu, X., Xiao, X., Han, X., Yao, L., and Lan, W. (2022). A New Therapeutic Trend: Natural Medicine for Ameliorating Ischemic Stroke via PI3K\/Akt Signaling Pathway. Molecules, 27.","DOI":"10.3390\/molecules27227963"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.4103\/NRR.NRR-D-24-00568","article-title":"PI3K\/AKT signaling and neuroprotection in ischemic stroke: Molecular mechanisms and therapeutic perspectives","volume":"20","author":"Liu","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1124\/pr.57.2.4","article-title":"The blood-brain barrier\/neurovascular unit in health and disease","volume":"57","author":"Hawkins","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.neuint.2018.01.008","article-title":"S-oxiracetam ameliorates ischemic stroke induced neuronal apoptosis through up-regulating \u03b17 nAChR and PI3K\/Akt\/GSK3\u03b2 signal pathway in rats","volume":"115","author":"Fan","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2400685","DOI":"10.1002\/mnfr.202400685","article-title":"Tea Polyphenols Reduced Obesity by Modulating Gut Microbiota-SCFAs-Barrier and Inflammation in High-Fat Diet-Induced Mice","volume":"68","author":"Tian","year":"2024","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1007\/s00394-022-02927-7","article-title":"Ferulic acid improves intestinal barrier function through altering gut microbiota composition in high-fat diet-induced mice","volume":"61","author":"Tian","year":"2022","journal-title":"Eur. J. Nutr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:44:23Z","timestamp":1760028263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052175"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052175","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,28]]}}}