Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke
IntroductionIschemic stroke is a leading cause of mortality and disability worldwide, with limited therapeutic options and high rates of recurrence. Mitochondrial dysfunction plays a critical role in neuronal injury during ischemia-reperfusion, making mitochondrial autophagy a potential therapeutic...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1600435/full |
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| author | Yonglei Liu Yonglei Liu Hongdie Mao Zhengguang Sha Jishuai Zhao Hui Cai Rong Xi Zhenzhu Zhao Xiaoling Yin Lin Yang Changyun Liu Changyun Liu |
| author_facet | Yonglei Liu Yonglei Liu Hongdie Mao Zhengguang Sha Jishuai Zhao Hui Cai Rong Xi Zhenzhu Zhao Xiaoling Yin Lin Yang Changyun Liu Changyun Liu |
| author_sort | Yonglei Liu |
| collection | DOAJ |
| description | IntroductionIschemic stroke is a leading cause of mortality and disability worldwide, with limited therapeutic options and high rates of recurrence. Mitochondrial dysfunction plays a critical role in neuronal injury during ischemia-reperfusion, making mitochondrial autophagy a potential therapeutic target. Gypenoside XLIX, a major active metabolite of Gynostemma pentaphyllum, exhibits antioxidant and organ-protective properties, but its effects on neuronal mitochondrial damage in stroke remain unclear. This study aimed to explore the neuroprotective mechanisms of Gypenoside XLIX in ischemic stroke, focusing on the PI3K/AKT/FOXO1 signaling pathway.MethodsNeuroprotective effects were evaluated in oxygen-glucose deprivation (OGD) neuronal cells and middle cerebral artery occlusion (MCAO) rat models. Cell viability, apoptosis, ROS production, mitochondrial membrane potential, and autophagic flux were assessed by CCK-8, flow cytometry, ELISA, TMRE staining, immunofluorescence, and Western blotting. Signaling pathway involvement was examined using PI3K inhibitor LY294002, AKT activator SC79, and FOXO1 knockdown.ResultsGypenoside XLIX significantly improved neuronal viability (p < 0.01), reduced apoptosis (p < 0.01), and decreased ROS levels (p < 0.001) in OGD cells. It enhanced p-PI3K and p-AKT expression while suppressing FOXO1 (p < 0.05), promoted Beclin-1, LC3, PINK1, and Parkin expression (p < 0.001), and reduced p62 (p < 0 .01). In MCAO rats, Gypenoside XLIX decreased infarct volume (p < 0.001), brain edema (p < 0.01), and TUNEL-positive cells (p < 0.001), while elevating mitochondrial membrane potential and antioxidant enzyme levels (SOD, GSH-Px, CAT; all p < 0.001).ConclusionGypenoside XLIX alleviates ischemic stroke injury by activating the PI3K/AKT/FOXO1 pathway, enhancing mitochondrial autophagy, and reducing oxidative stress, supporting its potential as a novel neuroprotective agent in stroke management. |
| format | Article |
| id | doaj-art-08a5483537ce4bd7badc68fb9921da06 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-08a5483537ce4bd7badc68fb9921da062025-08-21T05:27:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-08-011610.3389/fphar.2025.16004351600435Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic strokeYonglei Liu0Yonglei Liu1Hongdie Mao2Zhengguang Sha3Jishuai Zhao4Hui Cai5Rong Xi6Zhenzhu Zhao7Xiaoling Yin8Lin Yang9Changyun Liu10Changyun Liu11Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, The First Affiliated Hospital of Dali University, Dali, Yunnan, ChinaDepartment of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, ChinaInstitute of Clinical Neurology, Fujian Medical University, Fuzhou, Fujian, ChinaIntroductionIschemic stroke is a leading cause of mortality and disability worldwide, with limited therapeutic options and high rates of recurrence. Mitochondrial dysfunction plays a critical role in neuronal injury during ischemia-reperfusion, making mitochondrial autophagy a potential therapeutic target. Gypenoside XLIX, a major active metabolite of Gynostemma pentaphyllum, exhibits antioxidant and organ-protective properties, but its effects on neuronal mitochondrial damage in stroke remain unclear. This study aimed to explore the neuroprotective mechanisms of Gypenoside XLIX in ischemic stroke, focusing on the PI3K/AKT/FOXO1 signaling pathway.MethodsNeuroprotective effects were evaluated in oxygen-glucose deprivation (OGD) neuronal cells and middle cerebral artery occlusion (MCAO) rat models. Cell viability, apoptosis, ROS production, mitochondrial membrane potential, and autophagic flux were assessed by CCK-8, flow cytometry, ELISA, TMRE staining, immunofluorescence, and Western blotting. Signaling pathway involvement was examined using PI3K inhibitor LY294002, AKT activator SC79, and FOXO1 knockdown.ResultsGypenoside XLIX significantly improved neuronal viability (p < 0.01), reduced apoptosis (p < 0.01), and decreased ROS levels (p < 0.001) in OGD cells. It enhanced p-PI3K and p-AKT expression while suppressing FOXO1 (p < 0.05), promoted Beclin-1, LC3, PINK1, and Parkin expression (p < 0.001), and reduced p62 (p < 0 .01). In MCAO rats, Gypenoside XLIX decreased infarct volume (p < 0.001), brain edema (p < 0.01), and TUNEL-positive cells (p < 0.001), while elevating mitochondrial membrane potential and antioxidant enzyme levels (SOD, GSH-Px, CAT; all p < 0.001).ConclusionGypenoside XLIX alleviates ischemic stroke injury by activating the PI3K/AKT/FOXO1 pathway, enhancing mitochondrial autophagy, and reducing oxidative stress, supporting its potential as a novel neuroprotective agent in stroke management.https://www.frontiersin.org/articles/10.3389/fphar.2025.1600435/fullischemic strokegypenoside XLIXmitochondrial autophagyFoxO1PI3K/AKT |
| spellingShingle | Yonglei Liu Yonglei Liu Hongdie Mao Zhengguang Sha Jishuai Zhao Hui Cai Rong Xi Zhenzhu Zhao Xiaoling Yin Lin Yang Changyun Liu Changyun Liu Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke Frontiers in Pharmacology ischemic stroke gypenoside XLIX mitochondrial autophagy FoxO1 PI3K/AKT |
| title | Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| title_full | Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| title_fullStr | Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| title_full_unstemmed | Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| title_short | Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| title_sort | gypenoside xlix inhibiting pi3k akt foxo1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke |
| topic | ischemic stroke gypenoside XLIX mitochondrial autophagy FoxO1 PI3K/AKT |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1600435/full |
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