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Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2022-09-11 , DOI: 10.2147/dddt.s378786 Jiangbo Xie 1, 2 , Tingting Zhang 3 , Peichun Li 3 , Dong Wang 2 , Tao Liu 2 , Shunliang Xu 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2022-09-11 , DOI: 10.2147/dddt.s378786 Jiangbo Xie 1, 2 , Tingting Zhang 3 , Peichun Li 3 , Dong Wang 2 , Tao Liu 2 , Shunliang Xu 1
Affiliation
Background: Dihydromyricetin (DHM) exerts protective effects in various brain diseases. The aim of this research was to investigate the biological role of DHM in cerebral ischemia reperfusion (I/R) injury.
Methods: We generated a rat model of cerebral I/R injury by performing middle cerebral artery occlusion/reperfusion (MCAO/R). The neurological score and brain water content of the experimental rats was then evaluated. The infarct volume and extent of apoptosis in brain tissues was then assessed by 2,3,5-triphenyltetrazolium (TTC) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Hippocampal neuronal cells (HT22) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) and cell counting kit-8 (CCK-8) assays and flow cytometry were performed to detect cell viability and apoptosis. The levels of lipid reactive oxygen species (ROS) and iron were detected and the expression levels of key proteins were assessed by Western blotting.
Results: DHM obviously reduced neurological deficits, brain water content, infarct volume and cell apoptosis in the brain tissues of MCAO/R rats. DHM repressed ferroptosis and inhibited the sphingosine kinase 1 (SPHK1)/mammalian target of rapamycin (mTOR) pathway in MCAO/R rats. In addition, DHM promoted cell viability and repressed apoptosis in OGD/R-treated HT22 cells. DHM also suppressed the levels of lipid ROS and intracellular iron in OGD/R-treated HT22 cells. The expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM. Moreover, the influence conferred by DHM was abrogated by the overexpression of SPHK1 or treatment with MHY1485 (an activator of mTOR).
Conclusion: This research demonstrated that DHM repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral I/R injury. Our findings suggest that DHM may be a candidate drug for cerebral I/R injury treatment.
Graphical Abstract:
中文翻译：
二氢杨梅素通过抑制 SPHK1/mTOR 信号传导和靶向铁死亡来减轻脑缺血再灌注损伤
背景：二氢杨梅素（DHM）在多种脑部疾病中发挥保护作用。本研究的目的是探讨 DHM 在脑缺血再灌注 (I/R) 损伤中的生物学作用。
方法：我们通过大脑中动脉闭塞/再灌注（MCAO/R）建立大鼠脑缺血再灌注损伤模型。然后评估实验大鼠的神经评分和脑含水量。然后通过 2,3,5-三苯基四唑 (TTC) 和 TdT 介导的 dUTP 缺口末端标记 (TUNEL) 染色评估脑组织中的梗死体积和凋亡程度。对海马神经元细胞 (HT22) 进行氧糖剥夺/再灌注 (OGD/R) 和细胞计数试剂盒 8 (CCK-8) 检测，并进行流式细胞术检测细胞活力和凋亡。检测脂质活性氧（ROS）和铁的水平，并通过蛋白质印迹评估关键蛋白的表达水平。
结果： DHM明显降低MCAO/R大鼠脑组织神经功能缺损、脑含水量、梗塞体积和细胞凋亡。DHM 可抑制 MCAO/R 大鼠的铁死亡并抑制鞘氨醇激酶 1 (SPHK1)/哺乳动物雷帕霉素靶蛋白 (mTOR) 通路。此外，DHM 促进 OGD/R 处理的 HT22 细胞的细胞活力并抑制细胞凋亡。DHM 还抑制 OGD/R 处理的 HT22 细胞中脂质 ROS 和细胞内铁的水平。在 OGD/R 处理的 HT22 细胞中，谷胱甘肽过氧化物酶 4 (GPX4) 的表达水平增强，而酰基辅酶 A 合成酶长链家族成员 4 (ACSL4) 和磷脂酰乙醇胺结合蛋白 1 (PEBP1) 的水平降低。 DHM 的。此外，DHM 赋予的影响被 SPHK1 的过表达或 MHY1485（mTOR 激活剂）处理所消除。
结论：本研究表明DHM通过抑制SPHK1/mTOR信号通路来抑制铁死亡，从而减轻脑I/R损伤。我们的研究结果表明 DHM 可能是治疗脑 I/R 损伤的候选药物。
图形概要：
更新日期：2022-09-10
Methods: We generated a rat model of cerebral I/R injury by performing middle cerebral artery occlusion/reperfusion (MCAO/R). The neurological score and brain water content of the experimental rats was then evaluated. The infarct volume and extent of apoptosis in brain tissues was then assessed by 2,3,5-triphenyltetrazolium (TTC) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Hippocampal neuronal cells (HT22) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) and cell counting kit-8 (CCK-8) assays and flow cytometry were performed to detect cell viability and apoptosis. The levels of lipid reactive oxygen species (ROS) and iron were detected and the expression levels of key proteins were assessed by Western blotting.
Results: DHM obviously reduced neurological deficits, brain water content, infarct volume and cell apoptosis in the brain tissues of MCAO/R rats. DHM repressed ferroptosis and inhibited the sphingosine kinase 1 (SPHK1)/mammalian target of rapamycin (mTOR) pathway in MCAO/R rats. In addition, DHM promoted cell viability and repressed apoptosis in OGD/R-treated HT22 cells. DHM also suppressed the levels of lipid ROS and intracellular iron in OGD/R-treated HT22 cells. The expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM. Moreover, the influence conferred by DHM was abrogated by the overexpression of SPHK1 or treatment with MHY1485 (an activator of mTOR).
Conclusion: This research demonstrated that DHM repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral I/R injury. Our findings suggest that DHM may be a candidate drug for cerebral I/R injury treatment.
Graphical Abstract:
中文翻译：
二氢杨梅素通过抑制 SPHK1/mTOR 信号传导和靶向铁死亡来减轻脑缺血再灌注损伤
背景：二氢杨梅素（DHM）在多种脑部疾病中发挥保护作用。本研究的目的是探讨 DHM 在脑缺血再灌注 (I/R) 损伤中的生物学作用。
方法：我们通过大脑中动脉闭塞/再灌注（MCAO/R）建立大鼠脑缺血再灌注损伤模型。然后评估实验大鼠的神经评分和脑含水量。然后通过 2,3,5-三苯基四唑 (TTC) 和 TdT 介导的 dUTP 缺口末端标记 (TUNEL) 染色评估脑组织中的梗死体积和凋亡程度。对海马神经元细胞 (HT22) 进行氧糖剥夺/再灌注 (OGD/R) 和细胞计数试剂盒 8 (CCK-8) 检测，并进行流式细胞术检测细胞活力和凋亡。检测脂质活性氧（ROS）和铁的水平，并通过蛋白质印迹评估关键蛋白的表达水平。
结果： DHM明显降低MCAO/R大鼠脑组织神经功能缺损、脑含水量、梗塞体积和细胞凋亡。DHM 可抑制 MCAO/R 大鼠的铁死亡并抑制鞘氨醇激酶 1 (SPHK1)/哺乳动物雷帕霉素靶蛋白 (mTOR) 通路。此外，DHM 促进 OGD/R 处理的 HT22 细胞的细胞活力并抑制细胞凋亡。DHM 还抑制 OGD/R 处理的 HT22 细胞中脂质 ROS 和细胞内铁的水平。在 OGD/R 处理的 HT22 细胞中，谷胱甘肽过氧化物酶 4 (GPX4) 的表达水平增强，而酰基辅酶 A 合成酶长链家族成员 4 (ACSL4) 和磷脂酰乙醇胺结合蛋白 1 (PEBP1) 的水平降低。 DHM 的。此外，DHM 赋予的影响被 SPHK1 的过表达或 MHY1485（mTOR 激活剂）处理所消除。
结论：本研究表明DHM通过抑制SPHK1/mTOR信号通路来抑制铁死亡，从而减轻脑I/R损伤。我们的研究结果表明 DHM 可能是治疗脑 I/R 损伤的候选药物。
图形概要：
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