a School of Traditional Chinese Materia Medica , Shenyang Pharmaceutical University , Shenyang , China.
b Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development , Shenyang Pharmaceutical University , Shenyang , China.
Free Radic Res. 2019 Jun;53(6):655-668. doi: 10.1080/10715762.2019.1620937. Epub 2019 Jun 11.
Oxidative stress accompanying excessive accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction leads to the occurrence of neurodegenerative diseases. Our previous study showed that Eclalbasaponin I (EcI), a triterpene saponin isolated from (Miq.) Seem. (), repressed oxidative stress in human neuroblastoma SH-SY5Y cells. However, the detailed mechanism remains unclear. In this study, pretreatment with EcI in SH-SY5Y cells significantly activated the p38-mitogenactivated protein kinase (p38), the extracellular regulated protein kinase (ERK), whereas it did not affect the c-jun NH2 terminal kinases (JNK). In accordance with the initial findings, EcI-induced neuroprotective effect was attenuated by SB203580 (SB, a p38 inhibitor) or FR180204 (FR, an ERK inhibitor), being further confirmed by specific small interfering RNA (siRNA). Inhibition of either p38 or ERK up-regulated the apoptosis induction in EcI- and HO-cotreated cells. Furthermore, p38 or ERK suppression enhanced intracellular and mitochondrial ROS generation, decreased the activities of endogenous antioxidant defences as well as the mitochondrial membrane potential (MMP), resulting in dysfunction of mitochondria. In addition, EcI-induced autophagy and mitophagy were obviously down-regulated when p38 or ERK activation was blocked. Cumulatively, these findings supported that EcI-caused mitophagy contributed to the neuroprotective effect through p38 or ERK activation. Mitophagy induction might be an effective therapeutic intervention in neurodegenerative diseases.
氧化应激伴随着活性氧（ROS）的过度积累和线粒体功能障碍，导致神经退行性疾病的发生。我们之前的研究表明，从 （Miq.）Seem.（）中分离出的三萜皂苷 Eclalbasaponin I（EcI）抑制人神经母细胞瘤 SH-SY5Y 细胞中的氧化应激。然而，其详细机制尚不清楚。在这项研究中，EcI 在 SH-SY5Y 细胞中的预处理显著激活了 p38-丝裂原激活蛋白激酶（p38）和细胞外调节蛋白激酶（ERK），而不影响 c-jun NH2 末端激酶（JNK）。与最初的发现一致，EcI 诱导的神经保护作用被 SB203580（SB，p38 抑制剂）或 FR180204（FR，ERK 抑制剂）减弱，这进一步被特异性小干扰 RNA（siRNA）所证实。抑制 p38 或 ERK 会增加 EcI 和 HO-共同处理细胞中的细胞凋亡诱导。此外，p38 或 ERK 的抑制会增强细胞内和线粒体中的 ROS 生成，降低内源性抗氧化防御的活性以及线粒体膜电位（MMP），导致线粒体功能障碍。此外，当阻断 p38 或 ERK 的激活时，EcI 诱导的自噬和线粒体自噬明显下调。总之，这些发现支持了 EcI 引起的线粒体自噬通过激活 p38 或 ERK 来发挥神经保护作用。线粒体自噬的诱导可能是神经退行性疾病的一种有效治疗干预措施。
