桑叶乙醇提取物通过诱导 2 型糖尿病中的自噬来保护胰岛细胞免于功能障碍和死亡。
Morus alba leaves ethanol extract protects pancreatic islet cells against dysfunction and death by inducing autophagy in type 2 diabetes.
机构信息
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
出版信息
Phytomedicine. 2021 Mar;83:153478. doi: 10.1016/j.phymed.2021.153478. Epub 2021 Jan 28.
BACKGROUND
Protection of pancreatic islet cells against dysfunction or death by regulating autophagy is considered to be an effective method for treatment of type 2 diabetes mellitus (T2DM). Morus alba leaves (mulberry leaves), a popular herbal medicine, have been used for prevention of T2DM since ancient times.
PURPOSE
This study aimed to clarify whether Morus alba leaves ethanol extract (MLE) could protect islet cells in vivo and in vitro by regulating autophagy in T2DM, and explore the possible mechanism of action.
METHODS
The main chemical constituents in MLE were analyzed by HPLC. The T2DM rat model was induced via high-fat diet combined with peritoneal injection of low-dose streptozotocin, and MLE was administered by oral gavage. Fasting blood glucose (FBG) and plasma insulin were measured, and homeostatic model assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR) were determined. The histomorphology of pancreas islets was evaluated by haematoxylin and eosin staining. In palmitic acid (PA)-stressed INS-1 rat insulinoma cells, cell viability was assayed by an MTT method. Expression of the autophagy-related proteins LC3 I/II, p62, p-AMPK and p-mTOR in islet tissues and INS-1 cells was evaluated by western blotting or immunohistochemistry analysis.
RESULTS
The four main chemical constituents in MLE were identified as chlorogenic acid, rutin, isoquercitrin and quercitrin. MLE ameliorated hyperglycemia, insulin resistance and dyslipidemia of T2DM rats with prominent therapeutic effect. Further study indicated that MLE observably improved islet function, alleviated islet injury of T2DM rats, and inhibited PA-induced INS-1 cell death. On the other hand, MLE significantly induced autophagy in islet cells both in vivo and in vitro, and autophagy inhibitors abolished its therapeutic effect on T2DM rats and protective effect on islet cells. Apart from this, MLE markedly activated the AMPK/mTOR pathway in INS-1 cells, and the AMPK inhibitor prevented the autophagy induction ability of MLE.
CONCLUSION
Together, MLE could protect islet cells against dysfunction and death by inducing AMPK/mTOR-mediated autophagy in T2DM, and these findings provide a new perspective for understanding the treatment mechanism of Morus alba leaves against T2DM.
背景
通过调节自噬来保护胰岛细胞功能障碍或免受死亡被认为是治疗 2 型糖尿病（T2DM）的有效方法。桑树叶（桑叶）作为一种常用的草药，自古以来就被用于预防 T2DM。
目的
本研究旨在阐明桑树叶乙醇提取物（MLE）是否通过调节 T2DM 中的自噬来保护体内和体外的胰岛细胞，并探讨其可能的作用机制。
方法
采用高效液相色谱法分析 MLE 的主要化学成分。通过高脂饮食联合小剂量链脲佐菌素腹腔注射诱导 T2DM 大鼠模型，通过灌胃给予 MLE。检测空腹血糖（FBG）和血浆胰岛素水平，并测定胰岛β细胞功能的稳态模型评估（HOMA-β）和胰岛素抵抗（HOMA-IR）。采用苏木精-伊红染色评估胰腺胰岛的组织形态。在棕榈酸（PA）应激的 INS-1 大鼠胰岛素瘤细胞中，通过 MTT 法测定细胞活力。采用 Western 印迹或免疫组化分析评估胰岛组织和 INS-1 细胞中自噬相关蛋白 LC3 I/II、p62、p-AMPK 和 p-mTOR 的表达。
结果
MLE 中的四种主要化学成分被鉴定为绿原酸、芦丁、异槲皮苷和槲皮苷。MLE 改善了 T2DM 大鼠的高血糖、胰岛素抵抗和血脂异常，具有显著的治疗作用。进一步的研究表明，MLE 显著改善了胰岛功能，减轻了 T2DM 大鼠的胰岛损伤，并抑制了 PA 诱导的 INS-1 细胞死亡。另一方面，MLE 体内、外均能显著诱导胰岛细胞自噬，自噬抑制剂消除了其对 T2DM 大鼠的治疗作用和对胰岛细胞的保护作用。此外，MLE 还显著激活了 INS-1 细胞中的 AMPK/mTOR 通路，而 AMPK 抑制剂则阻止了 MLE 诱导自噬的能力。
结论
MLE 可通过诱导 AMPK/mTOR 介导的自噬来保护 T2DM 中的胰岛细胞免受功能障碍和死亡，这为理解桑叶治疗 T2DM 的作用机制提供了新的视角。
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