Kinsenoside Alleviates Alcoholic Liver Injury by Reducing Oxidative Stress, Inhibiting Endoplasmic Reticulum Stress, and Regulating AMPK-Dependent Autophagy.
Kinsenoside Alleviates Alcoholic Liver Injury by Reducing Oxidative Stress, Inhibiting Endoplasmic Reticulum Stress, and Regulating AMPK-Dependent Autophagy.
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DOI：
10.3389/fphar.2021.747325
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Gao L;Chen X;Fu Z;Yin J;Wang Y;Sun W;Ren H;Zhang Y
背景：金线莲（兰科）是一种传统中药材，具有抗炎、降血脂、保肝、免疫调节等药理活性。 Kinsenoside (KD) 是从金线莲中提取的活性成分，对多种类型的肝损伤具有保护作用。然而，KD 对酒精性肝病 (ALD) 的肝脏保护作用和潜在机制仍不清楚。本研究旨在探讨 KD 对 ALD 的肝脏保护活性及其潜在机制。 方法：采用AML12正常小鼠肝细胞，检测KD对乙醇诱导的细胞损伤的保护作用。通过给雄性 C57BL/6J 小鼠喂食含乙醇的流质饲料，并结合腹腔注射 5% 四氯化碳 (CCl4) 橄榄油溶液，诱导酒精性肝损伤模型。将小鼠分为对照组、模型组、水飞蓟素组（阳性对照）和两个KD组，接受不同剂量的治疗。治疗后，对肝组织进行苏木精-伊红和马森三色染色，并测定血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，以评估川芎嗪对酒精性肝损伤的保护作用。此外，利用蛋白质组学技术探讨KD作用的潜在机制，并利用ELISA测定、免疫组织化学、TUNEL测定和蛋白质印迹来验证其机制。 结果：结果显示 KD 浓度依赖性地减少 AML12 细胞中乙醇诱导的脂质积累。在ALD小鼠模型中，肝组织的组织学检查，结合ALT和AST血清水平的测定，证明了KD对酒精性肝损伤小鼠的保护作用。此外，与模型组相比，KD治疗显着增强了抗氧化能力，并减少了内质网（ER）应激、炎症和细胞凋亡。此外，KD 增加了 AMP 激活蛋白激酶（AMPK）的磷酸化水平，抑制雷帕霉素的机制靶点，促进 ULK1（Ser555）的磷酸化，增加自噬标记物 LC3A/B 的水平，并恢复乙醇抑制的自噬流，从而激活 AMPK 依赖性自噬。 结论：本研究表明，KD 通过减少氧化应激和 ER 应激，同时激活 AMPK 依赖性自噬来减轻酒精性肝损伤。所有结果表明 KD 可能是 ALD 的潜在治疗剂。
Background: Anoectochilus roxburghii (Orchidaceae) is a traditional Chinese medicinal herb with anti-inflammatory, antilipemic, liver protective, immunomodulatory, and other pharmacological activities. Kinsenoside (KD), which shows protective effects against a variety types of liver damage, is an active ingredient extracted from A. roxburghii. However, the liver protective effects and potential mechanisms of KD in alcoholic liver disease (ALD) remain unclear. This study aimed to investigate the liver protective activity and potential mechanisms of KD in ALD. Methods: AML12 normal mouse hepatocyte cells were used to detect the protective effect of KD against ethanol-induced cell damage. An alcoholic liver injury model was induced by feeding male C57BL/6J mice with an ethanol-containing liquid diet, in combination with intraperitoneal administration of 5% carbon tetrachloride (CCl4) in olive oil. Mice were divided into control, model, silymarin (positive control), and two KD groups, treated with different doses. After treatment, hematoxylin–eosin and Masson’s trichrome staining of liver tissues was performed, and serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were determined to assess the protective effect of KD against alcoholic liver injury. Moreover, proteomics techniques were used to explore the potential mechanism of KD action, and ELISA assay, immunohistochemistry, TUNEL assay, and western blotting were used to verify the mechanism. Results: The results showed that KD concentration-dependently reduced ethanol-induced lipid accumulation in AML12 cells. In ALD mice model, the histological examination of liver tissues, combined with the determination of ALT and AST serum levels, demonstrated a protective effect of KD in the alcoholic liver injury mice. In addition, KD treatment markedly enhanced the antioxidant capacity and reduced the endoplasmic reticulum (ER) stress, inflammation, and apoptosis compared with those in the model group. Furthermore, KD increased the phosphorylation level of AMP-activated protein kinase (AMPK), inhibited the mechanistic target of rapamycin, promoted the phosphorylation of ULK1 (Ser555), increased the level of the autophagy marker LC3A/B, and restored ethanol-suppressed autophagic flux, thus activating AMPK-dependent autophagy. Conclusion: This study indicates that KD alleviates alcoholic liver injury by reducing oxidative stress and ER stress, while activating AMPK-dependent autophagy. All results suggested that KD may be a potential therapeutic agent for ALD.
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影响因子：
7.4
作者：
Abdelmegeed, Mohamed A.;Banerjee, Atrayee;Jang, Sehwan;Yoo, Seong-Ho;Yun, Jun-Won;Gonzalez, Frank J.;Keshavarzian, Ali;Song, Byoung-Joon
通讯作者：
Song, Byoung-Joon
DOI：
10.3390/molecules22020191
发表时间：
2017-01-24
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Federico A;Dallio M;Loguercio C
通讯作者：
Loguercio C
影响因子：
3
作者：
Ji C
通讯作者：
Ji C
酒精性肝病：发病机制和新的治疗靶点。
影响因子：
29.4
作者：
Gao B;Bataller R
通讯作者：
Bataller R
影响因子：
13.5
作者：
Dara, Lily;Ji, Cheng;Kaplowitz, Neil
通讯作者：
Kaplowitz, Neil