2-杰拉尔基-1-甲氧基赤藓霉素II通过AMPK激活和AKT抑制减轻肝细胞中的脂质积聚和炎症。

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Yiyuan Xi, Soeun Kim, Thi Thanh Thuy Nguyen, Phil Jun Lee, Jujia Zheng, Zhuofeng Lin, Namki Cho
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引用次数: 0

摘要

目前,全球越来越多的成人和儿童人群受到非酒精性脂肪性肝炎(NASH)的影响,导致在没有有效药物治疗的情况下肝纤维化和肝细胞癌的发病率上升。在这里,我们研究了从双色胡枝子中分离的2-香叶基-1-甲氧基赤藓霉素II(GMET)是否可以缓解NASH模型中的脂质积聚和炎症反应。GMET在体外和体内表现出强大的抗脂质积聚作用,并在没有细胞毒性的情况下减弱炎症反应。从机制上讲,GMET抑制乙酰辅酶A羧化酶(ACC)、甾醇调节元件结合蛋白-1c(SREBP1)和哺乳动物雷帕霉素靶点(mTOR),并通过激活AMP活化激酶(AMPK)激活PPARα,从而减缓脂质积聚。此外,GMET通过激活AMPK和抑制活化蛋白激酶B(AKT)/IκB激酶(IKK)途径来抑制NF-κB途径,从而抑制肝细胞的炎症反应。通过与AMPK抑制剂dorsomorphin共同治疗,GMET对体内外脂质积聚和炎症的所有这些保护作用基本上被消除。总之,在脂肪性肝炎中,GMET减轻了脂质积聚和炎症,以保持正常的肝细胞功能。因此,GMET是一种新的潜在的多靶向化合物,可以改善脂肪性肝炎。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition

2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition

A growing proportion of the global adult and pediatric populations are currently affected by nonalcoholic steatohepatitis (NASH), leading to rising rates of liver fibrosis and hepatocellular carcinoma without effective pharmacotherapy. Here, we investigated whether 2-geranyl-1-methoxyerythrabyssin II (GMET), isolated from Lespedeza bicolor, could alleviate lipid accumulation and inflammatory responses in a NASH model. GMET exhibited potent in vitro and in vivo effects against lipid accumulation and attenuated inflammatory responses without cytotoxicity. Mechanistically, GMET inhibits acetyl-CoA carboxylase (ACC), sterol regulatory element-binding proteins-1c (SREBP1), and mammalian target of rapamycin (mTOR), and activates PPARα by activating AMP-activated kinase (AMPK), leading to the alleviation of lipid accumulation. In addition, GMET suppresses the NF-κB pathway by activating AMPK and inhibiting the activated protein kinase B (AKT)/IκB-kinase (IKK) pathway, leading to the inhibition of the inflammatory response in hepatocytes. All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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