Astragaloside IV and cycloastragenol promote liver regeneration through regulation of hepatic oxidative homeostasis and glucose/lipid metabolism

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2024-10-20 DOI:10.1016/j.phymed.2024.156165
Yanghao Li , Xu Yang , Xiang Li , Shaodong Wang , Peng Chen , Tonghui Ma , Bo Zhang
{"title":"Astragaloside IV and cycloastragenol promote liver regeneration through regulation of hepatic oxidative homeostasis and glucose/lipid metabolism","authors":"Yanghao Li ,&nbsp;Xu Yang ,&nbsp;Xiang Li ,&nbsp;Shaodong Wang ,&nbsp;Peng Chen ,&nbsp;Tonghui Ma ,&nbsp;Bo Zhang","doi":"10.1016/j.phymed.2024.156165","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>The regenerative capacity of the liver is pivotal for mitigating various forms of liver injury and requires the rapid proliferation of hepatocytes. Aquaporin-9 (AQP9) provides vital support for hepatocyte proliferation by preserving hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) oxidative balance and glucose/lipid metabolism equilibrium within hepatocytes. Our previous study demonstrated that Radix Astragali (RA) decoction promotes liver regeneration by upregulating hepatic expression of AQP9, possibly via two major active constituents: astragaloside IV (AS-IV) and cycloastragenol (CAG).</div></div><div><h3>Purpose</h3><div>To verify that upregulated AQP9 expression in hepatocytes maintains liver oxidative balance and glucose/lipid metabolism homeostasis, and is the main pharmacological mechanism by which AS-IV and CAG promote liver regeneration.</div></div><div><h3>Study Design/Methods</h3><div>Effects of AS-IV and CAG on liver regeneration were scrutinized using a mouse model of 70 % partial hepatectomy (PHx). AQP9-targeted liver regeneration mediated by AS-IV and CAG was verified using AQP9 gene knockout mice (AQP9<sup>−/−</sup>). The AQP9 protein expression pattern in hepatocytes was determined using tdTomato-tagged AQP9 transgenic mice (AQP9-RFP). Potential mechanisms of AS-IV and CAG on liver regeneration were studied using real-time quantitative PCR, immunoblotting, staining with hematoxylin and eosin, oil red O, and periodic acid-Schiff, and immunofluorescence, immunohistochemistry, HyPerRed fluorescence, and biochemical analyses.</div></div><div><h3>Results</h3><div>AS-IV and CAG promoted substantial liver regeneration and increased hepatic AQP9 expression in wild-type mice (AQP9<sup>+/+</sup>) following 70 % PHx, but had no discernible benefits in AQP9<sup>−/-</sup> mice. Both saponin compounds also helped maintain oxidative homeostasis by reducing levels of oxidative stress markers (reactive oxygen species [ROS], H<sub>2</sub>O<sub>2</sub>, and malondialdehyde) and elevating levels of ROS scavengers (glutathione and superoxide dismutase) in AQP9<sup>+/+</sup> mice post-70 % PHx. This further activated the PI3K-AKT and insulin signaling pathways, thereby fostering liver regeneration. Furthermore, AS-IV and CAG both promoted hepatocyte glycerol uptake, increased gluconeogenesis, facilitated lipolysis, reduced glycolysis, and inhibited glycogen deposition, thus ensuring the energy supply required for liver regeneration.</div></div><div><h3>Conclusion</h3><div>This research is the first to demonstrate AS-IV and CAG as major active ingredients of RA that promote liver regeneration by upregulating hepatocyte AQP9 expression, improving hepatocyte glucose/lipid metabolism, and reducing oxidative stress damage, constituting a crucial pharmacological mechanism underlying the liver-protective effects of RA. The augmentation of hepatocyte AQP9 expression underscores an important aspect of the Qi-tonifying effect of RA. This study establishes AQP9 as an effective target for regulation of liver regeneration and provides a universal strategy for clinical drug intervention aimed at enhancing liver regeneration.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711324008225","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Background

The regenerative capacity of the liver is pivotal for mitigating various forms of liver injury and requires the rapid proliferation of hepatocytes. Aquaporin-9 (AQP9) provides vital support for hepatocyte proliferation by preserving hydrogen peroxide (H2O2) oxidative balance and glucose/lipid metabolism equilibrium within hepatocytes. Our previous study demonstrated that Radix Astragali (RA) decoction promotes liver regeneration by upregulating hepatic expression of AQP9, possibly via two major active constituents: astragaloside IV (AS-IV) and cycloastragenol (CAG).

Purpose

To verify that upregulated AQP9 expression in hepatocytes maintains liver oxidative balance and glucose/lipid metabolism homeostasis, and is the main pharmacological mechanism by which AS-IV and CAG promote liver regeneration.

Study Design/Methods

Effects of AS-IV and CAG on liver regeneration were scrutinized using a mouse model of 70 % partial hepatectomy (PHx). AQP9-targeted liver regeneration mediated by AS-IV and CAG was verified using AQP9 gene knockout mice (AQP9−/−). The AQP9 protein expression pattern in hepatocytes was determined using tdTomato-tagged AQP9 transgenic mice (AQP9-RFP). Potential mechanisms of AS-IV and CAG on liver regeneration were studied using real-time quantitative PCR, immunoblotting, staining with hematoxylin and eosin, oil red O, and periodic acid-Schiff, and immunofluorescence, immunohistochemistry, HyPerRed fluorescence, and biochemical analyses.

Results

AS-IV and CAG promoted substantial liver regeneration and increased hepatic AQP9 expression in wild-type mice (AQP9+/+) following 70 % PHx, but had no discernible benefits in AQP9−/- mice. Both saponin compounds also helped maintain oxidative homeostasis by reducing levels of oxidative stress markers (reactive oxygen species [ROS], H2O2, and malondialdehyde) and elevating levels of ROS scavengers (glutathione and superoxide dismutase) in AQP9+/+ mice post-70 % PHx. This further activated the PI3K-AKT and insulin signaling pathways, thereby fostering liver regeneration. Furthermore, AS-IV and CAG both promoted hepatocyte glycerol uptake, increased gluconeogenesis, facilitated lipolysis, reduced glycolysis, and inhibited glycogen deposition, thus ensuring the energy supply required for liver regeneration.

Conclusion

This research is the first to demonstrate AS-IV and CAG as major active ingredients of RA that promote liver regeneration by upregulating hepatocyte AQP9 expression, improving hepatocyte glucose/lipid metabolism, and reducing oxidative stress damage, constituting a crucial pharmacological mechanism underlying the liver-protective effects of RA. The augmentation of hepatocyte AQP9 expression underscores an important aspect of the Qi-tonifying effect of RA. This study establishes AQP9 as an effective target for regulation of liver regeneration and provides a universal strategy for clinical drug intervention aimed at enhancing liver regeneration.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
黄芪皂苷 IV 和环黄芪醇通过调节肝脏氧化平衡和葡萄糖/脂质代谢促进肝脏再生。
背景:肝脏的再生能力对于减轻各种形式的肝损伤至关重要,并且需要肝细胞的快速增殖。水传导蛋白-9(AQP9)通过维持肝细胞内过氧化氢(H2O2)氧化平衡和葡萄糖/脂质代谢平衡,为肝细胞增殖提供重要支持。我们之前的研究表明,黄芪水煎剂通过上调肝脏中 AQP9 的表达促进肝脏再生,这可能是通过两种主要活性成分:黄芪皂苷 IV(AS-IV)和环黄芪醇(CAG)实现的。目的:验证上调肝细胞中 AQP9 的表达维持肝脏氧化平衡和糖/脂代谢平衡,是 AS-IV 和 CAG 促进肝脏再生的主要药理机制:研究设计/方法:利用小鼠70%肝部分切除术(PHx)模型仔细研究了AS-IV和CAG对肝再生的影响。利用AQP9基因敲除小鼠(AQP9-/-)验证了AS-IV和CAG介导的AQP9靶向肝再生作用。利用tdTomato标记的AQP9转基因小鼠(AQP9-RFP)确定了肝细胞中AQP9蛋白的表达模式。使用实时定量 PCR、免疫印迹、苏木精和伊红染色、油红 O、周期性酸-Schiff、免疫荧光、免疫组织化学、HyPerRed 荧光和生化分析等方法研究了 AS-IV 和 CAG 对肝脏再生的潜在机制:结果:AS-IV和CAG可促进野生型小鼠(AQP9+/+)肝脏再生,并增加肝脏AQP9的表达,但对AQP9-/-小鼠无明显益处。这两种皂苷化合物还通过降低氧化应激标志物(活性氧 [ROS]、H2O2 和丙二醛)的水平和提高 ROS 清除剂(谷胱甘肽和超氧化物歧化酶)的水平,帮助 70 % PHx 后的 AQP9+/+ 小鼠维持氧化平衡。这进一步激活了 PI3K-AKT 和胰岛素信号通路,从而促进了肝脏再生。此外,AS-IV和CAG都能促进肝细胞摄取甘油,增加糖元生成,促进脂肪分解,减少糖酵解,抑制糖原沉积,从而确保肝脏再生所需的能量供应:该研究首次证明了AS-IV和CAG是RA的主要活性成分,可通过上调肝细胞AQP9表达、改善肝细胞糖/脂代谢、减少氧化应激损伤来促进肝脏再生,是RA保肝作用的重要药理机制。肝细胞 AQP9 表达的增强强调了 RA 补气作用的一个重要方面。这项研究确定了 AQP9 是调节肝脏再生的有效靶点,并为旨在促进肝脏再生的临床药物干预提供了通用策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
期刊最新文献
Huangqi Jianzhong decoction improves gastric intestinal metaplasia in rats by regulating the gut‒thyroid axis Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism A stepwise integrated strategy to explore quality markers of Qishen Yiqi dripping pills against myocardial ischemia Echinacoside inhibits tumor immune evasion by downregulating inducible PD-L1 and reshaping tumor immune landscape in breast and colorectal cancer. Huangqi-Danshen decoction improves heart failure by regulating pericardial adipose tissue derived extracellular vesicular miR-27a-3p to activate AMPKα2 mediated mitophagy
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1