Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
J Ethnopharmacol. 2024 Jun 12;327:118009. doi: 10.1016/j.jep.2024.118009. Epub 2024 Mar 4.
ETHNOPHARMACOLOGICAL RELEVANCE: According to traditional Chinese medicine (TCM) theory, cholestasis belongs to category of jaundice. Artemisia capillaris Thunb. has been widely used for the treatment of jaundice in TCM. The polysaccharides are the one of main active components of the herb, but its effects on cholestasis remain unclear. AIM OF THE STUDY: To investigate the protective effect and mechanism of Artemisia capillaris Thunb. polysaccharide (APS) on cholestasis and liver injury. MATERIALS AND METHODS: The amelioration of APS on cholestasis was evaluated in an alpha-naphthyl isothiocyanate (ANIT)-induced mice model. Then nuclear Nrf2 knockout mice, mass spectrometry, 16s rDNA sequencing, metabolomics, and molecular biotechnology methods were used to elucidate the associated mechanisms of APS against cholestatic liver injury. RESULTS: Treatment with low and high doses of APS markedly decreased cholestatic liver injury of mice. Mechanistically, APS promoted nuclear translocation of hepatic nuclear factor erythroid 2-related factor (Nrf2), upregulated downstream bile acid (BA) efflux transporters and detoxifying enzymes expression, improved BA homeostasis, and attenuated oxidative liver injury; however, these effects were annulled in Nrf2 knock-out mice. Furthermore, APS ameliorated the microbiota dysbiosis of cholestatic mice and selectively increased short-chain fatty acid (SCFA)-producing bacteria growth. Fecal microbiota transplantation of APS also promoted hepatic Nrf2 activation, increased BA efflux transporters and detoxifying enzymes expression, ameliorated intrahepatic BA accumulation and cholestatic liver injury. Non-targeted metabolomics and in vitro microbiota culture confirmed that APS significantly increased the production of a microbiota-derived SCFA (butyric acid), which is also able to upregulate Nrf2 expression. CONCLUSIONS: These findings indicate that APS can ameliorate cholestasis by modulating gut microbiota and activating the Nrf2 pathway, representing a novel therapeutic approach for cholestatic liver disease.
民族药理学相关性：根据中医理论，胆石症属于黄疸范畴。青蒿已广泛用于中医治疗黄疸。多糖是该草药的主要活性成分之一，但它对胆石症的作用尚不清楚。
研究目的：研究青蒿多糖（APS）对胆汁淤积和肝损伤的保护作用及其机制。
材料和方法：采用α-萘基异硫氰酸酯（ANIT）诱导的小鼠模型评价 APS 对胆汁淤积的改善作用。然后采用核 Nrf2 敲除小鼠、质谱、16s rDNA 测序、代谢组学和分子生物技术方法，阐明 APS 对抗胆汁淤积性肝损伤的相关机制。
结果：APS 低、高剂量治疗可显著减轻小鼠胆汁淤积性肝损伤。从机制上讲，APS 促进了肝核因子红细胞 2 相关因子（Nrf2）的核转位，上调了下游胆汁酸（BA）外排转运体和解毒酶的表达，改善了 BA 内稳态，减轻了氧化肝损伤；然而，这些作用在 Nrf2 敲除小鼠中被消除。此外，APS 改善了胆汁淤积小鼠的微生物失调，并选择性地增加了短链脂肪酸（SCFA）产生菌的生长。APS 的粪便微生物移植也促进了肝 Nrf2 的激活，增加了 BA 外排转运体和解毒酶的表达，改善了肝内 BA 积累和胆汁淤积性肝损伤。非靶向代谢组学和体外微生物培养证实，APS 可显著增加微生物衍生的 SCFA（丁酸）的产生，这也能上调 Nrf2 的表达。
结论：这些发现表明，APS 通过调节肠道微生物群和激活 Nrf2 通路来改善胆汁淤积，为胆汁淤积性肝病提供了一种新的治疗方法。
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