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Archive > Volume 16 Issue 4 > 2024,16(4):667-678. DOI:https://doi.org/10.1016/j.chmed.2023.12.006 Prev Next

旋覆花通過調(diào)節(jié)SIRT1-AMPK/Nrf2/NF-κB信號通路改善酒精性肝損傷

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Inula britannica ameliorates alcohol-induced liver injury by modulating SIRT1-AMPK/Nrf2/NF-jB signaling pathway

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    摘要:
    目的：旋覆花是一種傳統(tǒng)的中藥和功能食品，具有抗肝損傷、降血糖、抗氧化、抗腫瘤等多種功效。本研究旨在探討旋覆花乙醇提取物對小鼠酒精性肝損傷的保護(hù)作用及機(jī)制。 方法：將56只雌性C57BL/6小鼠隨機(jī)分為7組：對照組（Con）、乙醇喂養(yǎng)模型組（EtOH）、水飛薊素陽性治療組（EtOH + Silibinin 100 mg/kg）、旋覆花乙醇提取物（EEIB）治療組（EtOH + EEIB 100、200和400 mg/kg）和EEIB對照組（EEIB 400 mg/kg）。采用美國國家酒精濫用和酒精中毒研究所（NIAAA）的乙醇喂養(yǎng)模型，通過組織病理學(xué)評估、免疫熒光染色、蛋白印跡分析和分子對接等方法，研究EEIB對酒精誘導(dǎo)的小鼠肝臟的脂質(zhì)代謝、炎癥、氧化應(yīng)激和纖維化的影響。 結(jié)果：EEIB可不同程度地降低小鼠肝臟指數(shù)至正常水平，并改善肝臟形態(tài)。EEIB通過激活酒精喂養(yǎng)小鼠肝臟中的沉默信息調(diào)節(jié)因子蛋白1(SIRT1)-腺苷酸活化蛋白激酶(AMPK)信號通路來抑制酒精誘導(dǎo)的肝損傷，倍半萜類化合物可能是其中的潛在活性成分。同時，EEIB下調(diào)α-平滑肌肌動蛋白(α-SMA)、膠原蛋白 Ⅰ(Collagen Ⅰ)、腫瘤壞死因子α(TNF-α)的表達(dá)減輕酒精誘導(dǎo)的肝損傷。此外，EEIB還能激活Nrf2信號通路，在氧化應(yīng)激水平上減輕酒精誘導(dǎo)的肝損傷。值得注意的是，EEIB對照組證明了EEIB對小鼠無毒性作用。EEIB以劑量依賴的方式減輕酒精性肝損傷，當(dāng)EEIB的劑量為400 mg/kg時，其治療效果與Silibinin相當(dāng)，甚至更好。 結(jié)論：EEIB對酒精誘導(dǎo)的小鼠肝損傷有明顯的治療效果，其作用機(jī)制與 SIRT1-AMPK、核轉(zhuǎn)錄因子κB(NF-κB)和核因子E2相關(guān)因子2(Nrf2)信號通路有關(guān)，倍半萜可能是其中的潛在活性成分。

    Abstract:
    Objective: Inula britannica is a traditional Chinese medicinal and functional food with various effects such as anti-liver injury, hypoglycemia, antioxidants, and anti-tumor. The aim of this study was to investigate the protective effects and mechanisms of the ethanolic extract of I. britannica (EEIB) on alcohol-induced liver injury in mice. Methods: Fifty-six female C57BL/6 mice were randomly divided into seven groups: control group (Con), ethanol feeding model group (EtOH), Silibinin positive treatment group (EtOH + Silibinin 100 mg/kg), EEIB treatment group (EtOH + EEIB 100, 200, and 400 mg/kg), and EEIB control group (EEIB 400 mg/kg). The National Institute on Alcohol Abuse and Alcoholism (NIAAA) ethanol-feeding model was used to study the effects of EEIB on alcohol-induced lipid metabolism, inflammation, oxidative stress, and fibril formation in mice by histopathological evaluation, immunofluorescence staining, Western blotting analysis and molecular docking. Results: EEIB reduced liver indices to different degrees to normal levels and improved liver morphology in mice. EEIB inhibited alcohol-induced liver injury by activating the sirtuin 1 (SIRT1)-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in the liver of alcohol-fed mice, in which sesquiterpenes may be the potential active ingredients, and also down-regulated the expression of alpha-smooth muscle actin (a-SMA), collagen alpha (Collagen I), tumor necrosis factor-alpha (TNFa) and attenuated alcohol-induced liver injury. In addition, EEIB also activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which alleviated alcohol-induced liver injury at the level of oxidative stress. Notably, the EEIB control group demonstrated that EEIB had no toxic effects in mice. EEIB reduced alcoholic liver injury in a dose-dependent manner. Its therapeutic efficacy was comparable to, if not better than, that of Silibinin when administered at a dose of 400 mg/kg. Conclusion: EEIB showed significant therapeutic effects on alcohol-induced liver injury in mice, and its mechanism of action was related to the SIRT1-AMPK, nuclear factor-kappa B (NF-jB), and Nrf2 signaling pathways, in which sesquiterpenes may be the potential active ingredients.

    關(guān)鍵詞:
    酒精性肝損傷;炎癥;旋覆花;倍半萜;SIRT1-AMPK/Nrf2

    Keywords:


    Project Supported:
    This work was supported by the National Natural Science Foundation of China (grant No. 81703389), Natural Science Foundation of Science and Technology Department of Liaoning Province (No. 2021-MS-215), and Youth Development Support Plan of Shenyang Pharmaceutical University (No. ZQN2021010).

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