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Archive > Volume 17 Issue 2 > 2025,17(2):392-403. DOI:https://doi.org/10.1016/j.chmed.2024.11.002 Prev Next

SULT1E1過(guò)表達(dá)可減輕鹽補(bǔ)骨脂所致的膽汁淤積性肝損傷

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Overexpression of SULT1E1 alleviates salt-processed Psoraleae Fructus-induced cholestatic liver damage

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    摘要:
    目的：臨床上補(bǔ)骨脂長(zhǎng)期使用可發(fā)生膽汁淤積性肝毒性。本研究結(jié)合網(wǎng)絡(luò)藥理學(xué)分析補(bǔ)骨脂致膽汁淤積性肝損害的機(jī)制。為了驗(yàn)證硫轉(zhuǎn)移酶家族成員1 （SULT1E1）是補(bǔ)骨脂致膽汁淤積性肝損傷中的關(guān)鍵靶點(diǎn)，我們構(gòu)建了過(guò)表達(dá)SULT1E1的腺相關(guān)病毒（rAAV8-SULT1E1），并研究了補(bǔ)骨脂組、補(bǔ)骨脂素組和異補(bǔ)骨脂素組的肝毒性。方法：將腺病毒載體通過(guò)尾靜脈注射到C57BL6小鼠體內(nèi)，補(bǔ)骨脂 （10 g/kg）、補(bǔ)骨脂素和異補(bǔ)骨脂素（各50 mg/kg）灌胃小鼠30 d，觀察SULT1E1過(guò)表達(dá)在補(bǔ)骨脂致膽汁淤積性肝毒性中的作用。結(jié)果：網(wǎng)絡(luò)藥理學(xué)預(yù)測(cè)補(bǔ)骨脂45種化學(xué)成分共有854個(gè)靶點(diǎn)，并獲得了151個(gè)膽汁積淤積肝毒性相關(guān)疾病靶點(diǎn)。通過(guò)KEGG通路分析，共富集了126條通路，其中“雌激素信號(hào)通路”位列前20條通路之一。在肝臟病理方面，補(bǔ)骨脂組肝組織細(xì)胞明顯腫脹，膽管擴(kuò)張，血清肝損生化指標(biāo)升高，異補(bǔ)骨脂素組比其他組肝損傷更為突出。值得注意的是，SULT1E1的過(guò)表達(dá)可以逆轉(zhuǎn)肝損傷。B超觀察活體膽囊大小實(shí)驗(yàn)發(fā)現(xiàn)，補(bǔ)骨脂組、補(bǔ)骨脂素組和異補(bǔ)骨脂素組，在給藥第30天后膽囊大小顯著增加。WB實(shí)驗(yàn)顯示，與陰性對(duì)照組（rAAV8-empty+con）相比，給藥各組FXR、Mrp2、Bsep、SULT1E1、SULT2A1、Ntcp和Nrf2的表達(dá)水平下降，而CYP7a1和IL-6的表達(dá)水平在補(bǔ)骨脂組、補(bǔ)骨脂素組和異補(bǔ)骨脂素組升高。結(jié)論：過(guò)表達(dá)SULT1E1可緩解補(bǔ)骨脂致膽汁淤積性肝損傷，提示SULT1E1是補(bǔ)骨脂膽汁淤積性肝損傷的重要靶基因。

    Abstract:
    Objective: Salt-processed Psoraleae Fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, due to improper clinical use or misuse, resulting in liver damage. In this study, network pharmacology was employed to analyze the mechanism of cholestatic liver damage. An adeno-associated virus overexpressing SULT1E1 (rAAV8-SULT1E1) was constructed and the hepatotoxicity of SPF, psoralen, and isopsoralen was determined. Methods: By utilizing three databases inclding TCMSP, TCMID, and BATMAN- TCM, the targets of the three databases were summarized, and a total of 45 psoralen compounds were included. Network pharmacology analysis was then performed. The adenoviral vectors were injected into the tail vein of C57BL6 mice to elucidate the role of SULT1E1 in SPF-induced cholestasis-mediated hepatotoxicity in vivo. SPF (10 g/kg), psoralen, and isopsoralen (50 mg/kg each) were intragastrically administered to mice for 30 d. B-ultrasound and samples were collected and examined for follow-up experiments. Results: A total of 854 targets were predicted for 45 active components, with 151 cholestasis-mediated hepatotoxicity-related disease targets obtained for SPF. A total of 126 pathways were enriched based on KEGG pathway analysis, with the ‘‘estrogen signaling pathway” identified as one of the top 20 pathways. In terms of pathological hepatic changes, treated mice had visually swollen hepatocytes, dilated bile ducts, and elevated serum biochemical markers, which were more prominent in mice treated with isopsoralen than in those treated with other compounds. Notably, the overexpression of SULT1E1 could reverse liver damage in each treatment group. B-ultrasound was used to observe the size of the gallbladder in vivo. The size of the gallbladder was found to significantly increase on day 30 after treatment in the SPF-, psoralen-, and isopsoralen-treated groups, especially the SPF group. Compared with the expression levels in the negative control group (rAAV8-empty + con), the expression levels of FXR, Mrp2, Bsep, SULT1E1, SULT2A1, Ntcp, and Nrf2 decreased, whereas those of CYP7a1 and IL-6 increased in the SPF-, psoralen-, and isopsoralen-treated groups. Conclusion: The overexpression of SULT1E1 could alleviate the decreased or increased expression of indicators, indicating that SULT1E1 is an important target gene for SPF-induced liver damage. The severity of liver damage was significantly lower in the rAAV8 SULT1E1 groups than in the rAAV8-empty groups.

    關(guān)鍵詞:
    膽汁淤積性肝損害;FXR-SULT1E1信號(hào);補(bǔ)骨脂素;異補(bǔ)骨脂素;rAAV8-SULT1E1;鹽補(bǔ)骨脂

    Keywords:


    Project Supported:
    This work was supported by the National Natural Science Foundation of China (81973484 and 82304736) and the 2022 Natural Science Foundation of Nanjing University of Chinese Medicine (XZR2021085).

    Clc Number:

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