桑白皮总黄酮对大鼠急性肝损伤的保护作用

Protective effect of total flavonoids from Cortex Mori on acute liver injury in rats

摘要

目的 探讨桑白皮总黄酮（TFMB）通过拮抗UⅡ/UT系统、调控JAK2/STAT3信号通路防治急性肝损伤（ALI）的作用。方法 将大鼠随机分为对照组、ALI模型组、MgIG组、Urantide组、TFMB组。MgIG组和Urantide组分别静脉注射MgIG和Urantide,剂量为10 mg·kg^-1,TFMB组分别灌胃1.8、3.6、7.2 g·kg^-1;对照组和ALI模型组给予等量生理盐水,各组治疗周期均为连续14 d。结果 ALI模型组大鼠的病理表现为肝脏明显水肿、严重脂肪变性、肝窦扩张,EIF4EBP1、p-p70s6蛋白表达增高,同时UⅡ/UT系统及JAK2/STAT3通路被激活,p-JAK2、p-STAT3主要表达于损伤部位。用TFMB进行预防性干预后,与ALI模型组相比,肝脏病理症状明显减轻,p-p70s6、EIF4EBP1表达明显降低,UⅡ/UT系统及JAK2/STAT3通路激活状态被抑制。此外,在H₂O₂诱导的大鼠肝细胞（BRL3A）细胞模型中,TFMB对JAK2/STAT3通路也有抑制作用,起到抑制增殖的作用。结论 TFMB可能通过拮抗UⅡ/UT系统、调控JAK2/STAT3信号通路对CCl₄诱导的大鼠急性肝损伤起到防治作用。

Abstract

Objective To investigate the effect of total flavonoids from mulberry bark (TFMB) on acute liver injury (ALI) by antagonizing UⅡ/UT system and regulating JAK2/STAT3 signaling pathway. Methods Rats were randomly divided into control group, ALI model group, MgIG group, Urantide group and TFMB group. MgIG and Urantide were intravenously injected at a dose of 10 mg . kg^-1 in MgIG group and Urantide group, respectively. TFMB groups was gavaged with 1.8, 3.6 and 7.2 g . kg^-1, respectively; the control group and ALI model group were given the same amount of normal saline by gavage, and the treatment cycle of each group was continuous for 14 days. Results The ALI model of rats was reproduced with CCl₄, and the pathological manifestations were obvious liver edema, severe steatosis, hepatic Sinus Dilation, and the expression of EIF4EBP1 and p-p70s6 protein increased. At the same time, UⅡ/UT system and JAK2/STAT3 pathway were activated, and p-JAK2 and p-STAT3 were mainly expressed in the injured site. After preventive intervention with tfmb, compared with ALI model group, the pathological symptoms of liver were significantly reduced, the expression of p-P70s6 and EIF4EBP1 were significantly reduced, and the activation of UⅡ/UT system and JAK2/STAT3 pathway were inhibited. In addition, in the H₂O₂ induced rat hepatocyte (BRL3A) cell model, TFMB also inhibited JAK2/STAT3 pathway and proliferation. Conclusion TFMB may play a preventive and therapeutic role in CCl₄ induced acute liver injury in rats by antagonizing UⅡ/UT system and regulating JAK2/STAT3 signaling pathway.

关键词

急性肝损伤 / 桑白皮总黄酮 / UⅡ/UT系统 / JAK2/STAT3信号通路

Key words

acute liver injury / total flavonoids from mulberry bark / UⅡ/UT system / JAK2/STAT3 signaling pathway

[1] Asrani SK, Devarbhavi H, Eaton J, et al.Burden of liver diseases in the world[J]. J Hepatol, 2019, 70(1): 151-171.
[2] Crismale JF, Friedman SL.Acute Liver Injury and Decompensated Cirrhosis[J]. Med Clin North Am, 2020, 104(4): 647-662.
[3] Leifeld L, Clemens C, Heller J, et al.Expression of urotensin Ⅱ and its receptor in human liver cirrhosis and fulminant hepatic failure[J]. Dig Dis Sci, 2010, 55(5): 1458-1464.
[4] Liu DG, Wang J, Zhang ZT, et al.The urotension Ⅱ antagonist SB-710411 arrests fibrosis in CCL₄ cirrhotic rats[J]. Mol Med Rep, 2009, 2(6): 953-961.
[5] Kemp W, Kompa A, Phrommintikul A, et al.Urotensin Ⅱ modulates hepatifibrosis and portal hemodynamic alterations in rats[J]. Am J Physiol Gastrointest Liver Physiol, 2009, 297(4): G762-G767.
[6] Huang B, Lang X, Li X.The role of IL-6/JAK2/STAT3 signaling pathway in cancers[J]. Front Oncol, 2022, 12: 1023177.
[7] Zhang B, Wu W, Huang C, et al.Shuxie-1 decoction alleviated CUMS-induced liver injury via IL-6/JAK2/STAT3 signaling[J]. Front Pharmacol, 2022, 13:848355.
[8] Lai V, Neshat SY, Rakoski A, et al.Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity[J]. Adv Drug Deliv Rev, 2021, 179: 113920.
[9] Khan MA, Rahman AA, Islam S, et al.A comparative study on the antioxidant activity of methanolic extracts from different parts of Morus alba L[J]. BMC Res Notes, 2013, 6: 24.
[10] Li N, Du X, Qu T, et al.Pharmacodynamic material basis and pharmacological mechanisms of Cortex Mori against diabetes mellitus[J]. J Ethnopharmacol, 2024, 324: 117781.
[11] Singab AN, Ayoub NA, Ali EN, et al.Antioxidant and hepatoprotective activities of Egyptian moraceous plants against carbon tetrachloride-induced oxidative stress and liver damage in rats[J]. Pharm Biol, 2010, 48(11): 1255-1264.
[12] Shi Y, Zhong L, Chen K, et al.Sanguinarine attenuates hydrogen peroxide-induced toxicity in liver of Monopterus albus: Role of oxidative stress, inflammation and apoptosis[J]. Fish Shellfish Immunol, 2022, 125: 190-199.
[13] Sidransky H.Ethanol and liver injury: aspects relating to hepatic protein synthesis[J]. Rev Environ Health, 1987, 7: 81-120.
[14] Cai C, Ma H, Peng J, et al.USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice[J]. Nat Commun, 2023, 14(1): 3648.
[15] Yu SW, Chen Z.Research progress of acute liver injury model and signalpathway[J]. J Pharm Res (Pharmaceutical Research), 2019, 33(1): 49-52.
[16] Ciftel S, Suleyman B, Mammadov R, et al.Adverse effects of metamizole onheart, lung, liver, kidney, and stomach in rats[J]. BMC Pharmacol Toxicol, 2024, 25(1): 55.
[17] 蒋伟业,王舜禹,周雨静,等. 棕榈油酸防治非酒精性脂肪性肝病的研究进展[J]. 江苏大学学报(医学版),2025,35(3):212-216.
[18] 田辉,寇娟. 桑白皮的炮制历史沿革、药理作用及临床应用研究进展[J]. 江苏中医药,2025,57(2):81-84.
[19] 李蕊,曾扬,张葵. 桑白皮的药理作用及其治疗老年病的临床应用[J]. 老年医学与保健,2021,27(6):1339-1342.
[20] 谭金枚,郭爱莉,戚本玲,等. 基于IGF-1R/β-catenin信号通路探讨桑白皮总黄酮对2型糖尿病大鼠肾损伤的保护作用[J]. 中国老年学杂志,2025,45(8):2013-2017.
[21] 黎玉华,温金华,周健,等. 桑皮苷的药理作用研究进展[J]. 中国药理学通报,2018,34(6):749-752.
[22] 蒋海生,王佳丽. 桑白皮的药理作用及临床应用研究进展[J]. 中药与临床,2021,12(2):79-82.
[23] Park HJ, Park SH.Root Bark of Morus Alba L. Induced p53-Independent Apoptosis in Human Colorectal Cancer Cells by Suppression of STAT3 Activity[J]. Nutr Cancer, 2022, 74(5): 1837-1848.

基金资助

河北省自然科学基金中医药联合基金重点项目（H2023406017）; 河北省自然科学基金（H2020406011）; 河北省教育厅高校重点学科建设项目（冀教高〔2013〕4号）; 河北省高等学校科学研究青年基金（QN2024116）; 承德医学院基本科研业务费（KY202227）; 承德医学院学科建设经费