Mechanisms of Fufang Biejia Ruangan Pills Against Alcoholic Liver Disease via Regulating Liver-brain Dialogue Mediated by HMGB1-BDNF Axis

LIU Yudong; YAN Xiangying; LI Tao; ZHANG Chu; CAI Bingbing; MA Zhaochen; LIN Na; ZHANG Yanqiong

doi:10.13422/j.cnki.syfjx.20241638

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Mechanisms of Fufang Biejia Ruangan Pills Against Alcoholic Liver Disease via Regulating Liver-brain Dialogue Mediated by HMGB1-BDNF Axis

更新时间：2025-05-28

- Mechanisms of Fufang Biejia Ruangan Pills Against Alcoholic Liver Disease via Regulating Liver-brain Dialogue Mediated by HMGB1-BDNF Axis
  增强出版
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 30, Issue 23, Pages: 214-223(2024)
- 作者机构：
  
  1.中国中医科学院中药研究所，道地药材与品质保障全国重点实验室，北京 100700
  2.福建中医药大学药学院，福州 350122
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20241638
  CLC： R2-0;R33;R289;R256.4
- Received：10 July 2024，
  
  Online First：26 September 2024，
  
  Published：05 December 2024
- 稿件说明：
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刘毓东,闫向英,李涛等.从HMGB1-BDNF互作轴所介导的肝-脑对话探讨复方鳖甲软肝片干预酒精性肝病的作用机制[J].中国实验方剂学杂志,2024,30(23):214-223.

LIU Yudong,YAN Xiangying,LI Tao,et al.Mechanisms of Fufang Biejia Ruangan Pills Against Alcoholic Liver Disease via Regulating Liver-brain Dialogue Mediated by HMGB1-BDNF Axis[J].Chinese Journal of Experimental Traditional Medical Formulae,2024,30(23):214-223.
刘毓东,闫向英,李涛等.从HMGB1-BDNF互作轴所介导的肝-脑对话探讨复方鳖甲软肝片干预酒精性肝病的作用机制[J].中国实验方剂学杂志,2024,30(23):214-223. DOI： 10.13422/j.cnki.syfjx.20241638.

LIU Yudong,YAN Xiangying,LI Tao,et al.Mechanisms of Fufang Biejia Ruangan Pills Against Alcoholic Liver Disease via Regulating Liver-brain Dialogue Mediated by HMGB1-BDNF Axis[J].Chinese Journal of Experimental Traditional Medical Formulae,2024,30(23):214-223. DOI： 10.13422/j.cnki.syfjx.20241638.

摘要

目的

该研究旨在利用急、慢性酒精性肝病（ALD）小鼠模型，系统且客观地表征复方鳖甲软肝片（FBRP）干预ALD的药效作用特点，并揭示其分子机制。

方法

将50只SPF级雄性BALB/c小鼠随机分为正常组、模型组、FBRP低、中、高剂量组（9.6、19.2、38.4 mg·kg

-1

）；除正常组外，其余各组给予56°白酒灌胃，构建急性ALD模型，4周后取材。将30只SPF级C57BL/6N性小鼠随机分为正常组、模型组、FBRP中剂量组（19.2 mg·kg

-1

），采用Lieber-DeCarli法，构建慢性ALD小鼠模型，持续10周。通过苏木素-伊红（HE）、天狼星红、油红O病理染色及酶联免疫吸附测定法（ELISA）检测，考察各组肝脏组织的炎症指标；通过醒酒时间、抓网和爬杆时间，客观评价各组小鼠的醉酒行为。进一步，开展基于临床转录组学数据的生物信息学分析，从肝-脑对话环节筛选FBRP缓解ALD的关键作用靶标及其相关分子机制，并采用ELISA、蛋白免疫印迹法（Western blot）和免疫组织化学染色对其加以实验验证。

结果

与正常组比较，急性和慢性ALD模型组小鼠肝脏组织天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）的水平均明显升高（

0.05）；与模型组比较，FBRP各剂量给药组小鼠肝脏组织AST、ALT的水平均明显下降（

0.05）。与正常组比较，急性ALD模型组小鼠在4周内的抓网和爬杆时间均显著下降（

0.01）；与模型组比较，FBRP高剂量给药组在4周内的抓网和爬杆时间明显上升（

0.05）。与正常组比较，慢性ALD模型组小鼠肝脏组织和大脑前额叶组织中高迁移率族蛋白B1（HMGB1）蛋白的表达量显著升高（

0.01）；与模型组比较，FBRP中剂量组HMGB1蛋白的表达量明显降低（

0.05，

0.01）。与正常组比较，模型组大脑前额叶组织中脑源性神经营养因子（BDNF）蛋白的表达量及

氨基丁酸（GABA）释放量均显著下降（

0.01）；与模型组比较，FBRP中剂量组BDNF蛋白的表达量及GABA释放量均明显升高（

0.05）。

结论

该研究揭示了FBRP可通过调节HMGB1-BDNF互作轴所介导的肝-脑对话而改善ALD的关键病理改变，为该中成药品种临床用治ALD提供了实验证据，也为开发ALD治疗新药提供新的研究思路。

Abstract

Objective

To systematically and objectively characterize the pharmacological effects of Fufang Biejia Ruangan pills （FBRP） in the intervention of alcoholic liver disease （ALD） using acute and chronic ALD mouse models and to elucidate its molecular mechanisms.

Method

Fifty SPF-grade male BALB/c mice were randomly divided into the normal group， model group， and FBRP low-， medium-， and high-dose groups （9.6， 19.2， 38.4 mg·kg

-1

）. Except for the normal group， the remaining groups were given 56° white wine by gavage to establish the acute ALD model， with samples collected after 4 weeks. Thirty SPF-grade male C57BL/6N mice were randomly divided into the normal group， model group， and FBRP medium-dose group （19.2 mg·kg

-1

）. The chronic ALD mouse model was established using the Lieber-DeCarli method over a 10-week period. Inflammatory markers in liver tissues were assessed using hematoxylin-eosin （HE）， Sirius Red， oil red O staining， and enzyme-linked immunosorbent assay （ELISA）. Intoxication behaviors of each group were objectively evaluated through sobering-up time， net-catching， and pole-climbing tests. Further bioinformatics analyses based on clinical transcriptomic data were conducted to identify key targets and molecular mechanisms of FBRP in alleviating ALD through liver-brain dialogue， with experimental validation by ELISA， Western blot， and immunohistochemical staining.

Result

Compared with the normal group

the levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT） in liver tissues of mice in the acute and chronic ALD model groups were significantly increased （

0.05）. Compared with the model group， the levels of AST and ALT in liver tissue of mice in FBRP groups were significantly decreased （

0.05）. Compared with the normal group， the time of grasping the net and climbing the pole in the acute ALD model group was significantly decreased within 4 weeks （

0.01）. Compared with the model group， the grasping and climbing time of FBRP high dose groups increased significantly within 4 weeks （

0.05）. Compared with

the normal group， the expression of high mobility group protein B1 （HMGB1） protein in liver tissue and prefrontal lobe tissue of mice in the chronic ALD model group was significantly increased （

0.01）. Compared with the model group， the expression of HMGB1 protein in FBRP medium dose group was significantly decreased （

0.05，

0.01）. Compared with the normal group， the expression of brain-derived neurotrophic factor （BDNF） protein and the release of

-aminobutyric acid （GABA） in the prefrontal cortex of the model group were significantly decreased （

0.01）. Compared with the model group

the expression of BDNF protein and the release of GABA in the FBRP medium dose group were significantly increased （

0.05）.

Conclusion

This study revealed that FBRP improved key pathological changes in ALD by modulating liver-brain dialogue mediated by the HMGB1-BDNF axis. These findings provide experimental evidence for the clinical use of FBRP in treating ALD and offer new insights for the development of ALD therapeutic agents.

关键词

Keywords

references

亓照耀，许源慧，刘金存，等 . 肉苁蓉苯乙醇苷对ALD小鼠肠道黏膜屏障和肠道菌群的影响［J］. 中国实验方剂学杂志， 2024 ， 30 （ 9 ）： 65 - 73 .

WU M ， QIN S ， TAN C ， et al . Estimated projection of incidence and mortality of alcohol-related liver disease in China from 2022 to 2040：A modeling study ［J］. BMC Med ， 2023 ， 21 （ 1 ）： 277 .

MACKOWIAK B ， FU Y ， MACCIONI L ， et al . Alcohol-associated liver disease ［J］. J Clin Invest ， 2024 ， 134 （ 3 ）： e176345 .

SINGAL A K ， LOUVET A ， SHAH V H ， et al . Grand rounds： Alcoholic hepatitis ［J］. J Hepatol ， 2018 ， 69 （ 2 ）： 534 - 543 .

SINGAL A K ， BATALLER R ， AHN J ， et al . ACG clinical guideline： Alcoholic liver disease ［J］. Am J Gastroenterol ， 2018 ， 113 （ 2 ）： 175 - 194 .

唐银佩，朱正望，王兵，等 . 中医药调控肠道菌群治疗代谢相关脂肪性肝病的机制［J］. 中国实验方剂学杂志， 2024 ， doi： 10.13422/j.cnki.syfjx.20240826 http://dx.doi.org/10.13422/j.cnki.syfjx.20240826 .

伏秀，马佳怡，朱思婷，等 . 中药解酒机制研究进展［J］. 吉林医药学院学报， 2023 ， 44 （ 6 ）： 458 - 461 .

LIU Y ， MAO X ， MA Z ， et al . Aberrant regulation of lncRNA TUG1-microRNA-328-3p-SRSF9 mRNA axis in hepatocellular carcinoma：A promising target for prognosis and therapy ［J］. Mol Cancer ， 2022 ， 21 （ 1 ）： 36 .

李丰衣，孙劲晖，田德禄，等 . 复方鳖甲软肝片抑制大鼠酒精性肝纤维化作用机制研究［J］. 中国中医药信息杂志， 2009 ， 16 （ 5 ）： 26 - 28 .

阚兴 . 培土益肝汤联合复方鳖甲软肝片与水飞蓟宾治疗肝郁脾虚型代偿期酒精性肝硬化随机平行对照研究［J］. 实用中医内科杂志， 2016 ， 30 （ 7 ）： 47 - 49 .

卢中明，许欣，杜礼泉，等 . 白酒醉酒度实验动物评价方法优化的研究［J］. 酿酒， 2021 ， 48 （ 1 ）： 32 - 36 .

罗丹，李媛媛，秦雪梅，等 . 黄芩叶总提物对急性醉酒小鼠的解酒护肝作用［J］. 山西医科大学学报， 2022 ， 53 （ 2 ）： 182 - 191 .

MORSELLI GYSI D ， DO V Í ， ZITNIK M ， et al . Network medicine framework for identifying drug-repurposing opportunities for COVID-19 ［J］. Proc Natl Acad Sci USA ， 2021 ， 118 （ 19 ）： e2025581118 .

GAO B ， AHMAD M F ， NAGY L E ， et al . Inflammatory pathways in alcoholic steatohepatitis ［J］. J Hepatol ， 2019 ， 70 （ 2 ）： 249 - 259 .

SHERIF F M ， TAWATI A M ， AHMED S S ， et al . Basic aspects of GABA-transmission in alcoholism， with particular reference to GABA-transaminase ［J］. Eur Neuropsychopharmacol ， 1997 ， 7 （ 1 ）： 1 - 7 .

TOMODA T ， SUMITOMO A ， SHUKLA R ， et al . BDNF controls GABA A R trafficking and related cognitive processes via autophagic regulation of p62 ［J］. Neuropsychopharmacology ， 2022 ， 47 （ 2 ）： 553 - 563 .

FRANK M G ， WEBER M D ， WATKINS L R ， et al . Stress sounds the alarmin：The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming ［J］. Brain Behav Immun ， 2015 ， 48 ： 1 - 7 .

DOYLE M A ， TAYLOR A ， WINDER D G . Neural circuitries and alcohol use disorder： Cutting corners in the cycle ［J］. Curr Top Behav Neurosci ， 2023 ， doi： 10.1007/7854_2023_454 http://dx.doi.org/10.1007/7854_2023_454 .

CRABB D W ， IM G Y ， SZABO G ， et al . Diagnosis and treatment of alcohol-associated liver diseases： 2019 practice guidance from the American association for the study of liver diseases ［J］. Hepatology ， 2020 ， 71 （ 1 ）： 306 - 333 .

SEITZ H K ， STICKEL F . Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress ［J］. Biol Chem ， 2006 ， 387 （ 4 ）： 349 - 360 .

LI J ， WANG Z ， LI J ， et al . HMGB1：A new target for ischemic stroke and hemorrhagic transformation ［J］. Transl Stroke Res ， 2024 ， doi： 10.1007/s12975-024-01258-5 http://dx.doi.org/10.1007/s12975-024-01258-5 .

HILLMER A T ， MASON G F ， FUCITO L M ， et al . How imaging glutamate， γ -aminobutyric acid， and dopamine can inform the clinical treatment of alcohol dependence and withdrawal ［J］. Alcohol Clin Exp Res ， 2015 ， 39 （ 12 ）： 2268 - 2282 .

OLSEN RW ， LIANG J . Role of GABA A receptors in alcohol use disorders suggested by chronic intermittent ethanol （CIE） rodent model ［J］. Mol Brain ， 2017 ， 10 （ 1 ）： 45 .

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