解毒化瘀颗粒对急性肝衰竭小鼠肝损伤的调控作用及机制分析

牙程玉; 王挺帅; 严惠萍; 王怡; 赵庆瑞; 曾胜澜; 陈玮钰; 张荣臻

doi:10.12449/JCH260117

解毒化瘀颗粒对急性肝衰竭小鼠肝损伤的调控作用及机制分析

DOI: 10.12449/JCH260117

牙程玉^{1, 2, 3},
王挺帅^{1, 3, 4},
严惠萍¹,
王怡¹,
赵庆瑞^{1, 3, 4},
曾胜澜^{1, 3, 4},
陈玮钰¹,
张荣臻^2, , ,

1.
广西中医药大学研究生院，南宁 530200
2.
广西中医药大学附属国际壮医医院肝胆内科，南宁 530201
3.
广西中医药大学第一附属医院中医临床研究重点实验室，南宁 530023
4.
广西中医药大学第一附属医院肝病科，南宁 530023

基金项目:

国家自然科学基金 (82160881);

国家自然科学基金 (82460901);

广西高校中青年教师科研基础能力提升项目 (2023KY0307);

广西自然科学基金 (2021GXNSFAA220112);

广西自然科学基金 (2024GXNSFDA999066);

广西中医药大学第三批“岐黄工程”高层次人才团队培育项目 (202409)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：牙程玉、王挺帅负责设计论文框架，起草论文；严惠萍、王怡、赵庆瑞负责实验操作，研究过程的实施；曾胜澜、陈玮钰负责数据收集、整理，统计学分析，绘制图表；张荣臻负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
张荣臻，zhangrongzhen2007@163.com （ORCID： 0000-0003-2243-665X）

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出版历程
- 收稿日期: 2025-07-23
- 录用日期: 2025-09-24
- 出版日期: 2026-01-25

Regulatory effect of Jiedu Huayu granules on liver injury in mice with acute liver failure and its mechanism

Chengyu YA^{1, 2, 3},
Tingshuai WANG^{1, 3, 4},
Huiping YAN¹,
Yi WANG¹,
Qingrui ZHAO^{1, 3, 4},
Shenglan ZENG^{1, 3, 4},
Weiyu CHEN¹,
Rongzhen ZHANG^{2
, ,
,}

1.
Graduate School of Guangxi University of Chinese Medicine，Nanning 530200，China
2.
Department of Hepatobiliary Medicine，International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine，Nanning 530201，China
3.
Key Laboratory of Clinical Research on Traditional Chinese Medicine，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China
4.
Department of Hepatology，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China

Research funding:

National Natural Science Foundation of China (82160881);

National Natural Science Foundation of China (82460901);

Guangxi University Young and Middle-aged Teachers’ Basic Research Ability Improvement Project (2023KY0307);

Guangxi Natural Science Foundation (2021GXNSFAA220112);

Guangxi Natural Science Foundation (2024GXNSFDA999066);

The Third Batch of “Qihuang Project” High-Level Talent Team Cultivation Program of Guangxi University of Chinese Medicine (202409)

More Information

Corresponding author: ZHANG Rongzhen， zhangrongzhen2007@163.com （ORCID： 0000-0003-2243-665X）

摘要

摘要: 目的通过观察解毒化瘀颗粒对急性肝衰竭（ALF）小鼠模型的影响，以预防性给药方式，探究该方改善ALF小鼠肝损伤的作用机制，以期为临床用药提供依据。方法将60只雄性SPF级C57BL/6J小鼠按随机数字表随机分为对照组、模型组、解毒化瘀颗粒组（JDHY组）和法尼醇X受体（FXR）激动剂（GW4064）组，每组各15只。采用D-氨基半乳糖联合脂多糖一次性腹腔注射诱导建立ALF模型，JDHY组小鼠在造模前3天预防性给予0.3 g/mL解毒化瘀颗粒中药液灌胃，对照组、模型组小鼠予以0.9% NaCl溶液灌胃，GW4064组在造模前3天连续予以腹腔注射GW4064。造模完成后，处死小鼠，并对小鼠血清、肝组织进行收集；采用兽用全自动生化分析仪测定各组小鼠血清总胆红素（TBil）、总胆汁酸（TBA）、γ-谷氨酰转移酶（GGT）、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平；苏木精-伊红（HE）染色法观察小鼠肝脏的病理学变化；运用逆转录PCR检测各组小鼠FXR、成纤维细胞生长因子15（FGF15）、成纤维细胞生长因子受体4（FGFR4）、小异二聚体伴侣（SHP）和胆盐输出泵（BSEP）的mRNA表达；蛋白免疫印迹法检测各组小鼠FXR、FGF15、FGFR4、SHP和BSEP的蛋白表达情况。组间比较采用One-way ANOVA方差分析，进一步的组间两两比较用Dunett法。结果与对照组相比，模型组小鼠血清TBil、ALT、AST、TBA、GGT表达水平均明显升高（P值均<0.01）；与模型组相比，JDHY组、GW4064组小鼠血清TBil、ALT、AST、TBA、GGT的表达水平均明显降低（P值均<0.01）。HE染色结果显示，与模型组相比，JDHY组、GW4064组的病理损伤较轻，肝细胞坏死面积减少，细胞肿胀、水肿程度明显减轻。与对照组相比，模型组小鼠肝组织中FXR、FGF15、FGFR4、SHP和BSEP的mRNA及蛋白表达水平均显著降低（P值均<0.01）；与模型组相比，JDHY组、GW4064组小鼠肝组织中FXR、FGF15、FGFR4、SHP、BSEP的mRNA及蛋白表达水平均明显升高（P值均<0.05）。结论解毒化瘀颗粒可能通过FXR/SHP轴调控ALF小鼠的肝损伤。
- 解毒化瘀颗粒 /
- 肝功能衰竭，急性 /
- 胆汁酸代谢
Abstract: Objective To investigate the mechanism of action of Jiedu Huayu granules in improving liver injury in mice with acute liver failure （ALF） by observing its effect on a mouse model of ALF after prophylactic administration， and to provide a basis for clinical medication. Methods A total of 60 specific pathogen-free male C57BL/6J mice were divided into normal group， model group， Jiedu Huayu granules group （JDHY group）， and farnesoid X receptor （FXR） agonist （GW4064） group using a random number table， with 15 mice in each group. The model of ALF was induced by a single intraperitoneal injection of D-galactosamine combined with lipopolysaccharide. The mice in the JDHY group were given prophylactic administration of 0.3 g/mL drug solution of Jiedu Huayu granules by gavage for 3 days before modeling， those in the normal group and the model group were given 0.9% NaCl solution by gavage， and those in the GW4064 group were given intraperitoneal injection of GW4064 for 3 consecutive days before modeling. The mice were sacrificed after modeling， and serum and liver tissue samples were collected. A veterinary automatic biochemical analyzer was used to measure the serum levels of total bilirubin （TBil）， total bile acids （TBA）， gamma-glutamyl transferase （GGT）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） in mice from each group； HE staining was used to observe liver pathological changes； RT-PCR was used to measure the mRNA expression levels of FXR， fibroblast growth factor 15 （FGF15）， fibroblast growth factor receptor 4 （FGFR4）， small heterodimer partner （SHP）， and bile salt export pump （BSEP） in mice， and Western blot was used to measure the protein expression levels of FXR， FGF15， FGFR4， SHP， and BSEP. A one-way analysis of variance was used for comparison between groups， and the Dunett method was used for further comparison between two groups. Results Compared with the normal group， the model group had significant increases in the serum levels of TBil， ALT， AST， TBA， and GGT （all P<0.01）， and compared with the model group， the JDHY group and the GW4064 group had significant reductions in the serum levels of TBil， ALT， AST， TBA， and GGT （all P <0.01）. HE staining showed that compared with the model group， the JDHY group and the GW4064 group had milder pathological injury， a reduction in the area of hepatocyte necrosis， and alleviation of cellular swelling and edema. Compared with the normal group， the model group had significant reductions in the mRNA and protein expression levels of FXR， FGF15， FGFR4， SHP， and BSEP in liver tissue （all P <0.01）， and compared with the model group， the JDHY group and the GW4064 group had significant increases in the mRNA and protein expression levels of FXR， FGF15， FGFR4， SHP， and BSEP in liver tissue （all P <0.05）. Conclusion Jiedu Huayu granules may alleviate liver injury in mice with ALF through the FXR/SHP axis.
- Jiedu Huayu Granules /
- Liver Failure，Acute /
- Bile Acid Metabolism

HTML全文

注： TBil，总胆红素；ALT，丙氨酸氨基转移酶；AST，天冬氨酸氨基转移酶；TBA，总胆汁酸；GGT，γ-谷氨酰转移酶。

图 1 各组小鼠血清肝功能水平比较

Figure 1. Comparison of serum liver function levels among different groups of mice

下载: 全尺寸图片幻灯片

注： a，对照组；b，模型组；c，JDHY组；d，GW4064组。

图 2 肝组织病理学结果（HE染色，×200）

Figure 2. Liver histopathology （HE staining，×200）

下载: 全尺寸图片幻灯片

注： FXR，法尼醇X受体；FGF15，成纤维细胞生长因子15；FGFR4，成纤维细胞生长因子受体4；SHP，小异二聚体伴侣；BSEP，胆盐输出泵；GAPDH，甘油醛-3-磷酸脱氢酶。

图 3 各组小鼠FXR、SHP、FGF15、FGFR4和BSEP的mRNA表达情况

Figure 3. mRNA expression levels of FXR， SHP， FGF15， FGFR4 and BSEPin mice from each group

下载: 全尺寸图片幻灯片

注： FXR，法尼醇X受体；FGF15，成纤维细胞生长因子15；FGFR4，成纤维细胞生长因子受体4；SHP，小异二聚体伴侣；BSEP，胆盐输出泵；β-actin，β-肌动蛋白。

图 4 各组小鼠FXR、FGF15、FGFR4、SHP和BSEP蛋白表达情况

Figure 4. Protein expression levels of FXR， FGF15， FGFR4， SHP and BSEP in mice from each group

下载: 全尺寸图片幻灯片

表 1 引物序列

Table 1. Primer sequences

基因	引物序列	长度（bp）
FXR	上游：CTAATGAGGACGACAGCGAAGG 下游：CCTGAGGCATTCTCTGTTTGTTGTA	147
FGF15	上游：GAAGACGATTGCCATCAAGGAC 下游：TCCTCCGAGTAGCGAATCAGC	93
FGFR4	上游：CTACCCACAGCAAGCACCCTA 下游：CCGAATGCCTCCAATACGAT	181
SHP	上游：ATCCTCTTCAACCCAGATGTGC 下游：GCCTGGAATGTTCTTGAGGGTAG	171
BSEP	上游：AGTCAATGTTCAGTTCCTCCGTT 下游：GCAATAGCAATGCGTTGTTTC	252
β-actin	上游：CCTCGTCCCGTAGACAAAATG 下游：TGAGGTCAATGAAGGGGTCGT	133
注：FXR，法尼醇X受体；FGF15，成纤维细胞生长因子15；FGFR4，成纤维细胞生长因子受体4；SHP，小异二聚体伴侣；BSEP，胆盐输出泵；β-actin，β-肌动蛋白。

下载: 导出CSV

表 2 目的蛋白灰度值/内参灰度值

Table 2. Target protein gray value / internal reference gray value

指标	例数	FXR	SHP	FGF15	FGFR4	BSEP
正常组	15	1.20±0.07^1）	0.95±0.05^1）	0.90±0.24^1）	0.90±0.13^1）	1.16±0.12^1）
模型组	11	0.65±0.18	0.58±0.09	0.37±0.10	0.50±0.06	0.52±0.09
JDHY组	13	0.89±0.18^1）	0.82±0.26^1）	0.49±0.07^1）	0.72±0.12^1）	0.71±0.05^1）
GW4064组	14	1.01±0.23^1）	0.90±0.10^1）	0.58±0.15^1）	0.83±0.16^1）	0.73±0.05^1）
F值		22.45	20.32	22.39	26.78	135.67
P值		<0.01	<0.01	<0.01	<0.01	<0.01
注：与模型组比较，1）P<0.01。FXR，法尼醇X受体；SHP，小异二聚体伴侣；FGF15，成纤维细胞生长因子15；FGFR4，成纤维细胞生长因子受体4；BSEP，胆盐输出泵。

下载: 导出CSV

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