血府逐瘀汤及其不同提取部位对高脂饮食诱导的非酒精性脂肪性肝病小鼠模型的影响

唐浩; 尹艺晓; 刘伟; 方怡; 王君; 胡义扬; 彭景华

doi:10.3969/j.issn.1001-5256.2022.12.010

血府逐瘀汤及其不同提取部位对高脂饮食诱导的非酒精性脂肪性肝病小鼠模型的影响

DOI: 10.3969/j.issn.1001-5256.2022.12.010

唐浩^{1, 2, 3, 4},
尹艺晓^{1, 2, 3, 4},
刘伟^{1, 2, 3, 4},
方怡^{1, 2, 3, 4},
王君^{1, 2, 3, 4},
胡义扬^{1, 2, 3, 4},
彭景华^{1, 2, 3, 4, , ,}

1.
上海中医药大学附属曙光医院，上海 201203
2.
上海中医药大学肝病研究所，上海 201203
3.
教育部肝肾疾病重点实验室(上海中医药大学)，上海 201203
4.
上海市中医临床重点实验室，上海 201203

基金项目:

国家自然科学基金面上项目 (81673750);

上海中医药大学附属曙光医院四明学者基金 (SGXZ-201911)

伦理学声明：本研究实验一于2020年7月15日经由上海南方模式生物研究中心动物看护与使用委员会审批，批号：IACUC2020-0018；实验二于2021年4月9日经由上海中医药大学实验动物福利与伦理委员会审批，批号：PZSHUTCM2100409023。两项实验均符合实验室动物管理与使用准则。

利益冲突声明：本研究不存在研究者、伦理委员会成员以及与公开研究成果有关的利益冲突。

作者贡献声明：唐浩负责研究数据收集分析，论文初稿撰写；尹艺晓、刘伟、方怡、王君参与研究数据的获取分析解释过程；胡义扬提供指导意见；彭景华负责研究设计，论文修改与定稿，研究资金获取。

详细信息

通信作者:
彭景华，pengjinghua2004@163.com

计量
- 文章访问数: 1872
- HTML全文浏览量: 1266
- PDF下载量: 98
- 被引次数: 0
出版历程
- 收稿日期: 2022-05-15
- 录用日期: 2022-06-20
- 出版日期: 2022-12-20

Effects of Xuefu Zhuyu decoction and its extracts on a mouse model of nonalcoholic fatty liver disease induced by high-fat diet

Hao TANG^{1, 2, 3, 4},
Yixiao YIN^{1, 2, 3, 4},
Wei LIU^{1, 2, 3, 4},
Yi FANG^{1, 2, 3, 4},
Jun WANG^{1, 2, 3, 4},
Yiyang HU^{1, 2, 3, 4},
Jinghua PENG^{1, 2, 3, 4
, ,
,}

1.
Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2.
Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3.
Key Laboratory of Liver and Kidney Diseases of the Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4.
Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China

Research funding:

General Project of National Natural Science Foundation of China (81673750);

Siming Scholar Foundation of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (SGXZ-201911)

More Information

Corresponding author: PENG Jinghua, pengjinghua2004@163.com (ORCID: 0000-0002-0665-7666)

摘要

摘要: 目的评价血府逐瘀汤对非酒精性脂肪性肝病(NAFLD)的药效，解析血府逐瘀汤发挥效应的物质基础。方法实验一探究血府逐瘀汤对高脂饮食诱导的小鼠NAFLD的作用，将50只C57BL/6J健康雄性小鼠随机分为正常组、模型组、血府逐瘀汤高剂量和低剂量组、奥贝胆酸对照组，每组10只。正常组小鼠予对照饮食，其余各组高脂饮食，造模第13周开始灌胃给药，16周末取材。记录进食量、体质量，酶联免疫法测定空腹血清胰岛素水平，检测空腹血糖并计算胰岛素抵抗指数。HE染色和NAFLD活动评分(NAS)观察小鼠肝组织病理；油红O染色观察脂质沉积；检测肝组织TG和血清ALT水平。实验二分析血府逐瘀汤各提取部位对高脂饮食诱导的小鼠NAFLD的作用，利用水煎、水提醇沉、石油醚萃取技术，获得血府逐瘀汤提取部位1、2、3。将54只C57BL/6J健康雄性小鼠随机分为正常组、模型组、血府逐瘀汤提取部位1、2、3和血府逐瘀汤对照组，每组9只。正常组予对照饮食，其余各组高脂饮食，造模第13周开始灌胃给药，16周末取材。记录进食量、体质量，酶联免疫法测定空腹血清胰岛素含量，检测空腹血糖并计算胰岛素抵抗指数。HE染色和NAS评分观察小鼠肝组织病理；油红O染色观察脂质沉积；检测肝组织TG、GGT、血清ALT水平。正态分布的计量资料两组间比较采用t检验；多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。非正态分布的计量资料多组间比较及进一步两两比较均采用Kruskal-Wallis H检验。结果实验一，血府逐瘀汤高、低剂量组和奥贝胆酸对照组均较模型组降低小鼠体质量和胰岛素抵抗指数(P值均＜0.05)，肝组织空泡状脂滴分布、小叶内炎症减少，肝细胞气球样变减轻，NAS评分下降(P值均＜0.05)，降低肝脏TG、血清ALT水平(P值均＜0.05)。血府逐瘀汤高、低剂量降低体质量、胰岛素抵抗指数和NAS总分的作用均优于奥贝胆酸(P值均＜0.05)。血府逐瘀汤低剂量改善血清ALT的作用优于奥贝胆酸(P＜0.05)。实验二，与模型组比较，血府逐瘀汤提取部位1、2、3组均显著降低小鼠空腹血糖及胰岛素抵抗指数(P值均＜0.05)，减少肝组织脂滴分布、小叶内炎症灶和肝细胞气球样变，降低NAS总分和肝脏TG水平(P值均＜0.05)。血府逐瘀汤提取部位1较模型组降低NAFLD小鼠体质量(P＜0.05)；提取部位2、3较模型组降低血清ALT水平(P值均＜0.05)；提取部位2较模型组降低肝组织GGT水平(P＜0.05)。提取部位2的作用最接近血府逐瘀汤复方。结论血府逐瘀汤及其各提取部位均可不同程度改善高脂饮食诱导的小鼠NAFLD，其中提取部位2很可能是血府逐瘀汤发挥效应的主要物质基础。
- 非酒精性脂肪性肝病 /
- 血府逐瘀汤 /
- 小鼠, 近交C57BL
Abstract: Objective To investigate the effect of Xuefu Zhuyu decoction on nonalcoholic fatty liver disease (NAFLD) and its material basis. Methods In experiment 1 for exploring the effect of Xuefu Zhuyu decoction on mice with NAFLD induced by high-fat diet, 50 healthy male C57BL/6J mice were randomly divided into normal group, model group, high- and low-dose Xuefu Zhuyu decoction groups, and obeticholic acid control group, with 10 mice in each group. The mice in the normal group were given control diet, and those in the other groups were given high-fat diet. Gastric administration was started at week 13, and related samples were collected at the end of week 16. Food intake and body weight were recorded, enzyme-linked immunosorbent assay was used to measure the serum level of fasting insulin, fasting blood glucose was measured, and insulin resistance index was calculated. HE staining and NAFLD activity score (NAS) were used to observe liver histopathology in mice, oil red O staining was used to observe lipid deposition, and triglyceride (TG) level in liver tissue and serum alanine aminotransferase (ALT) level were measured. In experiment 2 for exploring the effect of different extracts of Xuefu Zhuyu decoction on mice with NAFLD induced by high-fat diet, the methods of water decocting, water extraction and alcohol precipitation, and petroleum ether extraction were used to obtain the extracts 1, 2, and 3 of Xuefu Zhuyu decoction, and 54 healthy male C57BL/6J mice were randomly divided into normal group, model group, Xuefu Zhuyu decoction extract 1, 2, and 3 groups, and Xuefu Zhuyu decoction control group, with 9 mice in each group. The mice in the normal group were given control diet, and those in the other groups were given high-fat diet. Gastric administration was started at week 13, and related samples were collected at the end of week 16. Food intake and body weight were recorded, and enzyme-linked immunosorbent assay was used to measure the serum level of fasting insulin, fasting blood glucose was measured, and insulin resistance index was calculated. HE and NAS were used to observe liver histopathology in mice, oil red O staining was used to observe lipid deposition, and the levels of TG and gamma-glutamyl transpeptidase (GGT) in liver tissue and the serum level of ALT were measured. The t-test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and further comparison between two groups. Results In experiment 1, compared with the model group, the high- and low-dose Xuefu Zhuyu decoction groups and the obeticholic acid control group had significant reductions in body weight, insulin resistance index, the distribution of vacuolar lipid droplets in liver tissue, intralobular inflammation, the ballooning degeneration of hepatocytes, NAS score, the level of TG in liver tissue, and the serum level of ALT (all P < 0.05). Compared with obeticholic acid, high- and low-dose Xuefu Zhuyu decoction had a significantly better effect in reducing body weight, insulin resistance index, and total NAS score (all P < 0.05), and low-dose Xuefu Zhuyu decoction had a significantly better effect in improving serum ALT (P < 0.05). In experiment 2, compared with the model group, the Xuefu Zhuyu decoction extract 1, 2, and 3 groups had significant reductions in fasting blood glucose, insulin resistance index, the distribution of lipid droplets in liver tissue, intralobular inflammation lesions, the ballooning degeneration of hepatocytes, total NAS score, and the level of TG in the liver (all P < 0.05). Compared with the model group, the extract 1 group had a significant reduction in body weight (P < 0.05); the extract 2 and 3 groups had a significant reduction in the serum level of ALT (P < 0.05); the extract 2 group had a significant reduction in the level of GGT in liver tissue (P < 0.05). The extract 2 of Xuefu Zhuyu decoction had the closest effect to compound Xuefu Zhuyu decoction. Conclusion Xuefu Zhuyu decoction and its extracts can help to achieve varying degrees of improvement in NAFLD induced by high-fat diet in mice, and the extract 2 of Xuefu Zhuyu decoction might be the main material basis for Xuefu Zhuyu decoction.
- Non-alcoholic Fatty Liver Disease /
- XuefuZhuyu Decoction /
- Mice, Inbred C57BL

HTML全文

图 1 血府逐瘀汤对NAFLD小鼠肝组织病理及脂质沉积的影响

注：绿色箭头指示空泡状脂肪变性；黄色箭头指示炎症灶；蓝色箭头指示肝细胞气球样变。

Figure 1. Effects of XuefuZhuyu Decoction on liver histopathology and lipid deposition in NAFLD mice

下载: 全尺寸图片幻灯片

图 2 血府逐瘀汤各提取部位对NAFLD小鼠肝组织病理及脂质沉积的影响

注：绿色箭头指示空泡状脂肪变性；黄色箭头指示炎症灶；蓝色箭头指示肝细胞气球样变。

Figure 2. Effects of each extract of XuefuZhuyu Decoction on liver histopathology and lipid deposition in NAFLD mice

下载: 全尺寸图片幻灯片

表 1 肝组织NAS评分标准

Table 1. NAS scoring criteria for liver tissue

项目	标准	评分
肝细胞脂肪变	＜5%	0
	5%~33%	1
	34%~66%	2
	＞67%	3
小叶内炎症(200倍镜计数坏死灶)	无	0
	＜2个	1
	2~4个	2
	＞4个	3
肝细胞气球样变	无	0
	少见	1
	多见	2

下载: 导出CSV

表 2 血府逐瘀汤对进食量、体质量、空腹血糖和胰岛素、胰岛素抵抗指数、肝脏TG、血清ALT的作用

Table 2. Effects of XuefuZhuyu Decoction on food intake, body weight, fasting blood glucose and insulin, insulin resistance index, liver TG, serum ALT

组别	动物数(只)	进食量(g/d)	体质量(g)	空腹血糖(mg/dL)	空腹血清胰岛素(ng/mL)	胰岛素抵抗指数	肝脏TG (mg/g)	血清ALT (U/L)
正常组	10	2.18±0.12	29.40±1.71	15.38±11.26	0.39±0.10	0.33±0.28	55.33±11.09	16.76±6.29
模型组	10	2.07±0.14	41.01±4.36¹⁾	52.08±19.79¹⁾	1.47±0.46¹⁾	4.16±2.31¹⁾	84.69±17.65¹⁾	77.03±42.46¹⁾
血府逐瘀汤高剂量组	7	1.96±0.31	30.46±1.30²⁾³⁾	35.05±15.89²⁾	0.39±0.14²⁾	0.75±0.48²⁾³⁾	37.19±19.03²⁾	4.54±2.91²⁾
血府逐瘀汤低剂量组	10	1.92±0.25	33.90±4.06²⁾³⁾	39.92±16.78	0.56±0.19²⁾	1.21±0.81²⁾³⁾	48.20±18.78²⁾	3.14±1.15²⁾³⁾
奥贝胆酸对照组	10	1.96±0.14	37.38±4.90²⁾	42.38±7.07	1.26±0.61	2.79±1.46²⁾	52.13±13.21²⁾	27.55±22.80²⁾
F值		1.37	16.24	8.42	17.98	13.59	11.10	16.07
P值		0.260	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001
注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05；与奥贝胆酸对照组比较，3)P＜0.05。

下载: 导出CSV

表 3 血府逐瘀汤对小鼠肝组织NAS评分的影响

Table 3. Effects of XuefuZhuyu Decoction on NAS score of mouse liver tissue

组别	动物数(只)	脂肪变	炎症浸润	气球样变	NAS总分
正常组	10	0	0	0	0
模型组	10	3.00(2.75~3.00)¹⁾	3.00(3.00~3.00)¹⁾	2.00(2.00~2.00)¹⁾	8.00(7.75~8.00)¹⁾
血府逐瘀汤高剂量组	7	0²⁾⁴⁾	0(0~1.00)²⁾	0(0~1.00)²⁾	0(0~1.00)²⁾⁴⁾
血府逐瘀汤低剂量组	10	0.50(0~1.00)²⁾³⁾	0(0~1.00)²⁾	0²⁾	1.00(0~1.25)²⁾⁴⁾
奥贝胆酸对照组	10	1.00(0.75~1.25)²⁾	1.00(0~1.00)²⁾	0(0~1.00)²⁾	1.50(1.00~4.00)²⁾
H值		35.76	32.49	37.64	36.70
P值		＜0.001	＜0.001	＜0.001	＜0.001
注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05；与血府逐瘀汤高剂量组比较，3)P＜0.05；与奥贝胆酸对照组比较，4)P＜0.05。

下载: 导出CSV

表 4 血府逐瘀汤各提取部位对进食量、体质量、空腹血糖和胰岛素、胰岛素抵抗指数、肝脏TG、血清ALT、肝脏GGT的作用

Table 4. Effects of each extract of XuefuZhuyu Decoction on food intake, body weight, fasting blood glucose and insulin, insulin resistance index, liver TG, serum ALT

组别	动物数(只)	进食量(g/d/)	体质量(g)	空腹血糖(mg/dL)	空腹血清胰岛素(ng/mL)	胰岛素抵抗指数	肝脏TG (mg/g)	血清ALT (U/L)	肝脏GGT (μmol/g)
正常组	9	2.49±0.09	28.74±2.15	59.26±5.86	1.14±0.54	3.74±1.94	27.12±15.60	17.35±3.51	4.22±1.72
模型组	9	2.51±0.18	44.61±3.61¹⁾	93.09±18.59¹⁾	4.58±1.46¹⁾	22.12±8.10¹⁾	68.57±26.47¹⁾	45.25±8.06¹⁾	7.58±2.78¹⁾
血府逐瘀汤提取部位1组	9	2.52±0.29	39.26±7.12²⁾	38.37±5.40²⁾³⁾	3.68±2.29	7.43±3.57²⁾	38.81±15.26²⁾⁴⁾	48.87±31.21	5.78±3.51
血府逐瘀汤提取部位2组	9	2.44±0.30	39.99±6.12	51.99±10.33²⁾	3.74±2.29	8.32±3.43²⁾	29.58±13.79²⁾	34.32±6.31²⁾	4.89±2.13²⁾
血府逐瘀汤提取部位3组	9	2.50±0.36	41.27±4.39	38.00±3.19²⁾³⁾	4.98±1.61	9.82±2.98²⁾⁴⁾	28.61±10.58²⁾	31.45±9.79²⁾	5.92±2.25
血府逐瘀汤对照组	8	2.40±0.29	34.83±4.28²⁾	38.81±5.41²⁾³⁾	2.64±1.40²⁾	5.33±2.72²⁾	20.45±8.86²⁾	31.41±5.78²⁾	3.42±0.58²⁾
F值		0.47	11.56	42.06	5.92	18.45	9.96	5.51	3.31
P值		0.798	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	0.012
注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05；与血府逐瘀汤提取部位2组比较，3)P＜0.05；与血府逐瘀汤对照组比较，4)P＜0.05。

下载: 导出CSV

表 5 血府逐瘀汤各提取部位对小鼠肝组织NAS评分的影响

Table 5. Effects of each extract of XuefuZhuyu Decoction on NAS score of mouse liver tissue

组别	动物数(只)	脂肪变	炎症浸润	气球样变	NAS总分
正常组	9	0	0	0	0
模型组	9	3.00(2.00~3.00)¹⁾	2.00(1.00~3.00)¹⁾	2.00(1.50~2.00)¹⁾	7.00(4.50~7.50)¹⁾
血府逐瘀汤提取部位1组	9	1.00(0.50~2.00)²⁾³⁾	0(0~1.00)²⁾	0²⁾	2.00(0.50~2.50)²⁾³⁾
血府逐瘀汤提取部位2组	9	0(0~1.00)²⁾	0(0~1.00)²⁾	0²⁾	1.00(0~2.00)²⁾
血府逐瘀汤提取部位3组	9	1.00(0~2.00)²⁾	0(0~1.00)²⁾	0²⁾	1.00(0~2.50)²⁾³⁾
血府逐瘀汤对照组	8	0²⁾	0²⁾	0²⁾	0²⁾
H值		31.56	29.84	51.69	34.97
P值		＜0.001	＜0.001	＜0.001	＜0.001
注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05；与血府逐瘀汤对照组比较，3)P＜0.05。

下载: 导出CSV

参考文献(38)

[1]	LOOMBA R, FRIEDMAN SL, SHULMAN GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease[J]. Cell, 2021, 184(10): 2537-2564. DOI: 10.1016/j.cell.2021.04.015.
[2]	GEIER A, TINIAKOS D, DENK H, et al. From the origin of NASH to the future of metabolic fatty liver disease[J]. Gut, 2021, 70(8): 1570-1579. DOI: 10.1136/gutjnl-2020-323202.
[3]	ZHOU J, ZHOU F, WANG W, et al. Epidemiological features of NAFLD from 1999 to 2018 in China[J]. Hepatology, 2020, 71(5): 1851-1864. DOI: 10.1002/hep.31150.
[4]	Branch of Gastrointestinal Diseases, China Association of Chinese Medicine. Expert consensus on TCM diagnosis and treatment of nonalcoholic fatty liver disease (2017)[J]. J Clin Hepatol, 2017, 33(12): 2270-2274. DOI: 10.3969/j.issn.1001-5256.2017.12.002. 中华中医药学会脾胃病分会. 非酒精性脂肪性肝病中医诊疗专家共识意见(2017)[J]. 临床肝胆病杂志, 2017, 33(12): 2270-2274. DOI: 10.3969/j.issn.1001-5256.2017.12.002.
[5]	DONG GF. Treatment of 50 cases of non-alcoholic fatty liver with Xuefu Zhuyu Decoction[J]. Guangming J Chin Med, 2013, 28(6): 1151-1152. DOI: 10.3969/j.issn.1003-8914.2013.06.034. 董桂芬. 血府逐瘀汤加减治疗非酒精性脂肪肝50例[J]. 光明中医, 2013, 28(6): 1151-1152. DOI: 10.3969/j.issn.1003-8914.2013.06.034.
[6]	YOUNOSSI ZM, RATZIU V, LOOMBA R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial[J]. Lancet, 2019, 394(10215): 2184-2196. DOI: 10.1016/S0140-6736(19)33041-7.
[7]	DUAN FJ. Traditional medical formulae[M]. Shanghai: Shanghai Scientific & Technical Publishers, 1995: 197. 段富津. 方剂学[M]. 上海: 上海科学技术出版社, 1995: 197.
[8]	RODRIGUES PM, AFONSO MB, SIMÃO AL, et al. miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice[J]. Cell Death Dis, 2017, 8(4): e2748. DOI: 10.1038/cddis.2017.172.
[9]	KLEINER DE, BRUNT EM, VAN NATTA M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease[J]. Hepatology, 2005, 41(6): 1313-1321. DOI: 10.1002/hep.20701.
[10]	WANG CE, XU WT, GONG J, et al. Advances in the treatment of nonalcoholic fatty liver disease[J]. Chin J Med Offic, 2022, 50(9): 897-899, 903. DOI: 10.16680/j.1671-3826.2022.09.06. 王彩娥, 许文涛, 宫建, 等. 非酒精性脂肪性肝病治疗研究进展[J]. 临床军医杂志, 2022, 50(9): 897-899, 903. DOI: 10.16680/j.1671-3826.2022.09.06.
[11]	NEUSCHWANDER-TETRI BA. Therapeutic landscape for NAFLD in 2020[J]. Gastroenterology, 2020, 158(7): 1984-1998. DOI: 10.1053/j.gastro.2020.01.051.
[12]	Digestive Diseases Professional Committee of Chinese Association of Integrated Traditional Chineseand Western Medicine. Consensus on diagnosis and treatment of nonalcoholic fatty liver disease with integrated traditional Chinese and western medicine(2017)[J]. Chin J Integr Trad West Med Dig, 2017, 25(11): 805-811. DOI: 10.3969/j.issn.1671-038X.2017.11.02. 中国中西医结合学会消化系统疾病专业委员会. 非酒精性脂肪性肝病中西医结合诊疗共识意见(2017年)[J]. 中国中西医结合消化杂志, 2017, 25(11): 805-811. DOI: 10.3969/j.issn.1671-038X.2017.11.02.
[13]	SHEN H, SHAHZAD G, JAWAIRIA M, et al. Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey[J]. Aliment Pharmacol Ther, 2014, 40(9): 1066-1073. DOI: 10.1111/apt.12944.
[14]	XIE JW, LI HC, YANG SL, et al. Change of hemorheology indexes in non-alcoholic fatty liver patients of blood congestion type[J]. Chin J Integr Trad West Med Dig, 2004, 12(5): 284-285. DOI: 10.3969/j.issn.1671-038X.2004.05.010. 谢纪文, 李宏春, 杨胜兰, 等. 非酒精性脂肪肝血瘀证患者血液流变学变化[J]. 中国中西医结合消化杂志, 2004, 12(5): 284-285. DOI: 10.3969/j.issn.1671-038X.2004.05.010.
[15]	LIU JH, DAI XH. Application of Xuefu Zhuyu Decoction in modern medicine[J]. Fujian J Tradit Chin Med, 1988, 19(1): 58-60. 刘建华, 戴西湖. 血府逐淤汤在近代医学中的应用[J]. 福建中医药, 1988, 19(1): 58-60.
[16]	SONG L, TANG SQ, TONG JW, et al. Study on the mechanism of Xuefu Zhuyu Decoction in preventing and treating NAFLD[J]. Chin J Integr Trad West Med, 2020, 40(9): 1103-1106. DOI: 10.7661/j.cjim.20200315.132. 宋丽, 唐宋琪, 童继威, 等. 血府逐瘀汤防治非酒精性脂肪肝的效应机制研究[J]. 中国中西医结合杂志, 2020, 40(9): 1103-1106. DOI: 10.7661/j.cjim.20200315.132.
[17]	QI L, XU J, XIANG Y, et al. Clinical effect of xuefu zhuyu decoction for liver fibrosis of chronic hepatitis B: a Meta-analysis[J]. Chin J Integr Tradit West Med Liver Dis, 2019, 29(5): 437-442. DOI: 10.3969/j.issn.1005-0264.2019.05.017. 戚璐, 徐俊, 向阳, 等. 血府逐瘀汤治疗慢性乙型肝炎肝纤维化临床疗效的Meta分析[J]. 中西医结合肝病杂志, 2019, 29(5): 437-442. DOI: 10.3969/j.issn.1005-0264.2019.05.017.
[18]	ZHANG XH. Clinical Efficacy of Treatment of Non-alcoholic Steatohepatitis by Modified Xuefu Zhuyu Decoction[J]. Chin Arch Tradit Chin Med, 2012, 30(10): 2356-2357. DOI: 10.13193/j.archtcm.2012.10.214.zhangxh.037. 张兴宏. 加味血府逐瘀汤治疗非酒精性脂肪肝疗效分析[J]. 中华中医药学刊, 2012, 30(10): 2356-2357. DOI: 10.13193/j.archtcm.2012.10.214.zhangxh.037.
[19]	ZHANG YL, HUANG MF, WANG YM, et al. Identification of active compounds and potential targets of Xue-Fu-Zhu-Yu-Tang[J]. World Sci Technol Modern Tradit Chin Med, 2012, 14(4): 1793-1797. DOI: 10.3969/j.issn.1674-3849.2012.04.008. 张燕玲, 黄明峰, 王元明, 等. 基于中药有效成分族辨识的血府逐瘀汤配伍研究[J]. 世界科学技术-中医药现代化, 2012, 14(4): 1793-1797. DOI: 10.3969/j.issn.1674-3849.2012.04.008.
[20]	ZHANG P, DAI H. Pharmacodynamics engineering of Chinese herbal compound[M]. Beijing: China Medical Science Press, 2005: 90. 张骠, 大海. 中药复方药效工程学[M]. 北京: 中国医药科技出版社, 2005: 90.
[21]	CAI CC, WANG HX, WANG S. Therapeutic effect of reglynan on obese diabetic rat models and effects on serum GLP-1 and GIP levels[J]. Chin J Gerontol, 2013, 33(18): 4506-4507. DOI: 10.3969/j.issn.1005-9202.2013.18.060. 蔡春沉, 王洪玺, 王肃. 地黄多糖对肥胖糖尿病大鼠模型的治疗作用及对血清中GLP-1、GIP水平的影响[J]. 中国老年学杂志, 2013, 33(18): 4506-4507. DOI: 10.3969/j.issn.1005-9202.2013.18.060.
[22]	WU Q. Hepatoprotective effects of crude Glycyrrhiza uralensis polysaccharide on non-alcoholic fatty liver disease in rats[D]. Yinchuan: Ningxia Medical University, 2019. 吴琼. 甘草粗多糖对非酒精性脂肪肝大鼠的保护作用[D]. 银川: 宁夏医科大学, 2019.
[23]	LIU LH. Study on antioxidant effect of Angelica Polysaccharide[J]. Contemp Med Forum, 2014, 12(3): 284-285. DOI: 10.3969/j.issn.2095-7629.2014.03.258. 刘丽花. 当归多糖抗氧化作用的研究[J]. 当代医药论丛, 2014, 12(3): 284-285. DOI: 10.3969/j.issn.2095-7629.2014.03.258.
[24]	LI WY, YU YT, YANG BH. Protective effect of hydroxysafflor yellow A against nonalcoholic fatty liver in high-fat diet induced mice by targeting Sirt1 signaling pathway[J]. Central South Pharm, 2018, 16(11): 1538-1542. DOI: 10.7539/j.issn.1672-2981.2018.11.008. 李望云, 喻娅婷, 阳碧辉. 羟基红花黄色素A通过调节Sirt1抑制高脂诱导的非酒精性脂肪肝[J]. 中南药学, 2018, 16(11): 1538-1542. DOI: 10.7539/j.issn.1672-2981.2018.11.008.
[25]	WANG CY, LIU Q, HUANG QX, et al. Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress[J]. Phytomedicine, 2013, 20(7): 592-599. DOI: 10.1016/j.phymed.2013.02.001.
[26]	LIU Q, WANG CY, LIU Z, et al. Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling[J]. Pharm Biol, 2014, 52(9): 1085-1093. DOI: 10.3109/13880209.2013.877491.
[27]	LI X, GE J, LI Y, et al. Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease[J]. Acta Pharm Sin B, 2021, 11(11): 3527-3541. DOI: 10.1016/j.apsb.2021.03.018.
[28]	HE Y, HU ZF, LI P, et al. Experimental study of saikosaponin-d (SSd) on lipid peroxidation of hepatic fibrosis on rat[J]. China J Chin Mater Med, 2008, 33(8): 915-919. DOI: 10.3321/j.issn:1001-5302.2008.08.013. 何燕, 胡志峰, 李平, 等. 柴胡皂苷d抗肝纤维化大鼠脂质过氧化作用的研究[J]. 中国中药杂志, 2008, 33(8): 915-919. DOI: 10.3321/j.issn:1001-5302.2008.08.013.
[29]	HWANG YP, CHOI JH, KIM HG, et al. Saponins, especially platycodin D, from Platycodon grandiflorum modulate hepatic lipogenesis in high-fat diet-fed rats and high glucose-exposed HepG2 cells[J]. Toxicol Appl Pharmacol, 2013, 267(2): 174-183. DOI: 10.1016/j.taap.2013.01.001.
[30]	CHOI JH, JIN SW, CHOI CY, et al. Saponins from the roots of Platycodon grandiflorum ameliorate high fat diet-induced non-alcoholic steatohepatitis[J]. Biomed Pharmacother, 2017, 86: 205-212. DOI: 10.1016/j.biopha.2016.11.107.
[31]	LI XX, XU Y, XU B, et al. Effects of hesperidin on nonalcoholic fatty liver rats induced by high fructose diet[J]. World Chin Med, 2021, 16(2): 249-253. DOI: 10.3969/j.issn.1673-7202.2021.02.011. 李晓霞, 许莹, 徐波, 等. 橙皮苷对果糖饮食诱导的非酒精性脂肪肝小鼠的作用研究[J]. 世界中医药, 2021, 16(2): 249-253. DOI: 10.3969/j.issn.1673-7202.2021.02.011.
[32]	LI XX, FANG CH, XU Y, et al. Effect of hesperidin on CYP2E1 expression in nonalcoholic fatty liver rats induced by high fructose diet[J]. Mod J Integr Tradit Chin West Med, 2020, 29(24): 2635-2639. DOI: 10.3969/j.issn.1008-8849.2020.24.003. 李晓霞, 方春华, 许莹, 等. 橙皮苷对果糖诱导的非酒精性脂肪肝病小鼠肝脏组织中CYP2E1表达的影响[J]. 现代中西医结合杂志, 2020, 29(24): 2635-2639. DOI: 10.3969/j.issn.1008-8849.2020.24.003.
[33]	LU KY, PRIMUS DASS KT, LIN SZ, et al. N-butylidenephthalide ameliorates high-fat diet-induced obesity in mice and promotes browning through adrenergic response/AMPK activation in mouse beige adipocytes[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2021, 1866(12): 159033. DOI: 10.1016/j.bbalip.2021.159033.
[34]	LI SW, WU Q, ZHAO SY, et al. Experimental study on antilipid effect of total flavonoids from Fructus aurantii[J]. Pract Clin J Integr Tradit Chin West Med, 2013, 13(3): 91, 94. DOI: 10.3969/j.issn.1671-4040.2013.03.063. 李顺文, 吴琦, 赵诗云, 等. 枳壳总黄酮降血脂作用的实验研究[J]. 实用中西医结合临床, 2013, 13(3): 91, 94. DOI: 10.3969/j.issn.1671-4040.2013.03.063.
[35]	LI T. Study on enzyme-assisted extraction, purification and hypoglycemic activity of glycyrrhizin[D]. Tianjin: Tianjin University of Science and Technology, 2019. 李婷. 甘草酸酶法提取、纯化及降血糖活性研究[D]. 天津: 天津科技大学, 2019.
[36]	YUAN DS, ZHOU LF, SHI L. Protective effect of total paeony glycoside on mice with liver injury induced by D-galactosamine[J]. J Trop Med, 2007, 7(2): 139-142. DOI: 10.3969/j.issn.1672-3619.2007.02.012. 袁冬生, 周兰芳, 石磊. 赤芍总苷对D-氨基半乳糖胺所致小鼠肝损伤的保护作用[J]. 热带医学杂志, 2007, 7(2): 139-142. DOI: 10.3969/j.issn.1672-3619.2007.02.012.
[37]	WU X, ZHANG F, XIONG X, et al. Tetramethylpyrazine reduces inflammation in liver fibrosis and inhibits inflammatory cytokine expression in hepatic stellate cells by modulating NLRP3 inflammasome pathway[J]. IUBMB Life, 2015, 67(4): 312-321. DOI: 10.1002/iub.1348.
[38]	WU GT, LIU WZ, DU LD, et al. Protective effects of angelica sinensis volatile oil on levels of blood fats and vascular endothelial structure in hyperlipidemia rats[J]. Chin J Arteriosclerosis, 2016, 24(10): 989-993. https://www.cnki.com.cn/Article/CJFDTOTAL-KDYZ201610004.htm 吴国泰, 刘五州, 杜丽东, 等. 当归挥发油对高血脂模型大鼠的降血脂作用及血管内皮保护作用[J]. 中国动脉硬化杂志, 2016, 24(10): 989-993. https://www.cnki.com.cn/Article/CJFDTOTAL-KDYZ201610004.htm