基于数据挖掘与药效筛选的中医药干预抗结核药物所致肝损伤核心方药研究

施铮; 王璐瑶; 韦英杰; 汪晶; 鲁晏武; 潘扬; 余黎; 虞舜

doi:10.14148/j.issn.1672-0482.2023.0170

基于数据挖掘与药效筛选的中医药干预抗结核药物所致肝损伤核心方药研究

doi: 10.14148/j.issn.1672-0482.2023.0170

施铮^1,,
王璐瑶²,
韦英杰³,
汪晶³,
鲁晏武⁴,
潘扬⁵,
余黎^5, ,,
虞舜^1, ,

1.
南京中医药大学中医药文献研究所, 江苏南京 210023
2.
南京中医药大学针灸推拿学院·养生康复学院, 江苏南京 210023
3.
江苏省中医药研究院, 江苏南京 210028
4.
宁波市中医院皮肤科, 浙江宁波 315010
5.
南京中医药大学药学院, 江苏南京 210023

基金项目:

国家自然科学基金青年科学基金项目 81904322

南京中医药大学自然科学基金 NZY.81904322

详细信息

作者简介:
施铮, 男, 讲师, E-mail: 361000@njucm.edu.cn

通讯作者:
余黎, 男, 副教授, 主要从事中药药理研究, E-mail: lyu@njucm.edu.cn

虞舜, 男, 研究员, 主要从事中医药文献研究, E-mail: yushun6336@163.com

中图分类号: R285.5
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出版历程
- 收稿日期: 2022-11-28
- 网络出版日期: 2023-02-17
- 发布日期: 2023-02-10

Study on Core Prescriptions and Drugs of TCM Against Antituberculosis Drug-Induced Liver Injury Based on Data Mining and Efficacy Screening

SHI Zheng^1
,,
WANG Lu-yao²,
WEI Ying-jie³,
WANG Jing³,
LU Yan-wu⁴,
PAN Yang⁵,
YU Li^{5
, ,},
YU Shun^{1
, ,}

1.
Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
2.
School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, China
3.
Jiangsu Academy of Chinese Medicine, Nanjing 210028, China
4.
Department of Dermatology, Ningbo Hospital of Chinese Medicine, Ningbo 315010, China
5.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

摘要

摘要: 目的基于数据挖掘与斑马鱼模型, 分析中医药干预抗结核药物所致肝损伤(ATDILI)的用药规律, 筛选核心方药。方法收集相关文献, 运用中医传承辅助系统建立方剂数据库进行数据挖掘, 将核心方药在斑马鱼模型进行药效验证。结果筛选方剂342首, 分析得到41味常用药物, 17种常用药对, 1组核心方。核心方药干预下的ATDILI模型, 斑马鱼幼鱼的畸形率、死亡率均显著下降(P < 0.05)，形态学改善，肝脏荧光面积显著上升、荧光光密度显著增强(P < 0.01)。结论中医药干预ATDILI以补虚、清热、利湿为总原则, 注重肝脾同治。数据挖掘得到的核心方药, 在斑马鱼ATDILI模型上均显示出一定的保肝作用, 验证了数据挖掘技术的可靠与适用。研究将数据挖掘与药理实验验证相结合，为ATDILI的治疗提供参考。
- 结核病 /
- 肝损伤 /
- 数据挖掘 /
- 斑马鱼 /
- 药物筛选
Abstract: OBJECTIVE Based on data mining and zebrafish model, to analyze the medication rules of TCM on antituberculosis drug-induced liver injury (ATDILI), and screen the core prescriptions and drugs. METHODS Literature was collected, prescriptions database was established by TCM inheritance system for data mining, and efficacy of core prescriptions and drugs were verified in zebrafish model. RESULTS A total of 342 prescriptions were screened, and 41 common drugs, 17 common drug pairs, and one core prescription were obtained. In the ATDILI model, the malformation rate and mortality rate of juvenile zebrafish were significantly reduced(P < 0.05), the morphology was improved, and the fluorescence area and intensity of liver increased significantly under the core prescriptions and drugs(P < 0.01). CONCLUSION TCM intervention in ATDILI is based on the general principle of tonifying deficiency, clearing heat and dampness, focusing on the simultaneous treatment of liver and spleen. The core prescriptions and drugs obtained from data mining showed liver protection effect in the ATDILI model of zebrafish, which verified the reliability and applicability of data mining technology. In this study, data mining and pharmacological experimental validation were combined to provide reference for the treatment of ATDILI.
- tuberculosis /
- hepatotoxicity /
- data mining /
- zebrafish /
- drug screening

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图 1 文献检索流程图

Figure 1. Data retrieval flow chart

下载: 全尺寸图片幻灯片

图 2 支持度个数为88时药物关联的网络图

Figure 2. Network diagram of drug associations in the support degree number of 88

下载: 全尺寸图片幻灯片

图 3 支持度个数为122时药物关联的网络图

Figure 3. Network diagram of drug associations in the support degree number of 122

下载: 全尺寸图片幻灯片

图 4 斑马鱼幼鱼形态图

注：Control.空白对照组；INH.INH 8 mmol·L^-1; DG和中药水提物浓度单位为μg·mL^-1；黑色箭头指示心包水肿; 红色箭头指示鱼鳔缺失或减小; 黄色箭头指示卵黄囊吸收延滞; 蓝色箭头指示脊柱弯曲。

Figure 4. Morphological diagram of zebrafish larval

下载: 全尺寸图片幻灯片

图 5 72 hpe斑马鱼幼鱼的肝脏荧光情况比较

注：Control.空白对照组；INH.INH 8 mmol·L^-1

Figure 5. Comparison of liver fluorescence of 72 hpe juvenile zebrafish

下载: 全尺寸图片幻灯片

表 1 高频药物

Table 1. High frequency drugs

序号	药名	频次	序号	药名	频次
1	柴胡	242	22	川芎	42
2	茯苓	170	23	百部	42
3	白芍	168	24	陈皮	41
4	炙甘草	152	25	党参	40
5	茵陈	151	26	熟地黄	39
6	丹参	147	27	生黄芪	36
7	郁金	132	28	泽泻	36
8	白术	129	29	生甘草	35
9	五味子	113	30	太子参	35
10	赤芍	103	31	制大黄	34
11	当归	99	32	枸杞子	33
12	黄芩	98	33	麦芽	31
13	枳壳	78	34	金钱草	30
14	生地黄	70	35	垂盆草	29
15	山药	64	36	牡丹皮	29
16	炙黄芪	60	37	香附	29
17	沙参	60	38	山楂	28
18	虎杖	54	39	白花蛇舌草	27
19	栀子	50	40	川楝子	27
20	麦冬	44	41	连翘	26
21	生大黄	43

下载: 导出CSV

表 2 支持度个数88条件下药对组合

Table 2. Drug pairs in the support degree number of 88

序号	药对	频次	序号	药对	频次
1	白芍, 柴胡	147	10	白芍, 茯苓	99
2	柴胡, 茯苓	127	11	炙甘草, 白芍, 柴胡	96
3	炙甘草, 柴胡	124	12	柴胡, 五味子	94
4	柴胡, 茵陈	122	13	白芍, 柴胡, 茯苓	92
5	丹参, 柴胡	121	14	赤芍, 柴胡	90
6	郁金, 柴胡	117	15	黄芩, 柴胡	90
7	炙甘草, 白芍	110	16	炙甘草, 茯苓	89
8	白术, 茯苓	108	17	丹参, 茵陈	88
9	白术, 柴胡	100

下载: 导出CSV

表 3 常用药物规则分析

Table 3. Analysis of common drug rules

序号	关联规则	置信度
1	白芍, 茯苓→柴胡	0.920 000
2	黄芩→柴胡	0.918 367
3	郁金→柴胡	0.886 364
4	白芍→柴胡	0.875 000
5	赤芍→柴胡	0.873 786
6	炙甘草, 白芍→柴胡	0.864 865
7	白术→茯苓	0.837 209
8	五味子→柴胡	0.831 858
9	丹参→柴胡	0.823 129
10	炙甘草→柴胡	0.815 789
11	茵陈→柴胡	0.807 947

下载: 导出CSV

表 4 核心方药对斑马鱼ATDILI模型死亡率的影响

Table 4. Effects of core prescriptions and drugs on mortality in zebrafish ATDILI models

组别	死亡率/%	χ²值	组别	死亡率/%	χ²值
空白对照组	0	-	INH8+柴胡50	11.1^**	24.171
INH8	48.6^##	46.239	INH8+柴胡100	0^**	46.239
INH8+DG4	0^**	46.239	INH8+柴胡200	9.7^**	26.353
INH8+DG20	0^**	46.239	INH8+柴胡400	20.8^**	12.255
INH8+DG100	0^**	46.239	INH8+柴胡800	26.4^**	7.585
INH8+DG500	0^**	46.239	INH8+白芍50	6.9^**	35.154
INH8+茯苓50	2.8^**	39.610	INH8+白芍100	0^**	46.239
INH8+茯苓100	2.8^**	39.610	INH8+白芍200	0^**	46.239
INH8+茯苓200	2.8^**	39.610	INH8+白芍400	1.4^**	42.815
INH8+茯苓400	1.4^**	42.815	INH8+白芍800	15.3^**	18.399
INH8+茯苓800	2.8^**	39.610	INH8+丹参50	2.8^**	39.610
INH8+炙甘草50	1.4^**	42.815	INH8+丹参100	0^**	46.239
INH8+炙甘草100	0^**	46.239	INH8+丹参200	1.4^**	42.815
INH8+炙甘草200	0^**	46.239	INH8+丹参400	9.7^**	26.353
INH8+炙甘草400	0^**	46.239	INH8+丹参800	11.1^**	24.171
INH8+炙甘草800	100.0^**	18.50	INH8+白术50	1.4^**	42.815
INH8+茵陈50	0^**	46.239	INH8+白术100	0^**	46.239
INH8+茵陈100	0^**	46.239	INH8+白术200	0^**	46.239
INH8+茵陈200	0^**	46.239	INH8+白术400	56.9	1.003
INH8+茵陈400	1.4^**	42.815	INH8+白术800	73.6^**	9.468
INH8+茵陈800	2.8^**	39.610	INH8+核心方50	1.4^**	42.815
INH8+郁金50	2.8^**	39.610	INH8+核心方100	0^**	46.239
INH8+郁金100	0^**	46.239	INH8+核心方200	13.9^**	20.202
INH8+郁金200	0^**	46.239	INH8+核心方400	27.8^*	6.619
INH8+郁金400	0^**	46.239	INH8+核心方800	100.0^**	18.50
INH8+郁金800	6.9^**	35.154
注: INH浓度单位为mmol·L^-1; DG和中药水提物浓度单位为μg·mL^-1；与空白组比较, ^##P < 0.01;与模型组比较, ^**P < 0.01。

下载: 导出CSV

表 5 核心方药对斑马鱼ATDILI模型畸形率的影响

Table 5. Effect of core prescriptions and drugs on malformation rate in zebrafish ATDILI models

组别	畸形率/%	χ²值	组别	畸形率/%	χ²值
空白对照组	0	-	INH8+柴胡50	65.6^**	13.373
INH8	97.3^##	104.601	INH8+柴胡100	63.9^**	14.638
INH8+DG4	48.6^**	25.511	INH8+柴胡200	75.4^**	8.152
INH8+DG20	26.4^**	49.159	INH8+柴胡400	89.5	1.019
INH8+DG100	27.8^**	47.284	INH8+柴胡800	97.8	0
INH8+DG500	59.7^**	17.299	INH8+白芍50	61.2^**	16.164
INH8+茯苓50	65.7^**	13.485	INH8+白芍100	27.8^**	47.284
INH8+茯苓100	64.3^**	14.340	INH8+白芍200	15.3^**	67.036
INH8+茯苓200	64.3^**	14.340	INH8+白芍400	64.8^**	14.063
INH8+茯苓400	45.1^**	28.451	INH8+白芍800	83.6	3.067
INH8+茯苓800	52.9^**	22.051	INH8+丹参50	65.7^**	13.485
INH8+炙甘草50	59.2^**	17.639	INH8+丹参100	13.9^**	69.708
INH8+炙甘草100	26.4^**	49.159	INH8+丹参200	28.2^**	46.559
INH8+炙甘草200	54.2^**	21.183	INH8+丹参400	61.5^**	15.874
INH8+炙甘草400	62.5^**	15.503	INH8+丹参800	96.9	0
INH8+炙甘草800	-	-	INH8+白术50	43.7^**	29.712
INH8+茵陈50	27.8^**	47.284	INH8+白术100	37.5^**	35.828
INH8+茵陈100	18.1^**	62.019	INH8+白术200	19.4^**	59.661
INH8+茵陈200	43.1^**	30.360	INH8+白术400	54.8^**	17.686
INH8+茵陈400	45.1^**	28.451	INH8+白术800	94.7	0
INH8+茵陈800	52.9^**	22.051	INH8+核心方50	18.3^**	61.228
INH8+郁金50	64.3^**	14.340	INH8+核心方100	11.1^**	75.417
INH8+郁金100	62.5^**	15.503	INH8+核心方200	77.4^**	7.122
INH8+郁金200	36.1^**	37.306	INH8+核心方400	98.1	0
INH8+郁金400	56.9^**	19.190	INH8+核心方800	-	-
INH8+郁金800	71.6^**	10.101
注: INH浓度单位为mmol·L^-1; DG和中药水提物浓度单位为μg·mL^-1；与空白组比较, ^##P < 0.01;与模型组比较, ^**P < 0.01。

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参考文献(13)

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基于数据挖掘与药效筛选的中医药干预抗结核药物所致肝损伤核心方药研究

doi: 10.14148/j.issn.1672-0482.2023.0170

作者简介:
施铮, 男, 讲师, E-mail: 361000@njucm.edu.cn

通讯作者:
余黎, 男, 副教授, 主要从事中药药理研究, E-mail: lyu@njucm.edu.cn

虞舜, 男, 研究员, 主要从事中医药文献研究, E-mail: yushun6336@163.com

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Study on Core Prescriptions and Drugs of TCM Against Antituberculosis Drug-Induced Liver Injury Based on Data Mining and Efficacy Screening

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基于数据挖掘与药效筛选的中医药干预抗结核药物所致肝损伤核心方药研究

doi: 10.14148/j.issn.1672-0482.2023.0170

作者简介: 施铮, 男, 讲师, E-mail: 361000@njucm.edu.cn

通讯作者: 余黎, 男, 副教授, 主要从事中药药理研究, E-mail: lyu@njucm.edu.cn 虞舜, 男, 研究员, 主要从事中医药文献研究, E-mail: yushun6336@163.com

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Study on Core Prescriptions and Drugs of TCM Against Antituberculosis Drug-Induced Liver Injury Based on Data Mining and Efficacy Screening

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出版历程

目录

作者简介:
施铮, 男, 讲师, E-mail: 361000@njucm.edu.cn

通讯作者:
余黎, 男, 副教授, 主要从事中药药理研究, E-mail: lyu@njucm.edu.cn

虞舜, 男, 研究员, 主要从事中医药文献研究, E-mail: yushun6336@163.com