药学学报, 2018, 53(4): 574-584
引用本文:
唐进法, 王晓艳, 杨伟, 李伟霞, 李宇辉, 柏兆方, 王伽伯, 肖小河. 基于统计建模的壮骨关节丸诱发特异质肝损伤相关易感性细胞因子分析[J]. 药学学报, 2018, 53(4): 574-584.
TANG Jin-fa, WANG Xiao-yan, YANG Wei, LI Wei-xia, LI Yu-hui, BAI Zhao-fang, WANG Jia-bo, XIAO Xiao-he. Cytokine analysis of Zhuangguguanjie wan-induced idiosyncratic liver injury based on mathematical modeling[J]. Acta Pharmaceutica Sinica, 2018, 53(4): 574-584.

基于统计建模的壮骨关节丸诱发特异质肝损伤相关易感性细胞因子分析
唐进法1,2, 王晓艳1,2, 杨伟3, 李伟霞1,2, 李宇辉2, 柏兆方4, 王伽伯4, 肖小河4
1. 河南中医药大学第一附属医院, 河南 郑州 450000;
2. 河南中医药大学, 河南 郑州 450008;
3. 中国中医科学院中医临床基础医学研究所, 北京 100700;
4. 解放军302医院全军中医药研究所, 北京 100039
摘要:
利用数据建模的方式筛选壮骨关节丸(Zhuangguguanjie wan,ZGW)特异质肝损伤相关易感细胞因子。以脂多糖(lipopolysaccharide,LPS)+ZGW大鼠肝脏组织中27种细胞因子水平作为数据源,以肝功能指标谷丙转氨酶(alanine aminotransferase,ALT)活力值高低作为肝损伤结局的评价指标,采用Logistic回归法、分类树及随机森林法、LASSO Logistics回归法、规则发现算法与LASSO相结合的变量筛选方法,筛查ZGW特异质肝损伤相关易感细胞因子,并在THP1细胞上进行再评价。结果表明,初步筛选分析得到ZGW特异质肝损伤密切相关的易感细胞因子组合为白介素-1β(interleukin-1β,IL-1β)、白介素-18(interleukin-18,IL-18)和表皮细胞生长因子(epidermal growth factor,EGF),ZGW醇提物(ethanolic extract of ZGW,EtZ)联合IL-1β或IL-18协同增强THP1细胞肿瘤坏死因子(tumor necrosis factor-α,TNF-α)分泌,EtZ联合IL-1β协同增强THP1细胞白介素-6(interleukin-6,IL-6)的分泌,但EtZ联合EGF协同抑制THP1细胞IL-6的分泌。上述结果表明,能表征ZGW特异质肝损伤相关易感性细胞因子为IL-1β和IL-18,为临床ZGW特异质肝损伤患者的筛查提供依据,为ZGW临床安全用药及风险防控提供了新的实验证据。
关键词:    壮骨关节丸      特异质肝损伤      细胞因子      Logistic回归      随机森林法      LASSO回归法     
Cytokine analysis of Zhuangguguanjie wan-induced idiosyncratic liver injury based on mathematical modeling
TANG Jin-fa1,2, WANG Xiao-yan1,2, YANG Wei3, LI Wei-xia1,2, LI Yu-hui2, BAI Zhao-fang4, WANG Jia-bo4, XIAO Xiao-he4
1. The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China;
2. Henan University of Chinese Medicine, Zhengzhou 450008, China;
3. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China;
4. China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China
Abstract:
In this study, we used a mathematic-based modeling system to screen the cytokines that are sensitive to Zhuangguguanjie wan (ZGW)-induced idiosyncratic liver injury. The values of 27 cytokines were used as the data source in rat liver of lipopolysaccharide (LPS) + ZGW group. The alanine aminotransferase (ALT) activity value of liver function indexes was used as the outcome evaluation index of liver injury. Cytokines of ZGW-induced idiosyncratic liver injury were screened using Logistic regression, random forest method, LASSO Logistics regression and method of combining rule discovery algorithm with LASSO, and cytokines filtered out were revalued in THP1 macrophage. Susceptible cytokine combinations:interleukin-1β (IL-1β), epidermal growth factor (EGF) and interleukin-18 (IL-18) closely related to ZGW-induced idiosyncratic liver injury were obtained after preliminary screening analysis. The result of revalued in THP1 showed that the ethanolic extract of ZGW (EtZ) combined with IL-1β or IL-18 synergistically enhanced tumor necrosis factor-α (TNF-α) secretion in THP1 macrophage, and EtZ combined with IL-1β significantly enhanced interleukin-6 (IL-6) secretion in THP1 macrophage, but EtZ combined with EGF markedly inhibited IL-6 secretion in THP1 macrophage. The results suggest that the sensitive cytokines that can be characterized in the ZGW-induced idiosyncratic liver injury are IL-1β and IL-18, which provides a basis for screening the ZGW-induced idiosyncratic liver injury patients, and a new experimental evidence for clinical safety medication and risk prevention of ZGW.
Key words:    Zhuangguguanjie wan    idiosyncratic hepatotoxicity    cytokine    Logistic regression    Random forest method    LASSO regression   
收稿日期: 2018-01-03
DOI: 10.16438/j.0513-4870.2018-0008
基金项目: 国家"重大新药创制"科技重大专项资助项目(2015ZX09501-004-001-008);国家自然科学基金重点资助项目(81630100);国家自然科学基金青年科学基金项目(81502898);河南省中医药科学研究专项(2016ZY2057).
通讯作者: 王伽伯,Tel:86-10-66933323,Fax:86-10-66933325,E-mail:wjb0128@126.com
Email: wjb0128@126.com
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