Rui Guo1, Xiaoxiao Zhang2, Jin Su3, Haiyu Xu4, Yanqiong Zhang5, Fangbo Zhang3, Defeng Li3, Yi Zhang3, Xuefeng Xiao6, Shuangcheng Ma7, Hongjun Yang3. 1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, PR China; Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China. 2. Beijing University of Chinese Medicine, Beijing 100029, PR China. 3. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, PR China. 4. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, PR China; Shanxi institute of international trade & Commerce, Xianyang 712046, PR China. Electronic address: hyxu@icmm.ac.cn. 5. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, PR China. Electronic address: yqzhang@icmm.ac.cn. 6. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China. Electronic address: kai1219@163.com. 7. National Institutes for Food and Drug Control, Beijing 100050, PR China. Electronic address: masc@nicpbp.org.cn.
Abstract
BACKGROUND: Quality marker (Q-markers) has been proposed as a novel concept for quality evaluation and standard elaboration of traditional Chinese medicine (TCM). Xin-Su-Ning capsule (XSNC) has been extensively used for the treatment of arrhythmia with the satisfactory therapeutic effects in clinics. However, it is lack of reliable and effective Q-markers of this prescription. PURPOSE: To identify potential Q-markers of XSNC against arrhythmia. STUDY DESIGN: An integrative pharmacology-based investigation was performed. METHODS: Ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was performed to identify the preliminary chemical profile of XSNC in a rapid and high-throughput manner. Then, in silico Absorption-Distribution-Metabolism-Excretion (ADME) models were utilized to screen candidate active chemical compounds characterized by drug-likeness features. In addition, drug target-disease gene interaction network was constructed, and network features were calculated to identify key candidate targets and the potential Q-markers of XSNC against arrhythmia. RESULTS: A total of 41 chemical compounds with good drug-likeness and more chances to be absorbed into body were identified as the candidate bioactive chemical compounds which might offer contributions to the therapeutic effects of XSNC against arrhythmia in vivo. Following the prediction of 921 XSNC putative targets and the construction of XSNC putative target-known therapeutic target of arrhythmia interaction network, 315 hub nodes with high connectivity were selected. Functionally, the hub nodes were involved into modulation of cardiac sympatho-vagal balance, regulation of energy production and metabolism, as well as angiogenesis and vascular circulation during the development and progression of arrhythmia. Moreover, 63 major hubs with network topological importance were chosen as XSNC candidate targets against arrhythmia. Furthermore, berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5-demethylnobiletin, kushenol E and kurarinone hitting the corresponding XSNC candidate targets were screened out to be the potential Q-markers of XSNC against arrhythmia. CONCLUSION: Our integrative pharmacology-based approach combining UHPLC-LTQ-Orbitrap, in silico ADME prediction and network target analysis may be efficient to identify potential Q-markers of TCM prescriptions. Our data showed that berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5-demethylnobiletin, kushenol E and kurarinone might function as candidate markers for qualitative evaluation of XSNC.
BACKGROUND: Quality marker (Q-markers) has been proposed as a novel concept for quality evaluation and standard elaboration of traditional Chinese medicine (TCM). Xin-Su-Ning capsule (XSNC) has been extensively used for the treatment of arrhythmia with the satisfactory therapeutic effects in clinics. However, it is lack of reliable and effective Q-markers of this prescription. PURPOSE: To identify potential Q-markers of XSNC against arrhythmia. STUDY DESIGN: An integrative pharmacology-based investigation was performed. METHODS: Ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was performed to identify the preliminary chemical profile of XSNC in a rapid and high-throughput manner. Then, in silico Absorption-Distribution-Metabolism-Excretion (ADME) models were utilized to screen candidate active chemical compounds characterized by drug-likeness features. In addition, drug target-disease gene interaction network was constructed, and network features were calculated to identify key candidate targets and the potential Q-markers of XSNC against arrhythmia. RESULTS: A total of 41 chemical compounds with good drug-likeness and more chances to be absorbed into body were identified as the candidate bioactive chemical compounds which might offer contributions to the therapeutic effects of XSNC against arrhythmia in vivo. Following the prediction of 921 XSNC putative targets and the construction of XSNC putative target-known therapeutic target of arrhythmia interaction network, 315 hub nodes with high connectivity were selected. Functionally, the hub nodes were involved into modulation of cardiac sympatho-vagal balance, regulation of energy production and metabolism, as well as angiogenesis and vascular circulation during the development and progression of arrhythmia. Moreover, 63 major hubs with network topological importance were chosen as XSNC candidate targets against arrhythmia. Furthermore, berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5-demethylnobiletin, kushenol E and kurarinone hitting the corresponding XSNC candidate targets were screened out to be the potential Q-markers of XSNC against arrhythmia. CONCLUSION: Our integrative pharmacology-based approach combining UHPLC-LTQ-Orbitrap, in silico ADME prediction and network target analysis may be efficient to identify potential Q-markers of TCM prescriptions. Our data showed that berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5-demethylnobiletin, kushenol E and kurarinone might function as candidate markers for qualitative evaluation of XSNC.