Shengnan Duan1, Lei Niu2, Taijun Yin3, Li Li3, Song Gao4, Dan Yuan5, Ming Hu6. 1. Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX 77204-5037, USA. 2. Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China. 3. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX 77204-5037, USA. 4. Department of Pharmaceutical and Environmental Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USA. 5. Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China. Electronic address: yuandan_kampo@163.com. 6. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX 77204-5037, USA. Electronic address: mhu@uh.edu.
Abstract
BACKGROUND: Major components are often used as marker compounds for quality control of traditional Chinese medicines (TCMs). However, these compounds may not necessarily bioavailable and active in vivo, thereby, failing to control the "quality". PURPOSE: The purpose of this paper is to develop a novel strategy integrating absorption and activity deduced from network pharmacology to identify more reasonable markers for quality control of TCM formulas using Wu Ji Bai Feng Pill (WJBFP) as an example. STUDY DESIGN: Human Caucasian colon adenocarcinoma (Caco-2) cell transport studies and a bioavailability-enhanced network pharmacological approach were integrated to identify better phytochemical markers for quality control. METHODS: The absorption of multiple components in WJBFP was evaluated by a Caco-2 cell culture model. Nine databases were used to identify potential targets in the network pharmacology analysis. Cytoscape 3.7.2 was employed for the network data integration, visualization, and centrality analysis. Molecular docking was carried out to investigate the binding affinity of the identified markers to their candidate targets. RESULTS: The apparent permeability coefficient (Papp) and efflux ratio (ER) of 66 compounds were determined. Five hundred and two putative targets and 187 primary dysmenorrhea (PD) related targets were identified. Twenty-two candidate targets interacting with 20 potential active compounds were screened with the putative PD related targets intersection network using Degree Centrality (DC) ranking. By integrating absorption, 16 candidate targets interacting with 8 potential active compounds were identified. Besides, 53 compounds hitting candidate targets were divided into two classes according to their DC values. Then each of the two classes of DC was stratified into two groups based on the Papp for a total of four classes. Finally, five compounds belonging to Class 1 with higher DC and higher Papp, formononetin, ferulic acid, isoliquiritigenin, neocryptotanshinone and senkyunolide A, were identified as potential bioavailable phytochemical markers for the quality control of WJBFP against PD. Furthermore, molecular docking analysis validated the interplay between candidate targets and marker ingredients. CONCLUSION: A novel strategy combining intestinal absorption with network pharmacology analysis was successfully established to identify bioavailable and bioactive markers for quality control of WJBFP against PD.
BACKGROUND: Major components are often used as marker compounds for quality control of traditional Chinese medicines (TCMs). However, these compounds may not necessarily bioavailable and active in vivo, thereby, failing to control the "quality". PURPOSE: The purpose of this paper is to develop a novel strategy integrating absorption and activity deduced from network pharmacology to identify more reasonable markers for quality control of TCM formulas using Wu Ji Bai Feng Pill (WJBFP) as an example. STUDY DESIGN:Human Caucasian colon adenocarcinoma (Caco-2) cell transport studies and a bioavailability-enhanced network pharmacological approach were integrated to identify better phytochemical markers for quality control. METHODS: The absorption of multiple components in WJBFP was evaluated by a Caco-2 cell culture model. Nine databases were used to identify potential targets in the network pharmacology analysis. Cytoscape 3.7.2 was employed for the network data integration, visualization, and centrality analysis. Molecular docking was carried out to investigate the binding affinity of the identified markers to their candidate targets. RESULTS: The apparent permeability coefficient (Papp) and efflux ratio (ER) of 66 compounds were determined. Five hundred and two putative targets and 187 primary dysmenorrhea (PD) related targets were identified. Twenty-two candidate targets interacting with 20 potential active compounds were screened with the putative PD related targets intersection network using Degree Centrality (DC) ranking. By integrating absorption, 16 candidate targets interacting with 8 potential active compounds were identified. Besides, 53 compounds hitting candidate targets were divided into two classes according to their DC values. Then each of the two classes of DC was stratified into two groups based on the Papp for a total of four classes. Finally, five compounds belonging to Class 1 with higher DC and higher Papp, formononetin, ferulic acid, isoliquiritigenin, neocryptotanshinone and senkyunolide A, were identified as potential bioavailable phytochemical markers for the quality control of WJBFP against PD. Furthermore, molecular docking analysis validated the interplay between candidate targets and marker ingredients. CONCLUSION: A novel strategy combining intestinal absorption with network pharmacology analysis was successfully established to identify bioavailable and bioactive markers for quality control of WJBFP against PD.