Senlin Li1, Ying Qian2, Rui Xie3, Yangsha Li4, Zhao Jia5, Zijun Zhang6, Rongrong Huang7, Lingling Tuo8, Yihong Quan9, Zhihong Yu10, Jue Liu11, Ming Xiang12. 1. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 1029262512@qq.com. 2. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 2462860555@qq.com. 3. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 932161336@qq.com. 4. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 771003671@qq.com. 5. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 980656485@qq.com. 6. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 3124198028@qq.com. 7. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 1105887072@qq.com. 8. Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 272680375@qq.com. 9. Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 1305859667@qq.com. 10. Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: whyzh518@qq.com. 11. Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 15562399@qq.com. 12. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: xiangming@tjmu.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: ShengMai-Yin and Ganmaidazao decoction are classic formulas in traditional Chinese medicine. Individually, Shengmai-Yin is used to treat cardiovascular diseases, and Ganmaidazao decoction for therapy of mental disorders. The combination of Shengmai-Yin and Ganmaidazao decoction (SGD) is normally used as adjuvant therapy for type 2 diabetes mellitus (T2DM). AIM OF THE STUDY: The central aim is to elucidate the pharmacological efficacy of SGD and its mechanism in the treatment of T2DM with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Active ingredients in SGD and their drug targets were identified using network analysis followed by experimental validation. First, existing databases were mined for information relevant to SGD, including pharmacological actions, chemical components, physicochemical characteristics, potential targets, and implicated diseases. Candidate patterns obtained with the network analysis were then tested in a KKAy mouse model of T2DM with NAFLD. Various doses of SGD were administered, followed by measurements of fasting blood glucose, oral glucose tolerance tests, insulin tolerance tests, markers of lipid metabolism - including free fatty acids (FFA), triglycerides (TG), and total cholesterol (TC) - liver histology, and expression levels of implicated molecules including PI3K/AKT and PPARα. RESULTS: Over 300 potential active compounds with their physicochemical characteristics and 562 candidate targets were collected, and then the network of them was constructed. Follow-up pathway and functional enrichment analyses indicated that SGD influences metabolism-related signaling pathways including PI3K-Akt, AMPK, and PPAR. In validation experiments, treatment of KKAy mice with SGD reduced serum levels of glucose, TC, TG, and FFA, decreased numbers of crown-like structures in visceral adipose tissue, reduced adipocyte size, and lowered liver lipid deposits. Further, SGD improved liver metabolism by increasing the expressions of PPARα, HSL, and PI3K/Akt, and decreasing expressions of SREBP-1 and FASN, inhibiting lipid biosynthesis, and increasing insulin sensitivity. CONCLUSION: Experimental validation of network analysis revealed anti-diabetic effects of the plant product SGD, manifested most notably by improved serum profiles and diminished insulin resistance. These experimental results may have clinical implications.
ETHNOPHARMACOLOGICAL RELEVANCE: ShengMai-Yin and Ganmaidazao decoction are classic formulas in traditional Chinese medicine. Individually, Shengmai-Yin is used to treat cardiovascular diseases, and Ganmaidazao decoction for therapy of mental disorders. The combination of Shengmai-Yin and Ganmaidazao decoction (SGD) is normally used as adjuvant therapy for type 2 diabetes mellitus (T2DM). AIM OF THE STUDY: The central aim is to elucidate the pharmacological efficacy of SGD and its mechanism in the treatment of T2DM with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Active ingredients in SGD and their drug targets were identified using network analysis followed by experimental validation. First, existing databases were mined for information relevant to SGD, including pharmacological actions, chemical components, physicochemical characteristics, potential targets, and implicated diseases. Candidate patterns obtained with the network analysis were then tested in a KKAy mouse model of T2DM with NAFLD. Various doses of SGD were administered, followed by measurements of fasting blood glucose, oral glucose tolerance tests, insulin tolerance tests, markers of lipid metabolism - including free fatty acids (FFA), triglycerides (TG), and total cholesterol (TC) - liver histology, and expression levels of implicated molecules including PI3K/AKT and PPARα. RESULTS: Over 300 potential active compounds with their physicochemical characteristics and 562 candidate targets were collected, and then the network of them was constructed. Follow-up pathway and functional enrichment analyses indicated that SGD influences metabolism-related signaling pathways including PI3K-Akt, AMPK, and PPAR. In validation experiments, treatment of KKAy mice with SGD reduced serum levels of glucose, TC, TG, and FFA, decreased numbers of crown-like structures in visceral adipose tissue, reduced adipocyte size, and lowered liver lipid deposits. Further, SGD improved liver metabolism by increasing the expressions of PPARα, HSL, and PI3K/Akt, and decreasing expressions of SREBP-1 and FASN, inhibiting lipid biosynthesis, and increasing insulin sensitivity. CONCLUSION: Experimental validation of network analysis revealed anti-diabetic effects of the plant product SGD, manifested most notably by improved serum profiles and diminished insulin resistance. These experimental results may have clinical implications.