PMID- 33771638 OWN - NLM STAT- MEDLINE DCOM- 20211115 LR - 20211115 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 274 DP - 2021 Jun 28 TI - Molecular mechanism of Fufang Zhenzhu Tiaozhi capsule in the treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease based on network pharmacology and validation in minipigs. PG - 114056 LID - S0378-8741(21)00283-X [pii] LID - 10.1016/j.jep.2021.114056 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu Tiaozhi formula (FTZ) of which a patented preparation of Chinese herbal medicine has been well documented with significant clinical curative effect for hyperglycemia and hyperlipidemia. Because of the complexity of the chemical constituents of Chinese herbal formulas, the holistic pharmacological mechanism of FTZ acting on type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) remains unclear. AIM OF THE STUDY: To investigate the pharmacological efficacy and mechanism of FTZ in the treatment of T2DM accompanied by NAFLD. MATERIALS AND METHODS: Network pharmacology and validation in minipigs were used in this study. First, potential bioactive compounds of FTZ were identified by the traditional Chinese medicine system pharmacology technology platform (TCMSP). Then, targets of compounds were gathered using DrugBank, SwissTargetPrediction and TCMSP, while targets for T2DM and NAFLD were collected from CTD (compounds-targets-diseases network) and GeneCards. Common targets were defined as direct therapeutic targets acting on T2DM with NAFLD. In addition, crucial targets were chosen by the protein-protein interaction (PPI) network and contribution to compound-therapeutic targets in T2DM with the NAFLD network. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the metabolism-related signaling pathways affected by FTZ. Candidate patterns selected by network pharmacology were tested in the minipigs model of T2DM with NAFLD. Measurements of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting insulin (FINS) and fasting blood glucose (FBG) in the blood and the expression levels of proteins, including PI3K-AKT and HIF-1alpha, in the livers of the minipigs were followed by the administration of FTZ. RESULTS: A total of 116 active compounds and 82 potential targets related to T2DM and NAFLD were found. Pathway and functional enrichment analysis showed that FTZ mainly regulates metabolism-related pathways, including PI3K-AKT, HIF-1alpha, TNFalpha and MAPK. Animal experiments showed that FTZ treatment significantly reduced the serum levels of TG, TC, LDL-C and FBG, increased serum levels of HDL-C, ameliorated systemic insulin resistance (IR), and attenuated liver damage in minipigs with T2DM and NAFLD. FTZ treatment has an obviously favorable influence on hepatic steatosis and liver lipid accumulation in the histopathologic features of HE, Oil red O staining, and electron microscopy. Mechanistically, FTZ improved liver metabolism by increasing the phosphorylation of PI3K-AKT and decreasing the expression of HIF-1alpha. CONCLUSION: Network pharmacology was supported by experimental studies, which indicated that FTZ has demonstrated therapeutic benefits in T2DM and NAFLD by regulating the PI3K-AKT and HIF-1alpha signaling pathways. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Wang, Hong AU - Wang H AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 791862979@qq.com. FAU - Tan, Haibo AU - Tan H AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 651819908@qq.com. FAU - Zhan, Wenjing AU - Zhan W AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 1309913854@qq.com. FAU - Song, Lixia AU - Song L AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 1780658602@qq.com. FAU - Zhang, Dongxing AU - Zhang D AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 438763194@qq.com. FAU - Chen, Xu AU - Chen X AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 1013234141@qq.com. FAU - Lin, Ziyang AU - Lin Z AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 1061025412@qq.com. FAU - Wang, Weixuan AU - Wang W AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: weixuanwang0614@163.com. FAU - Yang, Yiqi AU - Yang Y AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: yangyiqi2011@163.com. FAU - Wang, Lexun AU - Wang L AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: wanglexun123456@163.com. FAU - Bei, Weijian AU - Bei W AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: 806362747@139.com. FAU - Guo, Jiao AU - Guo J AD - Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China. Electronic address: gyguoyz@163.com. LA - eng PT - Journal Article DEP - 20210323 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Blood Glucose) RN - 0 (Capsules) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Hypoglycemic Agents) RN - 0 (Hypolipidemic Agents) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Insulin) RN - 0 (Phytochemicals) RN - 0 (fufang-zhenzhu-tiaozhi) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Blood Glucose/drug effects MH - Capsules MH - Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology MH - Diabetes Mellitus, Type 2/*drug therapy/metabolism/pathology MH - Drugs, Chinese Herbal/chemistry/pharmacology/*therapeutic use MH - Hypoglycemic Agents/chemistry/pharmacology/*therapeutic use MH - Hypolipidemic Agents/chemistry/pharmacology/*therapeutic use MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Insulin/blood MH - Lipid Metabolism/drug effects MH - Liver/drug effects/metabolism/pathology MH - Male MH - Metabolic Networks and Pathways/drug effects MH - Non-alcoholic Fatty Liver Disease/*drug therapy/metabolism/pathology MH - Pharmacology/methods MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phytochemicals/analysis/pharmacology/therapeutic use MH - Proto-Oncogene Proteins c-akt/metabolism MH - Reproducibility of Results MH - Swine MH - Swine, Miniature OTO - NOTNLM OT - Fufang zhenzhu tiaozhi OT - HIF-1alpha signaling pathway OT - Network pharmacology OT - Nonalcoholic fatty liver disease OT - PI3K-AKT signaling pathway OT - Type 2 diabetes mellitus EDAT- 2021/03/28 06:00 MHDA- 2021/11/16 06:00 CRDT- 2021/03/27 05:49 PHST- 2020/12/08 00:00 [received] PHST- 2021/03/18 00:00 [revised] PHST- 2021/03/19 00:00 [accepted] PHST- 2021/03/28 06:00 [pubmed] PHST- 2021/11/16 06:00 [medline] PHST- 2021/03/27 05:49 [entrez] AID - S0378-8741(21)00283-X [pii] AID - 10.1016/j.jep.2021.114056 [doi] PST - ppublish SO - J Ethnopharmacol. 2021 Jun 28;274:114056. doi: 10.1016/j.jep.2021.114056. Epub 2021 Mar 23.