PMID- 33636476 OWN - NLM STAT- MEDLINE DCOM- 20210511 LR - 20210511 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 83 DP - 2021 Mar TI - A bioinformatics and transcriptomics based investigation reveals an inhibitory role of Huanglian-Renshen-Decoction on hepatic glucose production of T2DM mice via PI3K/Akt/FoxO1 signaling pathway. PG - 153487 LID - S0944-7113(21)00029-5 [pii] LID - 10.1016/j.phymed.2021.153487 [doi] AB - BACKGROUND: Excessive hepatic glucose production (HGP) largely promotes the development of type 2 diabetes mellitus (T2DM), and the inhibition of HGP significantly ameliorates T2DM. Huanglian-Renshen-Decoction (HRD), a classic traditional Chinese herb medicine, is widely used for the treatment of diabetes in clinic for centuries and proved effective. However, the relevant mechanisms of HRD are not fully understood. PURPOSE: Based on that, this study was designed to identify the potential effects and underlying mechanisms of HRD on HGP by a comprehensive investigation that integrated in vivo functional experiments, network pharmacology, molecular docking, transcriptomics and molecular biology. METHODS: After confirming the therapeutic effects of HRD on T2DM mice, the inhibitory role of HRD on HGP was evaluated by pyruvate and glucagon tolerance tests, liver positron emission tomography (PET) imaging and the detection of gluconeogenic key enzymes. Then, network pharmacology and transcriptomics approaches were used to clarify the underlying mechanisms. Molecular biology, computational docking analysis and in vitro experiments were applied for final mechanism verification. RESULTS: Here, our results showed that HRD can decrease weight gain and blood glucose, increase fasting insulin, glucose clearance and insulin sensitivity in T2DM mice. Dysregulated lipid profile was also corrected by HRD administration. Pyruvate, glucagon tolerance tests and liver PET imaging all indicated that HRD inhibited the abnormal HGP of T2DM, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) were significantly suppressed by HRD as expected. Network pharmacology and transcriptomics approaches illustrated that PI3K/Akt/FoxO1 signaling pathway may be responsible for the inhibitory effect of HRD on HGP. Afterward, further western blot and immunoprecipitation found that HRD did activate PI3K/Akt/FoxO1 signaling pathway in T2DM mice, which confirmed previous results. Additionally, the conclusion was further supported by molecular docking and in vitro experiments, in which identified HRD compound, oxyberberine, was proven to exert an obvious effect on Akt. CONCLUSION: Our data demonstrated that HRD can treat T2DM by inhibiting hepatic glucose production, the underlying mechanisms were associated with the activation of PI3K/Akt/FoxO1 signaling pathway. CI - Copyright (c) 2021 Elsevier GmbH. All rights reserved. FAU - Wu, Fan AU - Wu F AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Shao, Qingqing AU - Shao Q AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Xia, Qingsong AU - Xia Q AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Hu, Meilin AU - Hu M AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Zhao, Yan AU - Zhao Y AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Wang, Dingkun AU - Wang D AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Fang, Ke AU - Fang K AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Xu, Lijun AU - Xu L AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Zou, Xin AU - Zou X AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Chen, Zhuo AU - Chen Z AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Chen, Guang AU - Chen G AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: guangchen@tjh.tjmu.edu.cn. FAU - Lu, Fuer AU - Lu F AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: felu@tjh.tjmu.edu.cn. LA - eng PT - Journal Article DEP - 20210130 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Blood Glucose) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) RN - 0 (Hypoglycemic Agents) RN - 0 (huanglian) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Blood Glucose/metabolism MH - Computational Biology MH - Diabetes Mellitus, Type 2/*drug therapy/genetics/metabolism MH - Drugs, Chinese Herbal/*pharmacology MH - Forkhead Box Protein O1/metabolism MH - Gene Expression Profiling MH - Gluconeogenesis/drug effects MH - Glucose/*metabolism MH - Hep G2 Cells MH - Humans MH - Hypoglycemic Agents/chemistry/pharmacology MH - Insulin Resistance MH - Liver/drug effects/metabolism MH - Male MH - Mice MH - Mice, Obese MH - Panax/chemistry MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/chemistry/metabolism OTO - NOTNLM OT - FoxO1 OT - Hepatic glucose production OT - Huanglian-Renshen-Decoction OT - PI3K/Akt pathway OT - T2DM EDAT- 2021/02/27 06:00 MHDA- 2021/05/12 06:00 CRDT- 2021/02/26 20:13 PHST- 2020/09/28 00:00 [received] PHST- 2021/01/07 00:00 [revised] PHST- 2021/01/28 00:00 [accepted] PHST- 2021/02/27 06:00 [pubmed] PHST- 2021/05/12 06:00 [medline] PHST- 2021/02/26 20:13 [entrez] AID - S0944-7113(21)00029-5 [pii] AID - 10.1016/j.phymed.2021.153487 [doi] PST - ppublish SO - Phytomedicine. 2021 Mar;83:153487. doi: 10.1016/j.phymed.2021.153487. Epub 2021 Jan 30.