PMID- 34464700 OWN - NLM STAT- MEDLINE DCOM- 20220124 LR - 20220124 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 281 DP - 2021 Dec 5 TI - Uncovering the active components, prospective targets, and molecular mechanism of Baihe Zhimu decoction for treating depression using network pharmacology-based analysis. PG - 114586 LID - S0378-8741(21)00815-1 [pii] LID - 10.1016/j.jep.2021.114586 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Zhimu decoction (BZD) is a classical traditional Chinese medicinal herbal formula. It consists of two herbal medicines, Rhizoma Anemarrhenae (Zhimu), the rhizomes of Anemarrhena asphodeloides Bge. (Liliaceae), and Bulbus Lilii (Baihe), the bulbs of Lilium brownii var. Viridulum Baker (Liliaceae). BZD has been widely used in China to treat depression and verified to be effective without evident side effects. AIM OF THE STUDY: The aim of this study was to elucidate the active components, potential targets, and molecular mechanism of Baihe Zhimu decoction for treating depression. MATERIALS AND METHODS: In this research, a chronic unpredictable mild stress (CUMS) mice was first established to evaluate the pharmacological effects of BZD for treating depression. A component database was then constructed for BZD. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) technique was used to identify the components in BZD and blood-absorbed components. Further screening and validation of protein targets were performed by molecule docking. The component-target binding affinity was validated by surface plasmon resonance analysis (SPR) assay. The related pathways were predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Relative proteins in the predicted pathways were finally assessed by Western blot. RESULTS: The pharmacology evaluation experiment demonstrated that BZD could improve depressive-like behavior, inhibit the hippocampal secretion of pro-inflammatory cytokines and reduce neuronal apoptosis in CUMS mice model. A component database containing 163 components and a target database covering 1286 proteins were constructed. HPLC-QTOF-MS assay identified twenty-six components from BZD and ten components absorbed into rat plasma after an intragastric treatment with BZD. Next, 56 underlying targets were screened out by a virtual high-throughput screening approach. Twenty-seven of them were further screened out and confirmed by molecular docking. Afterward, a component-target network was established, and the component-protein binding affinities were validated by SPR assays. By KEGG pathway enrichment analysis, two signaling pathways PI3K/Akt and MAPK were predicted as the potential signaling cascades. Finally, Western blot showed that BZD dramatically reversed the suppression of PI3K/Akt/GSK-3beta pathway and the activation of MAPK pathway in CUMS mice model. CONCLUSIONS: BZD demonstrated a substantial pharmacological effect on CUMS mice model. Network pharmacology-based analysis predicted that ten blood-absorbed components can act on 27 target proteins. KEGG and Western blotting analysis suggested that BZD could exert antidepressant effects by regulating the PI3K/Akt and MAPK signaling pathways. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Wang, Hai-Qiao AU - Wang HQ AD - Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, China. Electronic address: haiqiaodr@163.com. FAU - Liu, Hong-Tao AU - Liu HT AD - Huantai County Psychiatric Hospital, Zibo, 256400, China. Electronic address: lhongtao01@sohu.com. FAU - Wang, Liang AU - Wang L AD - Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China. Electronic address: lw08010801@163.com. FAU - Min, Liang AU - Min L AD - Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, China. Electronic address: liangmin0512@126.com. FAU - Chen, Bin AU - Chen B AD - Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, China. Electronic address: chenbin@renji.com. FAU - Li, He AU - Li H AD - Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, China. Electronic address: lihe1972@hotmail.com. LA - eng PT - Journal Article DEP - 20210828 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Antidepressive Agents) RN - 0 (Drugs, Chinese Herbal) RN - 0 (zhimu-baihe) SB - IM MH - Animals MH - Antidepressive Agents/*chemistry/*pharmacology MH - Behavior, Animal/*drug effects MH - Drugs, Chinese Herbal/*chemistry/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Network Pharmacology MH - *Phytotherapy MH - Random Allocation MH - Rats MH - Rats, Sprague-Dawley OTO - NOTNLM OT - Baihe Zhimu decoction OT - Depression OT - MAPK OT - Network pharmacology OT - PI3K OT - Signaling pathway EDAT- 2021/09/01 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/08/31 20:13 PHST- 2021/05/12 00:00 [received] PHST- 2021/08/10 00:00 [revised] PHST- 2021/08/27 00:00 [accepted] PHST- 2021/09/01 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/08/31 20:13 [entrez] AID - S0378-8741(21)00815-1 [pii] AID - 10.1016/j.jep.2021.114586 [doi] PST - ppublish SO - J Ethnopharmacol. 2021 Dec 5;281:114586. doi: 10.1016/j.jep.2021.114586. Epub 2021 Aug 28.