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Molecular Mechanism of the Effect of Huanglian Jiedu Decoction on Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular Docking.

ABSTRACT: Background:Huanglian Jiedu Decoction (HLJDD) is a Traditional Chinese Medicine (TCM) formula comprising four herbal medicines. This decoction has long been used in China for clinically treating T2DM. However, the molecular mechanism of HLJDD treat for T2DM is still not fully known. Hence, this study was designed to reveal the synergistic mechanism of HLJDD formula in the treatment of T2DM by using network pharmacology method and molecular docking. Methods:Retrieving and screening of active components of different herbs in HLJDD and corresponding T2DM-related target genes across multiple databases. Subsequently, STRING and Cytoscape were applied to analysis and construct PPI network. In addition, cluster and topological analysis were employed for the analysis of PPI networks. Then, the GO and KEGG enrichment analysis were performed by using ClueGO tool. Finally, the differentially expressed analysis was used to verify whether the expression of key target genes in T2DM and non-T2DM samples was statistically significant, and the binding capacity between active components and key targets was validated by molecular docking using AutoDock. Results:There are 65 active components involved in 197 T2DM-related targets that are identified in HLJDD formula. What is more, 39 key targets (AKT1, IL-6, FOS, VEGFA, CASP3, etc.) and 3 clusters were obtained after topological and cluster analysis. Further, GO and KEGG analysis showed that HLJDD may play an important role in treating T2DM and its complications by synergistically regulating many biological processes and pathways which participated in signaling transduction, inflammatory response, apoptotic process, and vascular processes. Differentially expressed analysis showed that AKT1, IL-6, and FOS were upregulated in T2DM samples and a significant between sample differential expression. These results were validated by molecular docking, which identified 5 high-affinity active components in HLJDD, including quercetin, wogonin, baicalein, kaempferol, and oroxylin A. Conclusion:Our research firstly revealed the basic pharmacological effects and relevant mechanisms of the HLJDD in the treatment of T2DM and its complications. The prediction results might facilitate the development of HLJDD or its active compounds as alternative therapy for T2DM. However, more pharmacological experiments should be performed for verification.

SUBMITTER: Yin B

PROVIDER: S-EPMC7593729 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular Mechanism of the Effect of Huanglian Jiedu Decoction on Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular Docking.

Yin Bei B Bi Yi-Ming YM Fan Guan-Jie GJ Xia Ya-Qing YQ

Journal of diabetes research 20201019

<h4>Background</h4>Huanglian Jiedu Decoction (HLJDD) is a Traditional Chinese Medicine (TCM) formula comprising four herbal medicines. This decoction has long been used in China for clinically treating T2DM. However, the molecular mechanism of HLJDD treat for T2DM is still not fully known. Hence, this study was designed to reveal the synergistic mechanism of HLJDD formula in the treatment of T2DM by using network pharmacology method and molecular docking.<h4>Methods</h4>Retrieving and screening ...[more]

PMID: 33134394

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Project description:BackgroundHuanglian Jiedu decoction (HLJDD) is a famous traditional Chinese medicine prescription, which is widely used in the treatment of Alzheimer's disease (AD). However, the interaction between bioactive substances in HLJDD and AD-related targets has not been well elucidated.AimA network pharmacology-based approach combined with molecular docking was performed to determine the bioactives, key targets, and potential pharmacological mechanism of HLJDD against AD, through the regulation of microbial flora.Materials and methodsBioactives and potential targets of HLJDD, as well as AD-related targets, were retrieved from Traditional Chinese Medicine Systems Pharmacology Analysis Database (TCMSP). Key bioactive components, potential targets, and signaling pathways were obtained through bioinformatics analysis, including protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, molecular docking was performed to predict the binding of active compounds with core targets.Results102 bioactive ingredients of HLJDD and 76 HLJDD-AD-related targets were screened. Bioinformatics analysis revealed that kaempferol, wogonin, beta-sitosterol, baicalein, acacetin, isocorypalmine, (S)-canadine, (R)-canadine may be potential candidate agents. AKT1, TNF, TP53, VEGFA, FOS, PTGS2, MMP9 and CASP3 could become potential therapeutic targets. 15 important signaling pathways including the cancer pathway, VEGF signaling pathway, and NF-κB signaling pathway might play an important role in HLJDD against AD. Moreover, molecular docking analysis suggested that kaempferol, wogonin, beta-sitosterol, baicalein, acacetin, isocorypalmine, (S)-canadine, and (R)-canadine combined well with AKT1, TNF, TP53, VEGFA, FOS, PTGS2, MMP9, CASP3, respectively.ConclusionOur results comprehensively illustrated the bioactives, potential targets, and possible molecular mechanisms of HLJDD against AD. HLJDD may regulate the microbiota flora homeostasis to treat AD through multiple targets and multiple pathways. It also provided a promising strategy for the use of traditional Chinese medicine in treating human diseases.

Project description:Objective: We aim at investigating the molecular mechanisms through which the Qingfei Jiedu decoction (QFJDD) regulates PD-L1 expression in lung adenocarcinoma (LUAD). Methods: Bioactive compounds and targets of QFJDD were screened from TCMSP, BATMAN-TCM, and literature. Then, GeneCard, OMIM, PharmGKB, Therapeutic Target, and DrugBank databases were used to identify LUAD-related genes. The protein-protein interaction (PPI) network was constructed using overlapping targets of bioactive compounds in LUAD with the Cytoscape software and STRING database. The potential functions and pathways in which the hub genes were enriched by GO, KEGG, and DAVID pathway analyses. Molecular docking of bioactive compounds and key genes was executed via AutoDock Vina. Qualitative and quantitative analyses of QFJDD were performed using UPLC-Q-TOF-MS and UPLC. Expressions of key genes were determined by qRT-PCR, immunoreactivity score (IRS) of PD-L1 was assessed by immunohistochemistry (IHC), while the CD8+PD-1+T% derived from spleen tissues of Lewis lung cancer (LLC) bearing-mice was calculated using flow cytometry (FCM). Results: A total of 53 bioactive compounds and 288 targets of QFJDD as well as 8151 LUAD associated genes were obtained. Further, six bioactive compounds, including quercetin, luteolin, kaempferol, wogonin, baicalein, and acacetin, and 22 hub genes were identified. The GO analysis showed that the hub genes were mainly enriched in DNA or RNA transcription. KEGG and DAVID pathway analyses revealed that 20 hub genes were primarily enriched in virus, cancer, immune, endocrine, and cardiovascular pathways. The EGFR, JUN, RELA, HIF1A, NFKBIA, AKT1, MAPK1, and MAPK14 hub genes were identified as key genes in PD-L1 expression and PD-1 checkpoint pathway. Moreover, ideal affinity and regions were identified between core compounds and key genes. Notably, QFJDD downregulated EGFR, JUN, RELA, HIF1A, NFKBIA, and CD274 expressions (p < 0.05), while it upregulated AKT1 and MAPK1 (p < 0.05) levels in A549 cells. The PD-L1 IRS of LLC tissue in the QFJDD high dose (Hd) group was lower than model group (p < 0.01). CD8+PD-1+T% was higher in the QFJDD Hd group than in normal and model groups (p < 0.05). Conclusion: QFJDD downregulates PD-L1 expression and increases CD8+PD-1+T% via regulating HIF-1, EGFR, JUN and NFκB signaling pathways. Therefore, QFJDD is a potential treatment option for LUAD.

Project description:BackgroundObese type 2 diabetes mellitus (obese T2DM) is one of the prime diseases that endangers human health. Clinical studies have confirmed the ability of the Huanglian Huazhuo capsule to treat obese T2DM; however, its mechanism of action is still unclear. In this study, effects and mechanisms of the Huanglian Huazhuo capsule in obese T2DM were systematically investigated using network pharmacology and molecular docking techniques.MethodsThe active ingredients and targets of the Huanglian Huazhuo capsule were extracted from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Obese T2DM diabetes-related targets were retrieved from a geographic dataset combined with a gene card database. A protein-protein interaction (PPI) network was constructed to screen core targets. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using Database for Annotation Visualization and Integrated Discovery (DAVID). Interactions between potential targets and active compounds were assessed using molecular docking. Molecular docking was performed on the best core protein complexes obtained using molecular docking.ResultsA total of 89 and 108 active ingredients and targets, respectively, were identified. Seven core targets were obtained using a topological analysis of the PPI network. The GO and KEGG pathway enrichment analyses showed that the effects of the Huanglian Huazhuo capsules were mediated by inflammation, lipid response, oxidative stress-related genes, and HIF-1 and IL-17 signaling pathways. Good binding ability was observed between the active compounds and screened targets using molecular docking.ConclusionsThe active ingredients, potential targets, and pathways of the Huanglian Huazhuo capsule for the treatment of obese T2DM were successfully predicted, providing a new strategy for further investigation of its molecular mechanisms. In addition, the potential active ingredients provide a reliable source for drug screening in obese T2DM.

Dataset Information

Molecular Mechanism of the Effect of Huanglian Jiedu Decoction on Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular Docking.

Publications

Molecular Mechanism of the Effect of Huanglian Jiedu Decoction on Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular Docking.

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