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Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of Cannabis sativa against Type 2 Diabetes.

ABSTRACT: The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a protein-protein and target-compound interactions network. We confirmed the binding activities of the hub proteins and compounds with molecular docking. We identified thirteen active compounds from C. sativa, which have 150 therapeutic targets in T2D. The enrichment analysis showed that these proteins are involved in the hormone, lipid, and stress responses. They bind transcription factors and metals and participate in the insulin, PI3K/Akt, HIF-1, and FoxO signaling pathways. We found four hub proteins (EGFR, ESR1, HSP90AA1, and SRC) that bind to the thirteen bioactive compounds. This was verified using molecular docking. Our findings suggest that C. sativa's antidiabetic action is carried out through the insulin signaling pathway, with the participation of HIF-1 and FoxO.

SUBMITTER: Guzman-Flores JM

PROVIDER: S-EPMC10529732 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of Cannabis sativa against Type 2 Diabetes.

Guzmán-Flores Juan Manuel JM Pérez-Vázquez Victoriano V Martínez-Esquivias Fernando F Isiordia-Espinoza Mario Alberto MA Viveros-Paredes Juan Manuel JM

Current issues in molecular biology 20230901 9

The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a pro ...[more]

PMID: 37754241

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Project description:Type 2 diabetes mellitus (T2DM) is a chronic and complex disease, and traditional drugs have many side effects. The active compound dihydromyricetin (DHM), derived from natural plants, has been shown in our previous study to possess the potential for reducing blood glucose levels; however, its precise molecular mechanism remains unclear. In the present study, network pharmacology and transcriptomics were performed to screen the molecular targets and signaling pathways of DHM disturbed associated with T2DM, and the results were partially verified by molecular docking, RT-PCR, and Western blotting at in vivo levels. Firstly, the effect of DHM on blood glucose, lipid profile, and liver oxidative stress in db/db mice was explored and the results showed that DHM could reduce blood glucose and improve oxidative stress in the liver. Secondly, GO analysis based on network pharmacology and transcriptomics results showed that DHM mainly played a significant role in anti-inflammatory, antioxidant, and fatty acid metabolism in biological processes, on lipoprotein and respiratory chain on cell components, and on redox-related enzyme activity, iron ion binding, and glutathione transferase on molecular functional processes. KEGG system analysis results showed that the PI3K-Akt signaling pathway, IL17 signaling pathway, HIF signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway were typical signaling pathways disturbed by DHM in T2DM. Thirdly, molecular docking results showed that VEGFA, SRC, HIF1A, ESR1, KDR, MMP9, PPARG, and MAPK14 are key target genes, five genes of which were verified by RT-PCR in a dose-dependent manner. Finally, Western blotting results revealed that DHM effectively upregulated the expression of AKT protein and downregulated the expression of MEK protein in the liver of db/db mice. Therefore, our study found that DHM played a therapeutic effect partially by activation of the PI3K/AKT/MAPK signaling pathway. This study establishes the foundation for DHM as a novel therapeutic agent for T2DM. Additionally, it presents a fresh approach to utilizing natural plant extracts for chemoprevention and treatment of T2DM.

Project description:ObjectiveYikunyin is an empirical prescription that exhibits good efficacy in the clinical treatment of menopausal syndrome; however, its underlying mechanism remains unclear. This study investigates the mechanism implicated in the therapeutic effect of Yikunyin by identifying its hub genes, central pathways, and key active ingredients.MethodThe active ingredients and targets of Yikunyin were obtained from the Traditional Chinese Medicine Systems Pharmacology database, whereas the targets related to menopausal syndrome were obtained from GeneCards, PharmGKB, Therapeutic Target Database (TTD), and Comparative Toxicogenomics Database (CTD). To reveal the pharmacological mechanism, the component-target and the intersecting protein-protein interaction (PPI) networks were constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Finally, molecular docking was carried out to assess the strength of binding between the key active ingredients and key targets.ResultsA total of 418 targets and 121 active ingredients were identified in Yikunyin. The intersection of Yikunyin's 418 targets with the 2822 targets related to menopausal syndrome shows that there are 247 common targets that can be considered potential targets of Yikunyin in the treatment of menopausal syndrome. The topology analysis of the constructed PPI network conducted using the Cytoscape software shows that there are 15 hub genes implicated in the therapeutic effect of Yikunyin: AKT1, PRKCA, TLR9, CXCL10, PRKCD, PARP1, ABCB1, TP53, CAV1, MAPK8, PPARA, GRB2, EGFR, IL-6, and JAK2. Moreover, the key active components acting on these genes are paeoniflorin, luteolin, quercetin, beta-sitosterol, and kaempferol. GO and KEGG analyses indicate that Yikunyin can treat menopausal syndrome by regulating cellular response to chemical stress (GO:0062197), cellular response to oxidative stress (GO:0034599), phosphatase binding (GO:0019902), cytokine receptor binding (GO:0005126), PI3K-Akt signaling (hsa04151), lipid and atherosclerosis (hsa05417), and hepatitis B (hsa05161). Finally, the results of molecular docking suggest that the key active ingredients and key targets can bind well, with binding energies of less than -5 kJ/mol.ConclusionThe research conducted herein reveals that Yikunyin treats menopausal syndrome by targeting AKT1 and IL-6 and by regulating the PI3K-Akt signaling pathway. Moreover, it provides a new idea for understanding the therapeutic effects of traditional Chinese medicines.

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Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of Cannabis sativa against Type 2 Diabetes.

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Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of <i>Cannabis sativa</i> against Type 2 Diabetes.

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