1. Dihydroartemisinin ameliorates experimental autoimmune myasthenia gravis by regulating CD4 + T cells and modulating gut microbiota.
- Author
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Li Y, Shan Y, Xu L, Chen W, and Li Y
- Subjects
- Animals, Rats, Female, Dysbiosis drug therapy, Dysbiosis immunology, Signal Transduction drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes drug effects, Proto-Oncogene Proteins c-akt metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory drug effects, Phosphatidylinositol 3-Kinases metabolism, Gastrointestinal Microbiome drug effects, Rats, Inbred Lew, Artemisinins pharmacology, Artemisinins therapeutic use, Myasthenia Gravis, Autoimmune, Experimental drug therapy, Myasthenia Gravis, Autoimmune, Experimental immunology, Molecular Docking Simulation
- Abstract
Background: Dihydroartemisinin (DHA), a derivative and active metabolite of artemisinin, possesses various immunomodulatory properties. However, its role in myasthenia gravis (MG) has not been clearly explored. Here, we investigated the role of DHA in experimental autoimmune myasthenia gravis (EAMG) and its potential mechanisms., Methods: The AChR97-116 peptide-induced EAMG model was established in Lewis rats and treated with DHA. Flow cytometry was used to assess the release of Th cell subsets and Treg cells, and 16S rRNA gene amplicon sequence analysis was applied to explore the relationship between the changes in the intestinal flora after DHA treatment. In addition, network pharmacology and molecular docking were utilized to explore the potential mechanism of DHA against EAMG, which was further validated in the rat model by immunohistochemical and RT-qPCR for further validation., Results: In this study, we demonstrate that oral administration of DHA ameliorated clinical symptoms in rat models of EAMG, decreased the expression level of Th1 and Th17 cells, and increased the expression level of Treg cells. In addition, 16S rRNA gene amplicon sequence analysis showed that DHA restored gut microbiota dysbiosis in EAMG rats by decreasing Ruminococcus abundance and increasing the abundance of Clostridium, Bifidobacterium, and Allobaculum. Using network pharmacology, 103 potential targets of DHA related to MG were identified, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that PI3K-AKT signaling pathway was related to the treatment of DHA on EAMG. Meanwhile, molecular docking verified that DHA has good binding affinity to AKT1, CASP3, EGFR, and IGF1. Immunohistochemical staining showed that DHA treatment significantly inhibited the phosphorylated expression of AKT and PI3K in the spleen tissues of EAMG rats. In EAMG rats, RT-qPCR results also showed that DHA reduced the mRNA expression levels of PI3K and AKT1., Conclusions: DHA ameliorated EAMG by inhibiting the PI3K-AKT signaling pathway, regulating CD4
+ T cells and modulating gut microbiota, providing a novel therapeutic approach for the treatment of MG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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