Abstract
The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination accompanied by axonal and neuronal degeneration [1, 2]
Following the algorithm described previously [21], the heat map showed the distribution of hematopoietic stem cells (HSC), stroma and epithelial cells, and immune cells in the brain tissues of two groups (Figure 1A)
Treatment at the acute stage is mainly to relieve symptoms and reduce the degree of disability as much as possible, while treatment at the remission stage is mainly to reduce the recurrence of brain and spinal lesions, to delay the accumulation of disabilities and to improve the quality of life
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination accompanied by axonal and neuronal degeneration [1, 2]. Depending on whether the brain, brain stem, cerebellum, spinal cord of MS patients are affected simultaneously or successively [5], the clinical features and symptoms vary, mainly for limb weakness, paresthesia, decreased vision, ataxia, etc. Immune cells play a crucial role in the development of MS, while the specific mechanisms involved need to be further explored. An increased number of IFN-g+ or IL17+ CD4+ T cells were found in brain and spinal cord lesion tissues in patients with MS, and lymphocytes from relapsing MS patients tended to differentiation of IFN-g+ or IL17+CD4+ T cells [12]. While different immune cells play their unique roles in MS, traditional detection methods are not capable of simultaneously detecting multiple immune cells. It is important to comprehensively evaluate the importance of immune cells during the pathogenesis of MS
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