Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

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.

Quantitative Expression of SFN, lncRNA CCDC18-AS1, and lncRNA LINC01343 in Human Breast Cancer as the Regulator Biomarkers in a Novel ceRNA Network: Based on Bioinformatics and Experimental Analyses

“…Our analysis also showed the shorter overall survival in patients with low expression of SFN in BC. Furthermore, SFN could be positively implicated as an oncogene in a variety of diseases, including Alzheimer's disease, Parkinsonian syndromes, and autoimmune disorders affecting the central nervous system [ 58 ].…”

Biological Activity of Naturally Derived Naphthyridines

“…Until now, research studies revealed their impressive antimicrobial [ 6 , 8 , 177 ], antifungal [ 6 , 8 , 111 , 112 ], and antimycobacterial [ 10 , 178 ] effects, and some of them displayed activity superior or comparable to those presented by chloramphenicol [ 112 ], amphotericin B [ 115 ], and rifampin [ 124 ]—drugs used in standard therapeutic regimens. Moreover, naphthyridines were shown to present significant properties including antiinfectious: antiviral [ 11 , 24 , 50 , 51 ], antiparasitic [ 9 , 176 ], and antimalarial [ 113 ]; anticancer [ 5 , 6 , 23 , 35 ]; influencing cardiovascular system: hypotensive [ 16 , 27 ], cardioprotective [ 43 , 44 ]; neurological: sedative [ 94 ], analgesic [ 15 ], anticonvulsant [ 78 ], stimulating neuritogenesis [ 188 ]; psychotropic: antianxiety [ 97 ], antidepressant [ 29 , 97 ]; and affecting immune system: anti-inflammatory [ 7 , 56 , 57 ], immunosuppressant [ 48 , 49 , 50 ]. The spectrum of activity of naturally-derived naphthyridines is wide, thus these compounds are undeniably fascinating subjects of research.…”

“…Compound 30 was also reported to decrease total bilirubin level and improve survival rates in liver transplant recipients [ 47 ]. Matrine 30 is also considered a promising candidate as an immunosuppressive drug due to inhibiting autoimmune response in experimental models of multiple sclerosis [ 48 , 49 ]. It also exerts antiviral activity [ 50 , 51 ].…”

“…Anti-inflammatory activity of naphthyridines is based on reducing iNOS and COX-2 release, decrease in NO production, and IL-6 and TNF-α secretion [ 7 , 15 , 54 , 56 , 57 ]. They suppress autoimmunity reactions through an IFN-β/IL-27/IL-10 pathway, and by targeting proautoimmunity gene expression including angiogenin and stratifin [ 48 , 49 ].…”

Oxymatrine ameliorates experimental autoimmune encephalomyelitis by rebalancing the homeostasis of gut microbiota and reducing blood-brain barrier disruption

“…However, long-term use of MS medications is costly and may cause certain side effects, such as liver injury, lymphopenia, and infections ( Antonazzo et al., 2019 ; Moiola et al., 2020 ). Importantly, recent studies have found that some types of traditional herbal medicine can ameliorate clinical severity and reduce the frequency of clinical exacerbations in relapsing MS with fewer side effects and minor financial burdens ( Kou et al., 2014 ; Zhou and Fan, 2015 ; Dou et al., 2021 ; Zha et al., 2021 ). Therefore, natural products may be a promising treatment for MS.…”