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Multiple sclerosis (MS) is a common chronic autoimmune disorder of the central nervous system that predominantly affects young adults. Mounting evidence indicates that deregulation of microRNAs (miRNAs) in cerebrospinal fluid (CSF) has been implicated in MS as a potential biomarker. However, comprehensive assessments of CSF miRNAs and their target genes are lacking. Here, aberrantly expressed CSF miRNAs of MS patients were obtained from numerous studies by manual search. With detailed information on these miRNAs, we utilized online databases to screen out immune-related target genes and further performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. To identify MS high-risk pathways and pivotal genes, pathway crosstalk and pathway-gene networks were constructed, followed by the establishment of a protein-protein interaction (PPI) network. The datasets collected from ArrayExpress were used to assess pivotal genes. Overall, 21 MS-related CSF miRNAs were included in this study. Subsequently, we identified 469 MS-related genes and 14 high-risk pathways. In the pathway-gene network, 27 critical MS-related genes participated in at least half of the high-risk pathways, and these genes were used to identify pivotal genes. Finally, miR-150, miR-328, and miR-34c-5p were determined to be risk miRNAs via the regulation of the pivotal risk genes MAPK1, AKT1, and VEGFA. Among them, VEGFA was validated to be significantly decreased in the CSF cells of MS patients by transcriptomic datasets. These findings may provide potential biomarkers or therapeutic targets and help elucidate the molecular mechanisms underlying the pathogenesis of MS.

Background: Migraine and multiple sclerosis (MS) are frequent clinical partners, but the mechanisms and treatments of the comorbidity of the two are still unclear. This study aimed to investigate the shared mechanisms and predict potential drugs of migraine and MS with a view to provide new clues and approaches for clinical management. Methods: So firstly, PRJEB40032 (migraine) from ENA and GSE21942 (MS) from GEO were analyzed for differentially expressed genes (DEGs). And then, gene clusters and hub genes for common DEGs were identified, as well as functional annotation and pathway enrichment analysis were performed for exploring the gene signatures and molecular mechanisms of the comorbidity. Further, hub genes and critical pathways were evaluated by the receiver operating characteristic curves (ROC) and previous studies. Finally, the drugs targeting hub genes and critical pathways were predicted, of which drugs targeting both hub genes and critical pathways were further screened. Results: 112 DEGs were identified to be related to the comorbidity of migraine and MS, of which 9 hub genes (IL1B,JUN, CXCL8, FOS, ICAM1, MMP9, EGR1,LCN2, MMP8) were of high diagnostic value for the comorbidity. Functional annotation and pathway enrichment analysis showed that inflammatory response regulation and reactive oxygen species metabolism played a major role, and multiple pathways such as IL17 signaling pathway were involved in the comorbidity. 5 hub genes and 17 critical pathways were further evaluated, with predicted 112 and 535 drugs, respectively, including aspirin (non-steroidal anti-inflammatory drugs (NSAIDs)), baclofen (gamma-aminobutyric acid (GABA) receptor agonist), and melatonin (antioxidant). Ultimately, 10 drugs targeting both hub genes and critical pathways were screened, mainly anti-inflammatory drugs, immunological agents and antineoplastic drugs, in which there were three IL-1β inhibitors with high potential research value for the treatments of the comorbidity. Conclusions: We found that inflammation and oxidative stress were closely related to the comorbidity of migraine and multiple sclerosis. We also predicted some drugs for drawing on from each other and the comorbidity, such as NSAIDs, GABA receptor agonists/analogs andIL-1β inhibitors.

Background: Multiple sclerosis (MS) is driven by the interaction between genetic susceptibility and environmental triggers, particularly to Epstein-Barr virus (EBV) infection. EBV-encoded microRNAs (miRNAs) are abundantly expressed in all stages of EBV infection and latency, which can target both viral and host cellular mRNAs, allowing EBV-infected B cells to evade the host immune response. However, it remains a big gap to understand the roles of EBV miRNAs and their target genes in MS pathogenesis.Methods: We investigated the correlation between MS-related viruses infection and MS risk quantitatively by systematic analysis. All MS-related genes in B cells were obtained by integrating MS susceptibility genes and differentially expressed genes from B cells. In comparison with differentially expressed genes from B cells after EBV infection in vitro, we confirmed EBV-regulated, MS-related genes. Subsequently, we obtained target EBV miRNAs which can regulate these genes from several online databases. By constructing pathway-pathway, pathway-gene and protein-protein interaction networks, we further screened out MS-related genes and risk pathways regulated by EBV miRNAs. Finally, we identified target EBV miRNAs may directly regulate MS-related genes through bioinformatic prediction and experimental validation.Results: EBV infection showed the strongest correlation with MS risk. A total of 873 MS-related genes and 52 risk pathways in B cells were obtained. We then identified 150 MS-related genes and 18 associated risk pathways that EBV was involved in. In addition, 42 human target genes regulated by 36 EBV miRNAs overlapped with EBV-regulated, MS-related genes. Finally, 15 target EBV miRNAs and their regulated, 6 MS-related genes (MALT1, BCL10, IFNGR2, STAT3, CDK6 and FOXP1) have been confirmed as crucial pathogenic molecules, which could promote the initiation and development of MS through NF-kappa B (MALT1 and BCL10) and PD-L1/PD-1 (IFNGR2 and STAT3) pathways. Surprisingly, ebv-miR-BHRF1-2-5p directly targeting MALT1 was confirmed by our experiments, and FOXP1 was identified as a target gene of ebv-miR-BART11.Conclusions: This work identified the target EBV miRNAs and their regulated, MS-related genes and risk pathways, which may provide a novel insight into discovering diagnostic biomarkers and therapeutic targets for MS.