This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y1, P2Y4, P2Y12, P2X4, P2X7, A1, A2A, A2B, and A3, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y1 and P2Y4 antagonists could attenuate BBB damage. In contrast, P2Y12-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1β), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A1 and A2A on BBB cells. Furthermore, A2B and A3 receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.
Background: Ulcerative colitis (UC) is a common chronic disease of the digestive system. Recently, competitive endogenous RNAs (ceRNAs) have been increasingly used to reveal key mechanisms for the pathogenesis and treatment of UC. However, the role of ceRNA in UC pathogenesis has not been fully clarified. This study aimed to explore the mechanism of the lncRNA-miRNA-mRNA ceRNA network in UC and identify potential biomarkers and therapeutic targets.Materials and Methods: An integrative analysis of mRNA, microRNA (miRNA), and long non-coding RNA (lncRNA) files downloaded from the Gene Expression Omnibus (GEO) was performed. Differentially expressed mRNA (DE-mRNAs), miRNA (DE-miRNAs), and lncRNA (DE-lncRNAs) were investigated between the normal and UC groups by the limma package. A weighted correlation network analysis (WGCNA) was used to identify the relative model for constructing the ceRNA network, and, concurrently, miRWalk and DIANA-LncBase databases were used for target prediction. Consecutively, the Gene Ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathway, and Reactome pathway enrichment analyses, protein-protein interaction (PPI) network, Cytohubba, and ClueGO were performed to identify hub genes. Additionally, we examined the immune infiltration characteristics of UC and the correlation between hub genes and immune cells using the immuCellAI database. Finally, the expression of potential biomarkers of ceRNA was validated via qRT-PCR in an experimental UC model induced by dextran sulfate sodium (DSS).Result: The ceRNA network was constructed by combining four mRNAs, two miRNAs, and two lncRNAs, and the receiver operating characteristic (ROC) analysis showed that two mRNAs (CTLA4 and STAT1) had high diagnostic accuracy (area under the curve [AUC] > 0.9). Furthermore, CTLA4 up-regulation was positively correlated with the infiltration of immune cells. Finally, as a result of this DSS-induced experimental UC model, CTLA4, MIAT, and several associate genes expression were consistent with the results of previous bioinformatics analysis, which proved our hypothesis.Conclusion: The investigation of the ceRNA network in this study could provide insight into UC pathogenesis. CTLA4, which has immune-related properties, can be a potential biomarker in UC, and MIAT/miR-422a/CTLA4 ceRNA networks may play important roles in UC.
Emerging evidence shows that peripheral systemic inflammation, such as inflammatory bowel disease (IBD), has a close even interaction with central nervous disorders such as Alzheimer’s disease (AD). This study is designed to further clarify the relationship between AD and ulcerative colitis (UC, a subclass of IBD). The GEO database was used to download gene expression profiles for AD (GSE5281) and UC (GSE47908). Bioinformatics analysis included GSEA, KEGG pathway, Gene Ontology (GO), WikiPathways, PPI network, and hub gene identification. After screening the shared genes, qRT-PCR, Western blot, and immunofluorescence were used to verify the reliability of the dataset and further confirm the shared genes. GSEA, KEGG, GO, and WikiPathways suggested that PPARG and NOS2 were identified as shared genes and hub genes by cytoHubba in AD and UC and further validated via qRT-PCR and Western blot. Our work identified PPARG and NOS2 are shared genes of AD and UC. They drive macrophages and microglia heterogeneous polarization, which may be potential targets for treating neural dysfunction induced by systemic inflammation and vice versa.
A new network platform named ACU&MOX-DATA (http://cbcb.cdutcm.edu.cn/ACU&MOX-DATA/) was recently set up and introduced. The purpose of this website is to integrate and analyze multi-omics data of acupuncture and moxibustion and serve as a disease, clinical, and laboratory experiment public database. Some existing functions and the future plan of the website were also discussed. This platform can help researchers to integrate analyses and visual interpretation of key scientific issues in acupuncture & moxibustion under the guidance of traditional Chinese medicine theory through heterogeneous and multi-level data fusion analysis. Graphical abstract: http://links.lww.com/AHM/A41.
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