Nonalcoholic fatty liver disease (NAFLD) is a global health threat. Here, we presented the significant role of a novel signaling axis comprising long non-coding RNA maternally expressed gene 3 (MEG3), enhancer of zeste homolog 2 (EZH2), and sirtuin 6 (SIRT6) in controlling lipid accumulation, inflammation, and the progression of NAFLD. Mice fed with high-fat diet (HFD) were established as in vitro and in vivo NAFLD models, respectively. Lipid accumulation was measured by oil red O staining and assays for triglycerides or cholesterol. Inflammation was examined by ELISA for pro-inflammatory cytokines. Gene expressions were examined by RT-qPCR or Western blot. Interactions between key signaling molecules were examined by combining expressional analysis, RNA immunoprecipitation, cycloheximide stability assay, co-immunoprecipitation, and chromatin immunoprecipitation. MEG3 level was reduced in FFA-challenged hepatocytes or liver from HFD-fed mice, and the reduction paralleled the severity of NAFLD in clinic. Overexpressing MEG3 suppressed FFA-induced lipid accumulation or inflammation in hepatocytes. By promoting the ubiquitination and degradation of EZH2, MEG3 upregulated SIRT6, an EZH2 target. SIRT6 essentially mediated the protective effects of MEG3 in hepatocytes. Consistently, overexpressing MEG3 alleviated HFD-induced NAFLD in vivo. By controlling the expressions of genes involved in lipid metabolism and inflammation, the MEG3/EZH2/SIRT6 axis significantly suppressed lipid accumulation and inflammation in vitro, and NAFLD development in vivo. Therefore, boosting MEG3 level may benefit the treatment of NAFLD.
Background: Kawasaki disease (KD) is the main cause of acquired heart disease in children and can lead to coronary artery lesions. This present study was designed to analyze the characteristics of KD peripheral blood mononuclear cells (PBMC) through single-cell RNA sequecing (scRNA-seq) and to explore the potential molecular mechanism of KD.Methods: PBMC was collected from one healthy child and one KD patient, and was used to single-cell RNA sequencing for cell clusters identification and differently expressed gene (DEG) determination. GO function enrichment analysis of DEG in B cell and T cells were performed to explore the most active biological function in KD immune cells. Results: 13 cell clusters can be identified in two samples. Compared with healthy child, naive CD8+ T cell, T helper cell and B cell in KD child were decreased, mainly immune-related T cells, and natural killer T (NKT) cell and neutrophil were increased. Cell activation, lymphocyte activation and regulation of immune system process were 3 GO function shared by all four types of T cells and B cell.Conclusions: Immune cell disorder appears in the KD patient at single cell level by scRNA-seq.
Background: Kawasaki disease (KD) is an acute self-limiting systemic vasculitis. In study, a randomized controlled trial regarding berberine (main component of Coptidis Rhizoma) function in treating KD was carried out and possible pharmacological mechanisms of Coptidis Rhizoma (CR) on KD therapy were investigated using an integrated network pharmacology approach. Methods: A total of 58 children with KD, younger than 5 years old, were enrolled in the study from October 2018 to May 2019. The patients were randomly divided into control group and BBR treatment group. The therapeutic indicators of the 2 groups before and after treatments were compared. Then, compounds and drug targets of CR from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the SWISS database, the SEA database and the STITCH database were collected, and targeted KD genes were retrieved from the DisGeNET databases, the DrugBank databases and the GeneCards databases. The network pharmacology approach involved network construction, target prediction, and module analysis. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to CR for KD treatments. Results: The berberine group was able to reduce the values of CRP, NLR and PLR significantly. Also, the effect of berberine improved the resistance rate of intravenous injection of gamma globulin significantly. In total, 9 compounds and 369 relative drug targets were collected from TCMSP, SWISS, SEA and STITCH database and 624 KD target genes were collected in DisGeNET, DrugBank and GeneCards database. The network analysis revealed that 41 targets might be the therapeutic targets of CR on KD, among which ATK1, RELA, SRC, CASP3 and MTOR ranked in top 5. Gene ontology enrichment analysis revealed that the reaction to bacteria-derived molecules and to lipopolysaccharide and the apoptosis process were the key biological procedures for CR treating KD. The KEGG pathway enrichment analysis pointed out that the four signaling pathways closely related to CR treating KD including age-rage signaling pathway, fluid shear stress and atherosclerosis, TNF signaling pathway and Toll-like receptor signaling pathway in diabetic complications. Conclusions: we concluded that the introduction of routine treatment combined with berberine in treating KD has advantages than routine treatment and can be considered as a preferred approach in KD. Network pharmacology showed that CR exerted the effect of prevention KD by regulating multi-targets and multi-components.
Background Kawasaki Disease (KD) is an acute self-limiting systemic vasculitis syndrome which can result in arterial damage especially in coronary artery. To find possible new biomarkers for the diagnosis of KD by Data independent acquisition (DIA) quantitative proteomics. Methods Twenty-seven patients with KD were enrolled in the present study, further, gingival crevicular fluid of before IVIG treatment with KD was collected as the experimental group. Meanwhile, 18 healthy volunteers were recruited as the control group.DIA quantitative proteomics mass spectrometry analysis was performed on the GCF samples of each group, and the protein expression profiles of the two groups of GCF were detected. Function enrichment of DEP by KEGG and GO, protein-protein interaction (PPI) analysis for all the DEPs detected, Finally, the multiple reaction monitoring mass spectrometry method was used to verify the selected DEPs. Results 197 DEPs (174 up-regulated and 23 down-regulated) were detected in the CGF between the KD group and the normal control group. Cellular process and metabolic process, binding and catalytic activity are the most altered biological process and molecular function, respectively. NOD−like receptor signaling pathway, Protein processing in endoplasmic reticulum pathway and influenza pathway are most significant pathway. EIF2AK2, B2M and GBP1 are kernel proteins in PPI network. The results of MRM-MS of 12 DEPs including IFIT3, UB2L6, HP, A1AT, HSP90AA1, HNRPC, HSP90AB1, SAA1, MX1, B2M, FKBP4 and TRAP1 were highly consistent with DIA. Conclusions We suggested that 12 proteins in GCF could be used as new biomarkers for early diagnosis of KD. We also found that KD is closely related to gingival inflammation at the molecular level, which provides new ideas and directions for the diagnosis and treatment of KD.
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