E3 ubiquitin ligase COP1-mediated CEBPB ubiquitination regulates the inflammatory response of macrophages in sepsis-induced myocardial injury.

CCAAT/enhancer-binding protein beta (CEBPB) has been associated with sepsis. However, its role in sepsis-induced myocardial injury (SIMI) remains ill-defined. This research was designed to illustrate the involvement of CEBPB in SIMI and its upstream modifier. The transcriptomic changes in heart biopsies of mice that had undergone polymicrobial sepsis were downloaded from the GEO dataset for KEGG enrichment analysis. CEBPB, on the TNF signaling pathway, was significantly enhanced in the myocardial tissues of mice with SIMI. Downregulation of CEBPB alleviated SIMI, as evidenced by minor myocardial injury and inflammatory manifestations. Moreover, ubiquitination modification of CEBPB by constitutive photomorphogenesis protein 1 homolog (COP1) led to the degradation of CEBPB and inhibited inflammatory responses in macrophages. Upregulation of COP1 protected against SIMI in mice overexpressing CEBPB. Collectively, our findings demonstrated that COP1 protected the heart against SIMI through the ubiquitination modification of CEBPB, which might be a novel therapeutic approach in the future.

Evidence from Machine Learning, Diagnostic Hub Genes in Sepsis and Diagnostic Models based on Xgboost Models, Novel Molecular Models for the Diagnosis of Sepsis.

BACKGROUND: Systemic multi-organ dysfunction resulting from dysregulated immune responses in the host triggered by microbial infection or other factors is a major cause of death in sepsis, and secretory pathways play an important role in it. METHODS: GSE57065, GSE65682, GSE145227, and GSE54514 from Gene Expression Omnibus (GEO) were derived for this study. Secretory pathways single sample gene set enrichment analysis (ssGSEA) scores in sepsis and normal samples were exposed. Gene modules associated with secretory pathways were selected by weighted gene coexpression network analysis (WGCNA) for Protein-Protein Interaction Networks (PPI) assessment, and crossover genes in both were evaluated by eXtreme Gradient Boosting (XGBoost) model in feature selection to identify hub genes in sepsis. In addition, we explored the immune cells and signaling pathways regulated by hub genes. RESULTS: Remarkable dysregulation of secretory pathways was demonstrated in sepsis. The secretory pathways-associated gene modules were intimately involved in cytokine and immune responses in infection. Four crossover genes (CD163, FCER1G, C3AR1, ARG1) were present in WGCNA and PPI, and training in the XGBoost model revealed the best diagnostic performance of these 4 genes, meaning that these genes were the hub genes for sepsis. The 4-hub genes showed a significant negative correlation with T cell activity and a significant positive correlation with inflammatory immune cells. In addition, we found that the 4-hub genes markedly positively regulated INFLAMMATORY RESPONSE, IL6 JAK STAT3 SIGNALING. CONCLUSION: Based on WGCNA, PPI, and XGBoost models, we identified hub genes that play an important regulatory role in sepsis. We also developed novel molecular models for the diagnosis of sepsis.