Cardioprotection effect of Yiqi-Huoxue-Jiangzhuo formula in a chronic kidney disease mouse model associated with gut microbiota modulation and NLRP3 inflammasome inhibition.

BACKGROUND: The pathogenesis and treatment of cardiovascular disease mediated by chronic kidney disease (CKD) are key research questions. Specifically, the mechanisms underlying the cardiorenal protective effect of Yiqi-Huoxue-Jiangzhuo formula (YHJF), a traditional Chinese herbal medicine, have not yet been clarified. METHODS: A classical CKD mouse model was constructed by 5/6 nephrectomy (Nx) to study the effects of YHJF intervention on 5/6 Nx mice cardiorenal function, gut microbial composition, gut-derived metabolites, and NLRP3 inflammasome pathways. RESULTS: YHJF improved cardiac dysfunction and reversed left ventricular hypertrophy, myocardial hypertrophy, and interstitial fibrosis in 5/6 Nx mice. In addition, YHJF inhibited activation of the NLRP3 inflammasome and downregulated the expression of TNF-α and IL-1ß both in the heart and serum; reconstitution of the intestinal flora imbalance was also found in 5/6 Nx mice treated with YHJF. Spearman's correlation and redundancy analyses showed that changes in the intestinal flora of 5/6 Nx mice were related to clinical phenotype and serum inflammatory levels. CONCLUSIONS: Treatment with YHJF effectively protected the heart function of 5/6 Nx mice; this effect was attributed to inhibition of NLRP3 inflammasome activation and regulation of intestinal microbial composition and derived metabolites. YHJF has potential for improving intestinal flora imbalance and gut-derived toxin accumulation in patients with CKD, thereby preventing cardiovascular complications.

Computational identification of microRNAs and their targets in liver cirrhosis.

Previous studies have revealed that the deregulation of circulating miRNAs is associated with liver cirrhosis. The present study aimed to identify reliable candidate biomarkers to improve the early detection of liver cirrhosis. An integrated analysis of expression profiles of microRNAs (miRNAs/miRs) and mRNAs in liver cirrhosis tissues from the GEO database was performed. Next, the regulatory targets of the differentially expressed miRNAs in liver cirrhosis tissues were predicted. In addition, a regulatory network of miRNA-target genes was constructed. A total of 4 eligible mRNA expression profiling studies and 2 miRNA expression profiling studies met the inclusion criteria, and were thus included. A total of 48 differentially expressed miRNAs and 1,773 differentially expressed genes were identified in liver cirrhosis tissues compared with normal tissues. There were 240 miRNA-target pairs whose expression was negatively correlated. In the miRNA-target regulatory network, overexpression of miR-21 and miR-199a-3p was suggested to be closely associated with the progression of liver cirrhosis. In addition, functional enrichment analysis of the target genes indicated that cell cycle was the most significantly enriched pathway, and the dysregulation of leukemia inhibitory factor, cancerous inhibitor of protein phosphatase 2A and retinoblastoma-associated protein 1 clearly suggested their importance in the development of liver cirrhosis. We hypothesized that miR-21 and miR-199a-3p may be promising non-invasive diagnostic biomarkers for the early diagnosis of liver cirrhosis. The miRNA-target regulatory network may provide additional insight into the current data regarding the role of miRNAs in liver cirrhosis.