Jie-Du-Hua-Yu Granules Promote Liver Regeneration in Rat Models of Acute Liver Failure: miRNA-mRNA Expression Analysis.

Tingshuai Wang,Na Wang,Shaodong Huang,Fuli Long,Rongzhen Zhang,Hua Qiu,Dewen Mao,Minggang Wang,Hua Li

doi:10.1155/2020/8180959

Abstract

Purpose Jie-Du-Hua-Yu (JDHY) granules are a traditional Chinese medicine with known therapeutic effects for the treatment of acute liver failure (ALF). This study explored the potential molecular mechanism(s) of JDHY granules in promoting liver regeneration and preventing ALF. Methods Rat models of ALF were constructed through administration of D-galactosamine (D-GalN) (600 mg/kg) and lipopolysaccharides (LPS) (20 μg/kg). Rats were gavaged with JDHY granules, and serum and liver samples were collected at 12 h post-D-GalN/LPS administration. The degree of liver injury was evaluated through hepatic pathology and alanine/aspartate aminotransferase (ALT/AST) activity. miRNA chips were used to detect the miRNA expression profiles of rat models. Bioinformatics analysis was used to identify the biological processes and cell signaling pathways mediating the therapeutic effects of JDHY. Real-time PCR (RT-PCR) and western blotting were used to validate the data. Results JDHY granules could effectively decrease the levels of ALT and AST, relieve D-GalN/LPS-induced liver injury, and improve hepatic function. JDHY granules were found to regulate the expression of 20 miRNAs and 19 mRNAs, which influenced 21 biological processes and 9 signaling pathways. Upon analysis of the therapeutic mechanism(s) governing the effects of JDHY granules on liver regeneration, enhanced DNA replication and an improved cholesterol metabolic ratio were identified. JDHY granules were also found to increase the expression of MCM3, CDK4, and TC, confirming the involvement of these pathways. Moreover, JDHY granules were found to promote hepatocyte mitosis and inhibit the progression of ALF. Conclusion JDHY granules protect against D-GalN/LPS-induced ALF in rats by promoting liver regeneration through enhanced DNA replication and an improved cholesterol metabolic ratio.

Highlights

Acute liver failure (ALF) is a life-threatening illness that is accompanied by rapid progression and poor prognosis [1]
Following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we examined the relationship between the miRNAs and mRNAs in terms of DNA replication. e JDHY granules downregulated the expression of miR-3573-5p, miR-3549, miR-328a-5p, and miR-672-5p and upregulated the expression of MCM2, MCM3, and MCM5
We demonstrated that JDHY granules can affect DNA replication by upregulating MCM2, MCM3, and MCM5 via the downregulation of miR-3573-5p, miR-3549, miR-328a-5p, and miR-672-5p (Figure 5(a))

Summary

Introduction

Acute liver failure (ALF) is a life-threatening illness that is accompanied by rapid progression and poor prognosis [1]. Hepatitis B virus (HBV)related ALF has a high incidence in China, with mortality rates as high as 60 to 80% without liver transplantation [2]. Hepatic failure is characterized by the loss of hepatocytes [4], the regeneration of which can compensate liver function, leading to a favorable prognosis during liver failure. Methods to promote hepatocyte regeneration in clinical medicine are currently lacking. MiRNAs are key to the control of liver function and hepatocyte proliferation [5, 6]. It has been shown that a number of miRNAs participate in cell proliferation and liver regeneration during ALF [7].

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Conclusion