Abstract
Background: Paeoniflorin (PF), the major active compound isolated from the roots of Paeonia lactiflora Pall., has been used in the treatment of severe hepatic diseases for several decades and displays bright prospects in liver protective effect. However, its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis.Methods: The hepatoprotective effect of PF against cholestasis liver injury, induced by α-naphthylisothiocyanate (ANIT), was evaluated in rats. The serum biochemical indices including ALT, AST, TBA, TBIL, ALP, ALB, and the pathological characteristics of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to explore the feces of rats with ANIT-induced cholestatic liver injury treated with PF and the potential biomarkers were screened by metabolomics. The targets for the regulation of potential biomarkers by PF were screened by network pharmacology, and then the relevant key targets were verified by immunohistochemical and western blotting methods.Results: PF significantly improved serum indexes and alleviated liver histological damage. Metabolomics analyses showed that the therapeutic effect of PF is mainly associated with the regulation of 13 metabolites involved in 16 metabolic pathways. The “PF-targets-metabolites” interaction network was constructed, and then five key targets including CDC25B, CYP2C9, MAOB, mTOR, and ABCB1 that regulated the potential biomarkers were obtained. The above five targets were further verified by immunohistochemistry and western blotting, and the results showed that PF significantly improved the expression of key proteins regulating these biomarkers.Conclusion: Our study provides direct evidence for the modulatory properties of PF treatment on ANIT-induced cholestatic liver injury using metabolomics and network pharmacology analyses. PF exhibits favorable pharmacological effect by regulating related signal pathways and key targets for biomarkers. Therefore, these findings may help better understand the complex mechanisms and provide a new and effective approach to the treatment of cholestatic liver injury.
Highlights
Cholestasis is a pathological process caused by the disturbance of bile secretion and excretion, which is characterized by excessive accumulation of bile acids, cholesterol, bilirubin and other bile components in the liver and systemic circulation, leading to liver lesions (Chen et al, 2018)
The levels of ALT, aspartate transaminase (AST), total bile acid (TBA), total bilirubin (TBIL), and alkaline phosphatase (ALP) were reduced after treatment with the PF, which coincided with the findings of our previous study (Chen et al, 2016)
The specimens from PFH group displayed potent decrease in inflammatory cell infiltration, destructive interlobular ducts and necrosis. These results indicated that PF significantly protected against ANIT-induced cholestatic liver injury (Figure 2)
Summary
Cholestasis is a pathological process caused by the disturbance of bile secretion and excretion, which is characterized by excessive accumulation of bile acids, cholesterol, bilirubin and other bile components in the liver and systemic circulation, leading to liver lesions (Chen et al, 2018). Obecholic acid (OCA) can significantly improve the biochemical indexes, delay the disease progression and improve the survival rate of PBC patients who do not respond well or tolerate UDCA treatment, but it produces serious side effects such as pruritus during OCA treatment, and excessive use of OCA aggravates liver injury (Kowdley et al, 2018). The search for drugs related to the treatment of cholestatic liver injury has been the focus of research in recent years. Its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis
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