Elsevier

Bioorganic Chemistry

Volume 96, March 2020, 103553
Bioorganic Chemistry

Network pharmacology based investigation into the bioactive compounds and molecular mechanisms of Schisandrae Chinensis Fructus against drug-induced liver injury

https://doi.org/10.1016/j.bioorg.2019.103553Get rights and content

Highlights

  • The blood components and network pharmacology were combined to predict targets.

  • 17 active ingredients, 15 signal pathways and 14 core key targets were predicted.

  • The S. Chinensis Fructus (SCF) against DILI were involved in the ErbB pathways.

  • Taking ALP and others as indicators, the pharmacodynamics of SCF was validated.

  • The SCF play a role against DILI by the inflammatory factors, oxidative stress.

Abstract

Objective

To investigate the against Drug-induced liver injury ingredients and their functional mechanisms in S. Chinensis Fructus.

Methods

Liquid chromatograph-mass spectrometry analysis was performed on S. Chinensis Fructus extrac. The “Components-Target-Disease” network model was constructed by network pharmacology-based approaches. String analysis was performed to reveal enrichment of these target proteins, protein-protein interactions, pathways and related diseases. And experiment of APAP-induced drug-induced liver injury was to be verified.

Results

Cytoscape was used to determine the potential protein targets for these components in S. Chinensis Fructus, indicating that 17 against Drug-induced liver injury compounds in S. Chinensis Fructus regulate 52 diabetes-related proteins in 15 signal pathways and involve 14 core key targets. Verification experiment results that S. Chinensis Fructus prevented the elevation of serum biochemical parameters including aspartate aminotransferase (AST), alanine aminotransferase (ALT), purine nucleoside phosphorylase (PNP) and alkaline phosphatase (ALP) against acute liver failure. Additionally, S. Chinensis Fructus reduced the content of malondialdehyde (MDA), increased the levels of the Superoxide dismutase (SOD) and Glutathione (GSH), and inhibited the production of proinflammatory cytokines in APAP-induced hepatotoxicity.

Conclusion

The mechanisms of S. Chinensis Fructus against Drug-induced liver injury were involved in the regulation of multiple targets, especially affecting the ErbB signaling pathways. The active ingredients of S. Chinensis Fructus may play a role against Drug-induced liver injury by participating in the regulation of inflammatory factors, oxidative stress.

Introduction

Acetaminophen (APAP) is one of the commonly drugs used for clinical analgesia, antipyretic and anti-inflammatory [1]. Although conventional dosage of APAP is safe and effective, excessive or long-term use of APAP can cause hepatotoxicity and acute liver failure (ALF), which can cause hepatocyte necrosis in the center of lobules, and can be fatal in severe cases [9], [12], [13]. As a traditional medicinal plant, Schisandrae Chinensis Fructus (SCF) has satisfactory drug efficacy for protect liver, which indicates the existence of certain pharmacological components in SCF. Schisandrin A, Schisandrin B and Schisandrin C can enhance the detoxification function of liver and the activity of hepatocyte cytochrome P450, promote the biosynthesis of hepatic protein and glycogen. Schisandrin B can also reduce serum Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST). Table.1.

As a new field in modern traditional Chinese medicine (TCM) pharmacological studies, network pharmacology can be used to predict the targets of action with TCM and identify the active components of TCM, explore the mechanism of the TCM as disease treatments using many existing databases, pathway analysis, and network analysis [26]. Network pharmacology is focused on the compounds and targets in the interactome. By establishing a multi-level network model of “multi-components-multi-targets-multiple diseases”, we can simultaneously investigate the regulatory role of TCM on multiple signaling pathways, systematically reveal the core molecular targets and pharmacodynamic biological network of TCM, and explain its molecular mechanism of action, which is becoming increasingly popular, particularly when deals with the complex systems [7], [8].

In the 1970s, Chinese scholars found that SCF have obvious liver-protecting and enzyme-lowering effects, and their active ingredients are mainly lignans of SCF [28]. Schisandrin A, Schisandrin B, Schisandrol A and Schisandrol B were the characteristic components of SCF [15]. Therefore, the key target and pathway of effective components in SCF to prevent and treat APAP-induced Drug-induced liver injury (DILI) were predicted by constructing the “Components-Target-Disease” network model. And combination with a prevention of drug-induced liver injury test to explore the potential pharmacodynamic material basis and prevention of DILI mechanism of SCF.

Section snippets

Extraction of bioactive ingredients from plasma of rats treated with SCF extraction

SCF was purchased from Anguo Chinese Herbal Medicine Co. Ltd. (Hebei, China) and was identified by professor Lin Ma (TianJin University of Traditional Chinese Medicine).

Preparation of SCF extracts, in simple terms, the 250 g sample powder was transferred into a 5L bottom flask followed by eight times of 85% ethanol (v/v) for two times (2 h/time). The solution was filtered and condensed. Then the solution evaporated under vacuum at 65 ℃ by rotary evaporation to obtain a solution with a crude

Identification of bioactive ingredients from plasma of mice treated with SCF extraction.

The UPLC-MS analysis showed strong signals, high peak capacity and good reproducibility for retention time. 17 metabolites including 7 prototype components and 10 metabolites were characterized in vivo following oral administration of SCF extract in mice. Typical BPI chromatograms of the substances in the SCF extract in vivo and the EICs were shown in Fig. 1.

Components-target network construction

17 active ingredients of SCF were mapped with ChemBioDraw Ultra 12.0 software and stored in mol2 format file. The reverse pharmacophore

Effect of SCF on serum biochemical markers

To evaluate the mouse liver damage affected by APAP, several serum biochemical markers (AST, ALT, PNP and ALP) of liver failure were determined. Increased levels of AST, ALT and PNP in all animals treated with APAP compared to the control group were observed (Fig. 5). Moreover, the APAP-induced mice had reduced the levels of serum ALP (Fig. 5). Compared with model group, the AST and ALT content in the high, middle, low dose groups, Schisandrin B, Schisandrol A and Schisandrol B decreased

Discuss

This study systematically explored the pharmacological mechanisms of SCF in the treatment of DILI through network pharmacology analysis and experimental verification. Network pharmacology can identify potentially active compounds, targets, and pharmacological mechanisms of complex compounds in Chinese herbal formulas [22], [24], [16]. A single component of SCF may act on multiple targets, while multiple components may act on a single target. It is possible that the active components with

Conclusion

In conclusion, Our research findings suggested that active ingredients in SCF may play a role against DILI by participating in the regulation of inflammatory factors, oxidative stress. This study provides a basis for further exploration on the DILI mechanism of SCF using a multi-compounds and multi-targets approach. In addition, it also provides a reference for the studies on the DILI mechanism of SCF.

Funding

This work was supported by Scientific Research Project of Tianjin Educational Committee (2019KJ081).

Declaration of Competing Interest

The authors declared that there is no conflict of interest.

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