RESUMO
Japanese Ardisia is widely used as a hepatoprotective and anti-inflammatory agent in China. However, the active ingredients in Japanese Ardisia and their potential mechanisms of action in the treatment of autoimmune hepatitis (AIH) are unknown. The pharmacodynamic substance and mechanism of action of Japanese Ardisia in the treatment of AIH were investigated using network pharmacology and molecular docking technology in this study. Following that, the effects of Japanese Ardisia were evaluated using the concanavalin A (Con A)-induced acute liver injury rat model. The active ingredients and targets of Japanese Ardisia were searched using the Traditional Chinese Medicine Systems Pharmacology database, and hepatitis-related therapeutic targets were identified through GeneCards and Online Mendelian Inheritance in Man databases. A compound-target network was then constructed using Cytoscape software, and enrichment analysis was performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Molecular docking technology was used to simulate the docking of key targets, and the AIH rat model was used to validate the expression of key targets. Nineteen active chemical components and 143 key target genes were identified. GO enrichment analysis revealed that the treatment of AIH with Japanese Ardisia mainly involved DNA-binding transcription factor binding, RNA polymerase II-specific DNA transcription factor binding, cytokine receptor binding, receptor-ligand activity, ubiquitin-like protein ligase binding, and cytokine activity. In the KEGG enrichment analysis, 165 pathways were identified, including the lipid and atherosclerotic pathway, IL-17 signaling pathway, TNF signaling pathway, hepatitis B pathway, and the AGE-RAGE signaling pathway in diabetic complications. These pathways may be the key to effective AIH treatment with Japanese Ardisia. Molecular docking showed that quercetin and kaempferol have good binding to AKT1, IL6, VEGFA, and CASP3. Animal experiments demonstrated that Japanese Ardisia could increase the expression of AKT1 and decrease the expression of CASP3 protein, as well as IL-6, in rat liver tissues. This study identified multiple molecular targets and pathways for Japanese Ardisia in the treatment of AIH. At the same time, the effectiveness of Japanese Ardisia in treating AIH was verified by animal experiments.
RESUMO
The mechanism of action of Ardisia japonica in the treatment of immune liver injury was systematically analyzed from the perspective of the biological metabolic network by using non-targeted metabolomics combined with biological network analysis tools. A rat model of acute immune hepatic injury was established by Concanavalin A (Con A) and the efficacy of the treatment of acute immune liver injury was judged by gavage of A. japonica. Liquid chromatography-mass spectrometry (LC-MS)-based plasma metabolomics was used to identify the key metabolites and metabolic pathways for the hepatoprotective effects of A. japonica. The results demonstrated that A. japonica reduced the levels of inflammatory parameters, decreased hepatic malondialdehyde levels, and enhanced hepatic antioxidant enzyme activity in animal experiments. The clustering of metabolomic samples showed significant separation in principal component analysis plots and the three groups in PLS-DA and OPLS-DA models could be clearly distinguished in multivariate statistical analysis. Among the 937 total metabolites, 445 metabolites were significantly different between the control and model groups, while 144 metabolites were identified as metabolites with differences between the model and administration groups, and a total of 39 differential metabolites were identified to affect the metabolic levels of the three groups. The differential metabolites were principally involved in the citric acid cycle, glutathione metabolism, vitamin B6 metabolism, and steroid hormone biosynthesis. This study found that A. japonica can significantly inhibit acute liver injury in rats, and exert a hepatoprotective effect through anti-inflammatory effect, inhibition of lipid peroxidation, improvement of the antioxidant defense system, and regulation of metabolites and related metabolic pathways. This study will provide a theoretical basis for the application of A. japonica in the treatment of the liver injury.
