Abstract | BACKGROUND: HYPOTHESIS/PURPOSE: This study aimed to elucidate the effects and mechanisms of action of taraxasterol on APAP-induced liver injury using network pharmacology and in vitro and in vivo experiments. METHODS: Online databases of drug and disease targets were used to screen the targets of taraxasterol and DILI, and a protein-protein interaction network (PPI) was constructed. Core target genes were identified using the tool of Analyze of Cytoscape, gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses were performed. Oxidation, inflammation and apoptosis were evaluated to determine the effect of taraxasterol on APAP-stimulated liver damage in AML12 cells and mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the potential mechanisms of taraxasterol against DILI. RESULTS: Twenty-four intersection targets for taraxasterol and DILI were identified. Among them, 9 core targets were identified. GO and KEGG analysis showed that core targets are closely related to oxidative stress, apoptosis, and inflammatory response. The in vitro findings showed that taraxasterol alleviated mitochondrial damage in AML12 cells treated with APAP. The in vivo results revealed that taraxasterol alleviated pathological changes in the livers of mice treated with APAP and inhibited the activity of serum transaminases. Taraxasterol increased the activity of antioxidants, inhibited the production of peroxides, and reduced inflammatory response and apoptosis in vitro and in vivo. Taraxasterol promoted Nrf2 and HO-1 expression, suppressed JNK phosphorylation, and decreased the Bax/Bcl-2 ratio and caspase-3 expression in AML12 cells and mice. CONCLUSION: By integrating network pharmacology with in vitro and in vivo experiments, this study indicated that taraxasterol inhibits APAP-stimulated oxidative stress, inflammatory response and apoptosis in AML12 cells and mice by regulating the Nrf2/HO-1 pathway, JNK phosphorylation, and apoptosis-related protein expression. This study provides a new evidence for the use of taraxasterol as a hepatoprotective drug.
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Authors | Bingjie Ge, Rui Sang, Wei Wang, Kexin Yan, Yifan Yu, Lin Kong, Minghong Yu, Xinman Liu, Xuemei Zhang |
Journal | Phytomedicine : international journal of phytotherapy and phytopharmacology
(Phytomedicine)
Vol. 116
Pg. 154872
(Jul 25 2023)
ISSN: 1618-095X [Electronic] Germany |
PMID | 37209606
(Publication Type: Journal Article)
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Copyright | Copyright © 2023 Elsevier GmbH. All rights reserved. |
Chemical References |
- Acetaminophen
- taraxasterol
- NF-E2-Related Factor 2
- Triterpenes
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Topics |
- Animals
- Mice
- Acetaminophen
(adverse effects)
- NF-E2-Related Factor 2
(metabolism)
- Chemical and Drug Induced Liver Injury, Chronic
(metabolism)
- Network Pharmacology
- Liver
- Triterpenes
(pharmacology, metabolism)
- Oxidative Stress
- Chemical and Drug Induced Liver Injury
(metabolism)
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