1. Lignans from Schisandra chinensis ameliorate alcohol and CCl 4 -induced long-term liver injury and reduce hepatocellular degeneration via blocking ETBR.
- Author
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Xu JB, Gao GC, Yuan MJ, Huang X, Zhou HY, Zhang Y, Zheng YX, Wu Z, Feng JM, and Wu JM
- Subjects
- Animals, Antioxidants isolation & purification, Antioxidants pharmacology, Apoptosis drug effects, Carbon Tetrachloride, Cell Line, Chemical and Drug Induced Liver Injury pathology, Computer Simulation, Disease Models, Animal, Hepatic Stellate Cells drug effects, Hepatic Stellate Cells pathology, Hepatocytes drug effects, Hepatocytes pathology, Humans, Lignans isolation & purification, Liver Diseases, Alcoholic pathology, Male, Mice, Mice, Inbred C57BL, Plant Extracts pharmacology, Receptor, Endothelin B drug effects, Chemical and Drug Induced Liver Injury prevention & control, Lignans pharmacology, Liver Diseases, Alcoholic prevention & control, Schisandra chemistry
- Abstract
Ethnopharmacological Relevance: Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl
4 -induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes., Aim of the Study: This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection., Materials and Methods: We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro., Results: The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl4 -induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCβ, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-β1 (TGF-β1) level., Conclusion: The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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