Abstract
Aim:
The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect.
Methods:
Male C57BL/6 mice were treated with SolB (200 mg·kg−1·d−1, ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay.
Results:
SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5–20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells.
Conclusion:
SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.
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Acknowledgements
This study was financially supported by the National Natural Science Foundation of China (No 81373470 and 81320108027), the Major Scientific and Technological Project (No 2012ZX09303012-002 and 2011A080300001), Guangdong Provincial Key Laboratory and Natural Science Foundation of Guangdong Province (No 2011A060901014 and S2012030006240), and the National Science and Technology Support Plan Projects (No 2012BAI29B09).
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Jiang, Ym., Wang, Y., Tan, Hs. et al. Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway. Acta Pharmacol Sin 37, 382–389 (2016). https://doi.org/10.1038/aps.2015.120
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DOI: https://doi.org/10.1038/aps.2015.120
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