Abstract
Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase-c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases.
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Funding
This work was supported by the National Natural Science Foundation of China (Nos. 81573332 and 81773620) and Special Research Foundation of State Key Laboratory of Medical Genomics and Collaborative Innovation Center of Systems Biomedicine.
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All animal care and experiment procedures complied with the Animal Management Rules of China and were approved by the Animal Care Committee of Fudan University.
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All applicable international, national, and institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Zai, W., Chen, W., Luan, J. et al. Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy. Appl Microbiol Biotechnol 102, 1443–1453 (2018). https://doi.org/10.1007/s00253-017-8686-6
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DOI: https://doi.org/10.1007/s00253-017-8686-6