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The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity.
Free Radic Biol Med. 2015 Aug; 85:12-23.FR

Abstract

Quercetin, one of the most abundant dietary flavonoids, is reported to have protective function against various hepatotoxicant-induced hepatotoxicity. The present study aims to investigate the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative signaling pathway in the protection of quercetin against hepatotoxicity. Quercetin prevented the cytotoxicity induced by a variety of hepatotoxicants including clivorine (Cliv), acetaminophen (APAP), ethanol, carbon tetrachloride (CCl4), and toosendanin (TSN) in human normal liver L-02 cells. Quercetin induced the nuclear translocation of Nrf2, along with the increased expression of the antioxidant responsive element (ARE)-dependent genes like catalytic or modify subunit of glutamate-cysteine ligase (GCLC/GCLM), and heme oxygenase-1 (HO-1). In addition, the HO-1 inhibitor zinc protoporphyrin (ZnPP) and the GCL inhibitor L-buthionine-(S,R)-sulfoximine (BSO) both reduced the hepatoprotection induced by quercetin. Quercetin had no effect on kelch-like ECH-associated protein-1(Keap1) expression, but molecular docking results indicated the potential interaction of quercetin with the Nrf2-binding site in Keap1 protein. Quercetin increased the expression of p62, and p62 siRNA decreased quercetin-induced hepatoprotection. Quercetin induced the activation of c-Jun N-terminal kinase (JNK) in hepatocytes. JNK inhibitor SP600125 and JNK siRNA both reduced quercetin-induced hepatoprotection. SP600125 and JNK siRNA decreased the increased p62 expression induced by quercetin. In addition, SP600125 also decreased the increased mRNA and protein expression of GCLC, GCLM, and HO-1 induced by quercetin. Taken together, our present study demonstrates that quercetin prevents hepatotoxicity by inducing p62 expression, inhibiting the binding of Keap1 to Nrf2, and thus leading to the increased expression of antioxidative genes dependent on Nrf2. Meanwhile, our study indicates that JNK plays some regulation in this process.

Authors+Show Affiliations

Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lichenyue1307@126.com.Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: ztwang@shutcm.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25881548

Citation

Ji, Li-Li, et al. "The Involvement of p62-Keap1-Nrf2 Antioxidative Signaling Pathway and JNK in the Protection of Natural Flavonoid Quercetin Against Hepatotoxicity." Free Radical Biology & Medicine, vol. 85, 2015, pp. 12-23.
Ji LL, Sheng YC, Zheng ZY, et al. The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radic Biol Med. 2015;85:12-23.
Ji, L. L., Sheng, Y. C., Zheng, Z. Y., Shi, L., & Wang, Z. T. (2015). The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radical Biology & Medicine, 85, 12-23. https://doi.org/10.1016/j.freeradbiomed.2015.03.035
Ji LL, et al. The Involvement of p62-Keap1-Nrf2 Antioxidative Signaling Pathway and JNK in the Protection of Natural Flavonoid Quercetin Against Hepatotoxicity. Free Radic Biol Med. 2015;85:12-23. PubMed PMID: 25881548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. AU - Ji,Li-Li, AU - Sheng,Yu-Chen, AU - Zheng,Zhi-Yong, AU - Shi,Liang, AU - Wang,Zheng-Tao, Y1 - 2015/04/14/ PY - 2014/10/31/received PY - 2015/03/23/revised PY - 2015/03/29/accepted PY - 2015/4/18/entrez PY - 2015/4/18/pubmed PY - 2016/5/27/medline KW - Hepatotoxicity KW - JNK KW - Keap1 KW - Nrf2 KW - Quercetin KW - p62 SP - 12 EP - 23 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 85 N2 - Quercetin, one of the most abundant dietary flavonoids, is reported to have protective function against various hepatotoxicant-induced hepatotoxicity. The present study aims to investigate the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative signaling pathway in the protection of quercetin against hepatotoxicity. Quercetin prevented the cytotoxicity induced by a variety of hepatotoxicants including clivorine (Cliv), acetaminophen (APAP), ethanol, carbon tetrachloride (CCl4), and toosendanin (TSN) in human normal liver L-02 cells. Quercetin induced the nuclear translocation of Nrf2, along with the increased expression of the antioxidant responsive element (ARE)-dependent genes like catalytic or modify subunit of glutamate-cysteine ligase (GCLC/GCLM), and heme oxygenase-1 (HO-1). In addition, the HO-1 inhibitor zinc protoporphyrin (ZnPP) and the GCL inhibitor L-buthionine-(S,R)-sulfoximine (BSO) both reduced the hepatoprotection induced by quercetin. Quercetin had no effect on kelch-like ECH-associated protein-1(Keap1) expression, but molecular docking results indicated the potential interaction of quercetin with the Nrf2-binding site in Keap1 protein. Quercetin increased the expression of p62, and p62 siRNA decreased quercetin-induced hepatoprotection. Quercetin induced the activation of c-Jun N-terminal kinase (JNK) in hepatocytes. JNK inhibitor SP600125 and JNK siRNA both reduced quercetin-induced hepatoprotection. SP600125 and JNK siRNA decreased the increased p62 expression induced by quercetin. In addition, SP600125 also decreased the increased mRNA and protein expression of GCLC, GCLM, and HO-1 induced by quercetin. Taken together, our present study demonstrates that quercetin prevents hepatotoxicity by inducing p62 expression, inhibiting the binding of Keap1 to Nrf2, and thus leading to the increased expression of antioxidative genes dependent on Nrf2. Meanwhile, our study indicates that JNK plays some regulation in this process. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/25881548/The_involvement_of_p62_Keap1_Nrf2_antioxidative_signaling_pathway_and_JNK_in_the_protection_of_natural_flavonoid_quercetin_against_hepatotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(15)00159-8 DB - PRIME DP - Unbound Medicine ER -