PMID- 29338970 OWN - NLM STAT- MEDLINE DCOM- 20190109 LR - 20220408 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 150 DP - 2018 Apr TI - Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: The involvement of ERK1/2 and PKC. PG - 9-23 LID - S0006-2952(18)30026-1 [pii] LID - 10.1016/j.bcp.2018.01.026 [doi] AB - Acetaminophen (APAP)-induced hepatotoxicity is the main cause of drug-induced liver injury. This study investigated the protection of baicalin and its aglycone baicalein against APAP-induced hepatotoxicity and its mechanism. Baicalein and baicalin alleviated APAP-induced hepatotoxicity both in vitro and in vivo. Moreover, this baicalin-provided protection was not diminished in hepatocytes or mice treated with beta-glucuronidase inhibitor. Results of liver glutathione (GSH) and reactive oxygen species (ROS) formation demonstrated the alleviation of baicalein and baicalin on APAP-induced liver oxidative stress injury. Baicalein and baicalin induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the expression of its downstream antioxidant genes. Baicalein and baicalin-provided protection was diminished after the application of Nrf2 siRNA in hepatocytes and Nrf2 knock-out mice. Molecular docking results indicate the potential interaction of baicalein and baicalin with kelch-like ECH-associated protein-1 (Keap1). Baicalein and baicalin induced the sustained phosphorylation of extracellular regulated protein kinases (ERK)1/2 and protein kinase C (PKC). Moreover, ERK1/2 and PKC inhibitors both abrogated Nrf2 phosphorylation and its subsequent activation, and the protection against APAP-induced hepatotoxicity induced by baicalein and baicalin. In summary, baicalein and baicalin alleviate APAP-induced hepatotoxicity by activating Nrf2 via blocking the binding of Nrf2 with Keap1 and inducing Nrf2 phosphorylation. ERK1/2 and PKC are both critical for regulating the phosphorylation of Nrf2 induced by baicalein or baicalin. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Shi, Liang AU - Shi L AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Hao, Zhanxia AU - Hao Z AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Zhang, Shaobo AU - Zhang S AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Wei, Mengjuan AU - Wei M AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Lu, Bin AU - Lu B AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Wang, Zhengtao AU - Wang Z AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. FAU - Ji, Lili AU - Ji L AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180112 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Analgesics, Non-Narcotic) RN - 0 (Antioxidants) RN - 0 (Enzyme Activators) RN - 0 (Flavanones) RN - 0 (Flavonoids) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Protein Kinase Inhibitors) RN - 347Q89U4M5 (baicalin) RN - 362O9ITL9D (Acetaminophen) RN - 49QAH60606 (baicalein) RN - EC 2.7.11.13 (Protein Kinase C) SB - IM MH - Acetaminophen/*toxicity MH - Analgesics, Non-Narcotic/toxicity MH - Animals MH - Antioxidants/pharmacology MH - Cell Line MH - Chemical and Drug Induced Liver Injury/*drug therapy/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activators/pharmacology MH - Flavanones/*pharmacology MH - Flavonoids/*pharmacology MH - MAP Kinase Signaling System/*drug effects/physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - NF-E2-Related Factor 2/*agonists/metabolism MH - Oxidative Stress/drug effects/physiology MH - Protein Kinase C/*antagonists & inhibitors/metabolism MH - Protein Kinase Inhibitors/pharmacology OTO - NOTNLM OT - Baicalin OT - ERK1/2 OT - Hepato-protection OT - Nrf2 OT - PKC EDAT- 2018/01/18 06:00 MHDA- 2019/01/10 06:00 CRDT- 2018/01/18 06:00 PHST- 2017/11/14 00:00 [received] PHST- 2018/01/10 00:00 [accepted] PHST- 2018/01/18 06:00 [pubmed] PHST- 2019/01/10 06:00 [medline] PHST- 2018/01/18 06:00 [entrez] AID - S0006-2952(18)30026-1 [pii] AID - 10.1016/j.bcp.2018.01.026 [doi] PST - ppublish SO - Biochem Pharmacol. 2018 Apr;150:9-23. doi: 10.1016/j.bcp.2018.01.026. Epub 2018 Jan 12.