Xanthohumol protect against acetaminophen-induced hepatotoxicity via Nrf2 activation through the AMPK/Akt/GSK3β pathway

被引:12
作者
Zhu, Laiyu [1 ]
Fan, Xiaoye [1 ]
Cao, Chunyuan [3 ]
Li, Kailiang [3 ]
Hou, Wenli [2 ]
Ci, Xinxin [1 ]
机构
[1] Jilin Univ, Inst Translat Med, Hosp 1, Changchun 130001, Jilin, Peoples R China
[2] Jilin Univ, Dept Cadre Ward, Hosp 1, 71 Xinmin St, Changchun 130021, Jilin, Peoples R China
[3] Jilin Prov Peoples Hosp, Dept Hepatobiliary Pancreat Surg, Changzhun, Peoples R China
基金
中国国家自然科学基金;
关键词
Acetaminophen; Hepatotoxicity; Oxidative stress; Xanthohumol; Nrf2; APAP-INDUCED HEPATOTOXICITY; OXIDATIVE STRESS; LIVER-INJURY; MITOCHONDRIA; AMPK; TRANSLOCATION; INHIBITION; MECHANISMS; APOPTOSIS; NECROSIS;
D O I
10.1016/j.biopha.2023.115097
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Objective: Acetaminophen (APAP) is one of the world's popular and safe painkillers, and overdose can cause severe liver damage and even acute liver failure. The effect and mechanism of the xanthohumol on acetaminophen-induced hepatotoxicity remains unclear.Methods: The hepatoprotective effects of xanthohumol were studied using APAP-induced HepG2 cells and acute liver injury of mouse, seperately.Results: In vitro, xanthohumol inhibited H2O2- and acetaminophen-induced cytotoxicity and oxidative stress. Xanthohumol up-regulated the expression of Nrf2. Further mechanistic studies showed that xanthohumol triggered Nrf2 activation via the AMPK/Akt/GSK3 & beta; pathway to exert a cytoprotective effect. In vivo, xanthohumol significantly ameliorated acetaminophen-induced mortality, the elevation of ALT and AST, GSH depletion, MDA formation and histopathological changes. Xanthohumol effectively suppressed the phosphorylation and mitochondrial translocation of JNK, mitochondrial translocation of Bax, the activation o cytochrome c, AIF secretion and Caspase-3. In vivo, xanthohumol increased Nrf2 nuclear transcription and AMPK, Akt and GSK3 & beta; phosphorylation in vivo. In addition, whether xanthohumol protected against acetaminophen-induced liver injury in Nrf2 knockout mice has not been illustated.Conclusion: Thus, xanthohumol exerted a hepatoprotective effect by inhibiting oxidative stress and mitochondrial dysfunction through the AMPK/Akt/GSK3 & beta;/Nrf2 antioxidant pathway.
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页数:14
相关论文
共 36 条
[1]   Mitochondrial Bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity [J].
Bajt, Mary Lynn ;
Farhood, Anwar ;
Lemasters, John J. ;
Jaeschke, Hartmut .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 324 (01) :8-14
[2]   Liver Regeneration after Acetaminophen Hepatotoxicity Mechanisms and Therapeutic Opportunities [J].
Bhushan, Bharat ;
Apte, Udayan .
AMERICAN JOURNAL OF PATHOLOGY, 2019, 189 (04) :719-729
[3]   Dual Role of Epidermal Growth Factor Receptor in Liver Injury and Regeneration after Acetaminophen Overdose in Mice [J].
Bhushan, Bharat ;
Chavan, Hemantkumar ;
Borude, Prachi ;
Xie, Yuchao ;
Du, Kuo ;
McGill, Mitchell R. ;
Lebofsky, Margitta ;
Jaeschke, Hartmut ;
Krishnamurthy, Partha ;
Apte, Udayan .
TOXICOLOGICAL SCIENCES, 2017, 155 (02) :363-378
[4]   Emergency Department Visits for Overdoses of Acetaminophen-Containing Products [J].
Budnitz, Daniel S. ;
Lovegrove, Maribeth C. ;
Crosby, Alexander E. .
AMERICAN JOURNAL OF PREVENTIVE MEDICINE, 2011, 40 (06) :585-592
[5]   Acetaminophen-related Hepatotoxicity [J].
Bunchorntavakul, Chalermrat ;
Reddy, K. Rajender .
CLINICS IN LIVER DISEASE, 2013, 17 (04) :587-+
[6]   An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen [J].
Chan, KM ;
Han, XD ;
Kan, YW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (08) :4611-4616
[7]   AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress [J].
Choi, Song Hwa ;
Kim, Young Woo ;
Kim, Sang Geon .
BIOCHEMICAL PHARMACOLOGY, 2010, 79 (09) :1352-1362
[8]  
Daskalopoulos EP, 2016, EXPERIENTIA SUPPL, V107, P179, DOI 10.1007/978-3-319-43589-3_8
[9]  
Degott Claude, 1997, Pathol Oncol Res, V3, P260
[10]   Isoorientin Ameliorates APAP-Induced Hepatotoxicity via Activation Nrf2 Antioxidative Pathway: The Involvement of AMPK/Akt/GSK3β [J].
Fan, Xiaoye ;
Lv, Hongming ;
Wang, Lidong ;
Deng, Xuming ;
Ci, Xinxin .
FRONTIERS IN PHARMACOLOGY, 2018, 9