Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis

被引:371
作者
Lv, Hongming [1 ,2 ]
Liu, Qinmei [1 ]
Wen, Zhongmei [1 ]
Feng, Haihua [2 ]
Deng, Xuming [1 ,2 ]
Ci, Xinxin [1 ]
机构
[1] Jilin Univ, Inst Translat Med, Hosp 1, Changchun 130001, Peoples R China
[2] Jilin Univ, Coll Vet Med, Key Lab Zoonosis, Minist Educ, Changchun 130061, Peoples R China
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
Xanthohumol; Acute lung injury; Oxidative stress; Inflammation; Nrf2/AMPK; NF-KAPPA-B; RESPIRATORY-DISTRESS-SYNDROME; OXIDATIVE STRESS; CELL-DEATH; NRF2; MICE; INFLAMMATION; PATHWAY; ACTIVATION; INHIBITION;
D O I
10.1016/j.redox.2017.03.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2) and/or AMP-activated protein kinase (AMPK) activation, which play crucial roles in the amelioration of various inflammation-and oxidative stress-induced diseases, including acute lung injury (ALI). Xanthohumol (Xn), a principal prenyl-flavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS) generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-kappa B signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3 beta phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-kappa B signaling pathway in WT mice were remarkably abrogated in Nrf2(-/-)mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3 beta, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-kappa B signaling pathway.
引用
收藏
页码:311 / 324
页数:14
相关论文
共 51 条
[1]   Reducing damage through Nrf-2 [J].
Balligand, Jean-Luc .
CARDIOVASCULAR RESEARCH, 2013, 100 (01) :1-3
[2]   AMP-activated protein kinase: new regulation, new roles? [J].
Carling, David ;
Thornton, Claire ;
Woods, Angela ;
Sanders, Matthew J. .
BIOCHEMICAL JOURNAL, 2012, 445 :11-27
[3]   Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice [J].
Cho, Hye-Youn ;
Jedlicka, Anne E. ;
Gladwell, Wesley ;
Marzec, Jacqui ;
McCaw, Zackary R. ;
Bienstock, Rachelle J. ;
Kleeberger, Steven R. .
ANTIOXIDANTS & REDOX SIGNALING, 2015, 22 (04) :325-338
[4]   NF-κB:: pivotal mediator or innocent bystander in atherogenesis? [J].
Collins, T ;
Cybulsky, MI .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (03) :255-264
[5]   Xanthohumol Modulates Inflammation, Oxidative Stress, and Angiogenesis in Type 1 Diabetic Rat Skin Wound Healing [J].
Costa, Raquel ;
Negrao, Rita ;
Valente, Ines ;
Castela, Angela ;
Duarte, Delfim ;
Guardao, Luisa ;
Magalhaes, Paulo J. ;
Rodrigues, Jose A. ;
Guimaraes, Joao T. ;
Gomes, Pedro ;
Soares, Raquel .
JOURNAL OF NATURAL PRODUCTS, 2013, 76 (11) :2047-2053
[6]   Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism [J].
Dong, Wen-Wen ;
Liu, Yu-Jian ;
Lv, Zhou ;
Mao, Yan-Fei ;
Wang, Ying-Wei ;
Zhu, Xiao-Yan ;
Jiang, Lai .
FREE RADICAL BIOLOGY AND MEDICINE, 2015, 88 :404-416
[7]   The inflammasome in lung diseases [J].
dos Santos, Gimena ;
Kutuzov, Mikhail A. ;
Ridge, Karen M. .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2012, 303 (08) :L627-L633
[8]   Inflammatory heart disease: a role for cytokines [J].
Fairweather, D ;
Rose, NR .
LUPUS, 2005, 14 (09) :646-651
[9]   Cytokine-mediated inflammation in acute lung injury [J].
Goodman, RB ;
Pugin, J ;
Lee, JS ;
Matthay, MA .
CYTOKINE & GROWTH FACTOR REVIEWS, 2003, 14 (06) :523-535
[10]   Contribution of Neutrophils to Acute Lung Injury [J].
Grommes, Jochen ;
Soehnlein, Oliver .
MOLECULAR MEDICINE, 2011, 17 (3-4) :293-307