title: Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis.
abstract: 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 prenylflavonoid, 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-κB 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 GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB 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/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway.
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China; Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130061, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Lv
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Qinmei
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130061, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China; Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130061, China.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China. Electronic address: cixinxin@jlu.edu.cn.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ci
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005419:Flavonoids / Q000008:administration & dosage* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011427:Propiophenones / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005419:Flavonoids; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011427:Propiophenones; D017382:Reactive Oxygen Species; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000263:Adenylate Kinase; C104536:xanthohumol
keywords: Acute lung injury; Inflammation; Nrf2/AMPK; Oxidative stress; Xanthohumol