Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis.
Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis.
复制标题
黄腐酚通过诱导 AMPK/GSK3 beta-Nrf2 信号轴改善脂多糖 (LPS) 诱导的急性肺损伤
DOI：
10.1016/j.redox.2017.03.001
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Ci X
中科院分区：
文献类型：
--
作者：
Lv H;Liu Q;Wen Z;Feng H;Deng X;Ci X
丰富的天然黄酮类化合物可诱导核因子-红细胞2相关因子2（Nrf 2）和/或腺苷酸活化蛋白激酶（AMPK）的活化，在改善包括急性肺损伤（ALI）在内的各种炎症和氧化应激诱导的疾病中发挥重要作用。黄腐酚（Xanthohumol，Xn）是一种重要的异戊烯基黄酮类化合物，具有抗炎和抗氧化活性。然而，Xn是否可以通过诱导AMPK/Nrf 2激活及其下游信号而保护LPS诱导的ALI，仍不清楚。因此，我们专注于探索Xn在ALI背景下的保护作用及其潜在的分子机制。结果表明，Xn通过降低肺W/D比值、蛋白水平、中性粒细胞浸润、MDA和MPO生成、降低SOD和GSH水平，有效减轻肺损伤。同时，Xn可显著减轻组织病理学改变、活性氧（ROS）产生、多种细胞因子分泌、iNOS和HMGB 1表达，抑制Txnip/NLRP 3炎性小体和NF-κB信号通路的激活。此外，Xn还能显著降低t-BHP诱导的细胞凋亡、ROS生成和GSH耗竭，并能增加由Keap 1-Nrf 2/ARE激活调控的多种抗氧化酶的表达，这可能与AMPK和GSK 3 β磷酸化有关。然而，在Nrf 2-/-小鼠中，WT小鼠中Xn介导的炎性细胞因子和ROS产生、组织病理学改变、Txnip/NLRP 3炎性体和NF-κB信号通路显著被废除。本实验结果首次证明，Xn通过激活AMPK/GSK 3 β上调Nrf 2通路，抑制LPS诱导的Txnip/NLRP 3炎性小体和NF-κB信号通路，从而有效地保护LPS诱导的ALI，对抗氧化应激和炎症损伤。总结Xn通过激活AMPK/GSK 3 β-Nrf 2轴对LPS诱导的急性肺损伤的保护作用的方案。Xn通过抗炎和抗氧化作用对LPS诱导的急性肺损伤具有保护作用。Xn诱导GCLC、GCLM、HO-1、NQO-1和Trx-1的表达。Xn阻断NF-κB和Txnip/NLRP 3炎性体活化。Xn上调AMPK/GSK 3 β-Nrf 2信号轴。Xn减弱的急性肺损伤在Nrf 2-/-小鼠中有效消除。
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. Scheme summarizing the protective effects of Xn on LPS-induced acute lung injury via activation of the AMPK/GSK3β-Nrf2 axis. Xn protects LPS-induced acute lung injury via anti-inflammation and anti-oxidant. Xn induces expressions of GCLC, GCLM, HO-1, NQO-1 and Trx-1. Xn blocks NF-κB and Txnip/NLRP3 inflammasome activation. Xn upregulates AMPK/GSK3β-Nrf2 signal axis. Xn-attenuated acute lung injury is effectively abrogated in Nrf2-/- mice.