The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy.
The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy.
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三萜类化合物CDDO-咪唑啉通过激活Nrf2/HO-1通路增强自噬改善小鼠肝脏缺血再灌注损伤
DOI：
10.1038/cddis.2017.386
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发表时间：
2017-08-10
影响因子：
9
通讯作者：
Kong X
中科院分区：
文献类型：
--
作者：
Xu D;Chen L;Chen X;Wen Y;Yu C;Yao J;Wu H;Wang X;Xia Q;Kong X
核因子红细胞2相关因子2（Nrf 2）介导的诱导抗氧化剂已被牵连在缺血再灌注（I/R）损伤在许多动物模型中的保护作用。然而，Nrf 2激活剂CDDO-咪唑（CDDO-Im）（1-[2-氰基-3-，12-二氧代齐墩果烷-1，9（11）-二烯-28-酰基]咪唑）在肝I/R损伤中的体内作用尚不清楚，其确切的分子机制仍不十分清楚。本研究的目的是确定CDDO-Im是否可以预防小鼠I/R诱导的肝损伤，并阐明药物作用的分子靶点。将小鼠随机等分为两组，并在进行90分钟肝脏70%缺血然后再灌注之前3小时腹膜内施用DMSO对照或CDDO-Im（2 mg/kg）。随后，收集这些小鼠的肝脏和血液样品以评价肝损伤。CDDO-Im预处理通过减轻肝细胞坏死和凋亡，降低活性氧（ROS）水平和炎症反应，改善线粒体功能障碍，显著改善肝I/R损伤。从机制上讲，通过使用Nrf 2敲除小鼠和血红素加氧酶1（HO-1）抑制剂，我们发现这些CDDO-Im保护作用归因于增强的自噬，其通过激活Nrf 2/HO-1通路介导。通过加速自噬和清除受损线粒体，CDDO-Im减少mtDNA释放和ROS过度产生，从而减少损伤相关分子模式诱导的炎症反应和继发性肝损伤。这些结果表明，通过增强自噬，CDDO-Im介导的Nrf 2/HO-1信号转导的激活可能是一种新的治疗策略，以最大限度地减少肝I/R损伤的不良反应。
Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidants has been implicated to have protective roles in ischemia-reperfusion (I/R) injury in many animal models. However, the in vivo effects of CDDO-imidazole (CDDO-Im)(1-[2-cyano-3-, 12-dioxooleana-1, 9 (11)-dien-28-oyl] imidazole), a Nrf2 activator, in hepatic I/R injury is lacking and its exact molecular mechanisms are still not very clear. The goals of this study were to determine whether CDDO-Im can prevent liver injury induced by I/R in the mouse, and to elucidate the molecular target of drug action. Mice were randomly equally divided into two groups and administered intraperitoneally with either DMSO control or CDDO-Im (2 mg/kg) 3 h before subjected to 90-min hepatic 70% ischemia followed by reperfusion. Subsequently, the Liver and blood samples of these mice were collected to evaluate liver injury. CDDO-Im pretreatment markedly improve hepatic I/R injury by attenuating hepatic necrosis and apoptosis, reducing reactive oxygen species (ROS) levels and inflammatory responses, and ameliorating mitochondrial dysfunction. Mechanistically, by using Nrf2 Knockout mice and hemeoxygenase 1 (HO-1) inhibitor, we found that these CDDO-Im protection effects are attributed to enhanced autophagy, which is mediated by activating Nrf2/HO-1 pathway. By accelerating autophagy and clearance of damaged mitochondria, CDDO-Im reduced the mtDNA release and ROS overproduction, and in turn decreased damage-associated molecular patterns induced inflammatory responses and the following secondary liver injury. These results indicate that by enhancing autophagy, CDDO-Im-mediated activation of Nrf2/HO-1 signaling could be a novel therapeutic strategy to minimize the adverse effects of hepatic I/R injury.
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影响因子：
3.8
作者：
Reisman SA;Buckley DB;Tanaka Y;Klaassen CD
通讯作者：
Klaassen CD
NRF2三萜活化剂CDDO-咪唑啉剂可保护肾脏免受小鼠缺血 - 再灌注损伤。
影响因子：
19.6
作者：
Liu M;Reddy NM;Higbee EM;Potteti HR;Noel S;Racusen L;Kensler TW;Sporn MB;Reddy SP;Rabb H
通讯作者：
Rabb H
DOI：
10.1164/rccm.201102-0271oc
发表时间：
2011-10-15
影响因子：
24.7
作者：
Kong, Xiaoni;Thimmulappa, Rajesh;Biswal, Shyam
通讯作者：
Biswal, Shyam
DOI：
10.1146/annurev-pathol-020712-163918
发表时间：
2013-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Murrow L;Debnath J
通讯作者：
Debnath J
影响因子：
11.2
作者：
Liby, K;Hock, T;Sporn, MB
通讯作者：
Sporn, MB