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三萜类化合物（CDDO-Im和CDDO-Me）靶向Nrf2通路对人外周血单个核细胞和中性粒细胞中脂多糖诱导的炎症反应和活性氧的保护作用的临床前评估。

Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils.

作者信息

Thimmulappa Rajesh K, Fuchs Ralph J, Malhotra Deepti, Scollick Catherine, Traore Kassim, Bream Jay H, Trush Michael A, Liby Karen T, Sporn Michael B, Kensler Thomas W, Biswal Shyam

机构信息

Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

出版信息

Antioxid Redox Signal. 2007 Nov;9(11):1963-70. doi: 10.1089/ars.2007.1745.

DOI:10.1089/ars.2007.1745
PMID:17822364
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2396226/
Abstract

Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-alpha, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome.

摘要

脓毒症的特征是机体免疫炎症反应失调以及持续的氧化损伤。Nrf2是一种碱性亮氨酸拉链氧化应激反应转录因子，可调控一系列细胞保护基因，包括抗氧化剂相关基因，从而维持细胞内氧化还原稳态。小鼠研究已证明Nrf2在改善脓毒症期间的生存率方面具有关键作用。这项临床前体外研究以中性粒细胞和外周血单核细胞（PBMC）作为替代细胞，评估了CDDO-Im和CDDO-Me [2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸（CDDO）的咪唑和甲酯衍生物]激活Nrf2通路并保护人体免受脂多糖（LPS）诱导的炎症反应的功效。CDDO-Im处理显著诱导了从六名正常受试者分离出的PBMC中Nrf2依赖的抗氧化基因（HO-1、GCLC、GCLM和NQO1）。CDDO-Im增加了Nrf2蛋白的核内积累。CDDO-Im对PBMC的预处理显著减弱了LPS诱导的细胞因子表达。CDDO-Me预处理后也观察到抗氧化基因水平有类似升高以及LPS诱导的细胞因子表达受到抑制。CDDO-Im还极大地抑制了LPS、fMLP、TNF-α和TPA诱导的中性粒细胞ROS生成。总之，这些结果表明，CDDO-Im或CDDO-Me激活Nrf2依赖的抗氧化通路可保护机体免受LPS诱导的炎症反应，并提示它们可能是干预脓毒症综合征的潜在治疗候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a13/2396226/04fe4b66f386/nihms-43269-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a13/2396226/04fe4b66f386/nihms-43269-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a13/2396226/a80fcf3b1901/nihms-43269-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a13/2396226/3977cc0013de/nihms-43269-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a13/2396226/04fe4b66f386/nihms-43269-f0006.jpg

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