FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Ameliorates DSS-Induced Colitis Against Oxidative Stress by Activating Nrf2/HO-1 Pathway
FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Ameliorates DSS-Induced Colitis Against Oxidative Stress by Activating Nrf2/HO-1 Pathway
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FA-97 是一种新型合成咖啡酸苯乙酯衍生物，通过激活 Nrf2/HO-1 通路改善 DSS 诱导的结肠炎，对抗氧化应激
DOI：
10.3389/fimmu.2019.02969
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发表时间：
2020-01-08
影响因子：
7.3
通讯作者：
Huang, Yujie
中科院分区：
文献类型：
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作者：
Mei, Yu;Wang, Zihao;Huang, Yujie
炎症性肠病(IBD)是一种慢性特发性胃肠道炎症性疾病，缺乏有效的药物靶点和药物。咖啡酸苯乙酯(CAPE)是从蜂胶中提取的一种酚类成分，因其水溶性低，生物利用度低，被认为是治疗IBD的潜在药物。在本研究中，我们合成了一种新的CAPE衍生物(FA-97)，旨在研究FA-97对DSS诱导的结肠炎的影响。在此，我们发现FA-97减轻了结肠炎小鼠的体重减轻、结肠长度缩短和结肠病理损害，并抑制了结肠炎细胞的浸润和促炎细胞因子的表达。此外，FA-97还减少了DSS诱导的结肠炎小鼠和脂多糖刺激的原代BMDM和RAW 264.7细胞的ROS生成和丙二醛生成，而总抗氧化能力都增强了。机械上，FA-97可激活Nrf2，增加HO-1和NQO-1，下调p65和c-jun的核水平，从而抑制DSS诱导的结肠氧化应激。此外，FA-97通过激活NRF2减少了RAW 264.7中促炎细胞因子的表达，增加了抗氧化防御能力。总体而言，本研究表明FA-97激活Nrf2/HO-1通路，最终减轻DSS诱导的结肠炎对氧化应激的影响，这具有潜在的活性，可能成为IBD治疗的候选药物。
Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder of gastro-intestinal tract, lacking effective drug targets and medications. Caffeic acid phenethyl ester (CAPE), a phenolic constituent derived from propolis, has been reported to be a potential therapeutic agent for IBD with low water solubility and poor bioavailability. In this study, we synthesized a new CAPE derivative (FA-97) and aimed to investigate the effect of FA-97 on DSS-induced colitis. Here, we found that FA-97 attenuated body weight loss, colon length shortening and colonic pathological damage in colitis mice, as well as inhibited inflammatory cell infiltration and expression of pro-inflammatory cytokines in colons. In addition, FA-97 reduced ROS production and MDA generation, while total antioxidant capacity both in DSS-induced colitis mice and LPS-stimulated primary BMDMs and RAW 264.7 cells were enhanced. Mechanically, FA-97 activated Nrf2 followed by increased HO-1 and NQO-1 and down-regulated nuclear levels of p65 and c-Jun, to suppress DSS-induced colonic oxidative stress. Moreover, FA-97 decreased pro-inflammatory cytokine expression and increased the antioxidant defenses in RAW 264.7 via Nrf2 activation. In general, this study reveals that FA-97 activates Nrf2/HO-1 pathway to eventually alleviate DSS-induced colitis against oxidative stress, which has potential activity and may serve as a candidate for IBD therapy.