BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages
BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages
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BZ-26 是一种新型 GW9662 衍生物，通过抑制炎症巨噬细胞的分化和活化来减轻炎症
DOI：
10.1016/j.biopha.2016.08.069
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发表时间：
2016-12-01
影响因子：
7.5
通讯作者：
Shen, Pingping
中科院分区：
文献类型：
--
作者：
Bei, Yuncheng;Chen, Jiajia;Shen, Pingping
过氧化物酶体增殖物激活受体-γ（PPARg）被认为是调节巨噬细胞分化和活化的重要转录因子。基于GW 9662的结构，我们合成了一系列新的结构分子（命名为BZ-24、BZ-25和BZ-26），并通过计算对接计算了相互作用活性。与GW 9662相比，BZ-26与PPARg的相互作用更强，在较低剂量下具有更高的PPARg转录抑制活性。证明BZ-26抑制炎性巨噬细胞分化。采用LPS诱导的小鼠急性炎症模型研究其抗炎活性。结果表明，BZ-26给药减弱了血浆肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的分泌，这两种细胞因子是急性炎症中的重要细胞因子。在THP-1细胞系中检测抗炎活性，并且TNF-α、IL-6和MCP-1被显著抑制。Western blot和荧光素酶报告基因检测结果表明，BZ-26不仅能抑制NF-κ B B的转录活性，而且能阻断LPS诱导的P65核转位。我们还测试了BZ-26在荷瘤慢性炎症小鼠模型中的作用，并且BZ-26能够改变巨噬细胞表型，从而产生抗肿瘤作用。我们的所有数据表明，BZ-26通过抑制炎性巨噬细胞的分化和活化，可能通过抑制NF-κ B信号通路来调节LPS诱导的急性炎症。(C)2016 Elsevier Masson SAS。All rights reserved.
Peroxisome proliferator-activated receptor-gamma (PPARg) is considered to be an important transcriptional factor in regulation of macrophages differentiation and activation. We have synthesized a series of novel structural molecules based on GW9662's structure (named BZ-24, BZ-25 and BZ-26), and interaction activity was calculated by computational docking. BZ-26 had shown stronger interaction with PPARg and had higher transcriptional inhibitory activity of PPARg with lower dosage compared with GW9662. BZ-26 was proved to inhibit inflammatory macrophage differentiation. LPS-induced acute inflammation mouse model was applied to demonstrate its anti-inflammatory activity. And the results showed that BZ-26 administration attenuated plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) secretion, which are vital cytokines in acute inflammation. The anti-inflammatory activity was examined in THP-1 cell line, and TNF-alpha, IL-6 and MCP-1, were significantly inhibited. The results of Western blot and luciferase reporter assay indicated that BZ-26 not only inhibited NF-kappa B transcriptional activity, but also abolished LPS-induce nuclear translocation of P65. We also test BZ-26 action in tumor-bearing chronic inflammation mouse model, and BZ-26 was able to alter macrophages phenotype, resulting in antitumor effect. All our data revealed that BZ-26 modulated LPS-induced acute inflammation via inhibiting inflammatory macrophages differentiation and activation, potentially via inhibition of NF-kappa B signal pathway. (C) 2016 Elsevier Masson SAS. All rights reserved.