Zhang Qing-Ye, Chu Xin-Yi, Jiang Ling-Han, Liu Meng-Yuan, Mei Zhi-Ling, Zhang Hong-Yu
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
Shanghai Thinkgene Biotech Co., LTD., Shanghai 200000, China.
Molecules. 2017 May 26;22(6):883. doi: 10.3390/molecules22060883.
Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of 'off-target' effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic. By determining the expression changes of antioxidant genes in MCF7 cells that were treated with the potential Nrf2 activators using quantitative real-time polymerase chain reaction RT-PCR (real-time polymerase chain reaction) (qRT-PCR), astemizole was found to have a greater scale of upregulating antioxidant genes , , and than the positive control d,l-sulforaphane, although the testing concentration was lower than that of the control. Astemizole is a good potential redox regulator and deserves more pharmacodynamic experimentation to test and verify its feasibility for use as an Nrf2 activator.
氧化损伤可导致多种疾病。Nrf2是一种重要的转录因子，可调节许多参与氧化应激反应的细胞保护酶。因此，靶向调控Nrf2激活是预防或降低氧化应激相关疾病风险的一种合理且有效的策略。到目前为止，大多数研究都集中在亲电间接Nrf2激活剂上，但这些激活剂可能存在“脱靶”效应的风险。为了寻找新型的非亲电Nrf2小分子调节剂，我们从连接图谱（cMap）衍生的化学试剂入手，通过药物重新定位策略鉴定出22种非亲电潜在Nrf2激活药物。通过使用定量实时聚合酶链反应RT-PCR（实时聚合酶链反应）（qRT-PCR）测定用潜在Nrf2激活剂处理的MCF7细胞中抗氧化基因的表达变化，发现阿司咪唑上调抗氧化基因、和的幅度比阳性对照d，l-萝卜硫素更大，尽管测试浓度低于对照。阿司咪唑是一种良好的潜在氧化还原调节剂，值得进行更多的药效学实验来测试和验证其作为Nrf2激活剂使用的可行性。
