PDF(Pubmed)
Abstract：
Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H2O2)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H2O2-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H2O2. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H2O2-induced cell death probably due to preventing the decrease in the mitochondrial membrane potential and the increase in caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway.
摘要：
沙得诺内酯是一种具有抗炎和抗肿瘤活性的生物活性化合物。尽管最近有人提出，sedanolide激活核因子E2相关因子2（NRF2）途径，关于其对细胞抵抗氧化应激的影响的研究很少。本研究的目的是研究sedanolide在抑制过氧化氢（H2O2）诱导的人肝母细胞瘤细胞系HepG2细胞氧化损伤中的功能及其潜在的分子机制。我们发现，sedanolide激活了NRF2核易位介导的抗氧化反应元件（ARE）依赖性转录。RNA测序数据的途径富集分析显示，sedanolide上调了参与NRF2途径和谷胱甘肽代谢的抗氧化酶的转录。然后，我们进一步研究了sedanolide是否对H2O2诱导的细胞死亡具有细胞保护作用.我们表明，sedanolide显着减弱了暴露于H2O2诱导的胞浆和线粒体活性氧（ROS）的产生。此外，我们证明，sedanolide预处理对H2O2诱导的细胞死亡具有显着的细胞保护作用，可能是由于阻止了线粒体膜电位的降低和caspase-3/7活性的增加。我们的研究表明，sedanolide通过激活Kelch样ECH相关蛋白1（KEAP1）-NRF2途径增强了细胞对氧化损伤的抵抗力。
