Sedanolide 激活 KEAP1–NRF2 通路并改善过氧化氢诱导的细胞凋亡,International Journal of Molecular Sciences

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Sedanolide 激活 KEAP1–NRF2 通路并改善过氧化氢诱导的细胞凋亡
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2023-11-20 , DOI: 10.3390/ijms242216532
Yosuke Tabei ₁ , Hiroko Abe ₁ , Shingo Suzuki _{1,

2} , Nobuaki Takeda ₃ , Jun-Ichiro Arai ₃ , Yoshihiro Nakajima ₁

Affiliation

Sedanolide 是一种具有抗炎和抗肿瘤活性的生物活性化合物。尽管最近有人提出景天内酯可以激活核因子E2相关因子2（NRF2）途径，但对其对细胞抗氧化应激的影响的研究很少。本研究的目的是探讨景天内酯在人肝母细胞瘤细胞系 HepG2 细胞中抑制过氧化氢 (H2O2) 诱导的氧化损伤的功能及其潜在的分子机制。我们发现景天内酯激活了由 NRF2 核易位介导的抗氧化反应元件 (ARE) 依赖性转录。RNA测序数据的通路富集分析表明，sedanolide上调了参与NRF2通路和谷胱甘肽代谢的抗氧化酶的转录。然后，我们进一步研究了景天内酯是否对 H2O2 诱导的细胞死亡发挥细胞保护作用。我们发现，sedanolide 可显着减弱 H2O2 诱导的细胞质和线粒体活性氧 (ROS) 的产生。此外，我们证明，用景天内酯预处理对 H2O2 诱导的细胞死亡具有显着的细胞保护作用，这可能是由于防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，景天内酯通过激活 Kelch 样 ECH 相关蛋白 1 (KEAP1)-NRF2 通路来增强细胞对氧化损伤的抵抗力。

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Sedanolide Activates KEAP1–NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death

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.

更新日期：2023-11-20

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