Green tea derivative ()-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo
Green tea derivative ()-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo
复制标题
DOI：
10.1016/j.freeradbiomed.2020.10.012
复制
发表时间：
2020-12-01
影响因子：
7.4
通讯作者：
Tian, Ye
中科院分区：
文献类型：
--
作者：
Xie, Li-Wei;Cai, Shang;Tian, Ye
辐射引起的肠道损伤（RIII）发生在有意或无意的辐射暴露过程中。然而，目前预防或缓解 RIII 的有效治疗方法很少。 (-)-表没食子儿茶素-3-没食子酸酯 (EGCG) 是绿茶中的一种主要多酚，具有强大的抗氧化活性，并已被证明可有效改善许多与氧化应激相关的疾病。 EGCG对RIII的治疗作用和机制尚未确定。在本研究中，我们研究了 EGCG 是否具有针对 RIII 的辐射防护作用。我们的数据表明，给予 EGCG 不仅可以延长受致命辐射小鼠的生存时间，还可以减少辐射引起的肠粘膜损伤。 EGCG治疗显着增加了Lgr5（+）肠道干细胞（ISC）及其后代Ki67（+）细胞的数量，并减少了辐射诱导的DNA损伤和细胞凋亡。此外，EGCG 在人肠上皮 HIEC 细胞中表现出与小鼠相同的放射防护作用，其特点是 γ H2AX 病灶数量减少和铁死亡。此外，EGCG 降低活性氧 (ROS) 水平并激活转录因子 Nrf2 及其下游靶标，包括抗氧化蛋白 Slc7A11、HO 1 和 GPX4。用 Nrf2 抑制剂 ML385 治疗消除了 EGCG 的保护作用，表明 Nrf2 激活对于 EGCG 活性至关重要。综上所述，我们的研究结果表明，EGCG 通过清除 ROS 并通过 Nrf2 信号通路抑制细胞凋亡和铁死亡来预防 RIII，这可能是缓解 RIII 的一种有前途的医学对策。
Radiation-induced intestinal injury (RIII) occurs during instances of intentional or accidental radiation exposure. However, there are few effective treatments available for the prevention or mitigation of RIII currently. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, possesses potent antioxidant activity and has been shown to be effective in ameliorating many oxidative stress-related diseases. The therapeutic effects and mechanism of EGCG on RIII have not yet been determined. In the present study, we investigated whether EGCG confers radioprotection against RIII. Our data demonstrated that administration of EGCG not only prolonged the survival time of lethally irradiated mice, but also reduced radiation-induced intestinal mucosal injury. Treatment with EGCG significantly increased the number of Lgr5(+) intestinal stem cells (ISCs) and their progeny Ki67(+) cells, and reduced radiation-induced DNA damage and apoptosis. Besides, EGCG displayed the same radioprotective effects in human intestinal epithelial HIEC cells as in mice, characterized by a decrease in the number of gamma H2AX foci and ferroptosis. Moreover, EGCG decreased the level of reactive oxygen species (ROS) and activated the transcription factor Nrf2 and its downstream targets comprising antioxidant proteins Slc7A11, HO 1 and GPX4. Treatment with the Nrf2 inhibitor ML385 abolished the protective effects of EGCG, indicating that Nrf2 activation is essential for EGCG activity. Taken together, our findings demonstrated that EGCG protects against RIII by scavenging ROS and inhibiting apoptosis and ferroptosis through the Nrf2 signal pathway, which could be a promising medical countermeasure for the alleviation of RIII.