Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Institute of Radiotherapy and Oncology, Soochow University, Suzhou, 215004, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
Free Radic Biol Med. 2020 Dec;161:175-186. doi: 10.1016/j.freeradbiomed.2020.10.012. Epub 2020 Oct 15.
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 γH2AX 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.
辐射诱导的肠道损伤（RIII）发生在故意或意外辐射暴露的情况下。然而，目前针对 RIII 还没有有效的预防或缓解措施。(-)-表没食子儿茶素没食子酸酯（EGCG）是绿茶中的一种主要多酚，具有强大的抗氧化活性，已被证明可有效改善许多与氧化应激相关的疾病。EGCG 对 RIII 的治疗效果和机制尚未确定。在本研究中，我们研究了 EGCG 是否对 RIII 具有放射防护作用。我们的数据表明，EGCG 的给药不仅延长了致死性辐射照射小鼠的存活时间，还减轻了辐射诱导的肠道黏膜损伤。EGCG 治疗可显著增加 Lgr5 肠道干细胞（ISCs）及其祖细胞 Ki67 细胞的数量，并减少辐射诱导的 DNA 损伤和细胞凋亡。此外，EGCG 在人肠道上皮细胞 HIEC 中表现出与在小鼠中相同的放射防护作用，表现为 γH2AX 焦点和铁死亡数量减少。此外，EGCG 降低了活性氧物种（ROS）的水平并激活了转录因子 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 处理可消除 EGCG 的保护作用，表明 Nrf2 激活对于 EGCG 的活性是必需的。综上所述，我们的研究结果表明，EGCG 通过清除 ROS 并抑制细胞凋亡和铁死亡来保护 RIII，这可能是缓解 RIII 的一种有前途的医学对策。
