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.
Suzhou Digestive Diseases and Nutrition Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, China.
Free Radic Biol Med. 2019 Dec;145:223-236. doi: 10.1016/j.freeradbiomed.2019.09.035. Epub 2019 Sep 30.
The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no effective prophylactic or therapeutic agents are available at present to manage radiation-induced intestinal injuries. We observed that the vanillin derivative VND3207 improved the survival of lethally irradiated mice by promoting intestinal regeneration and increasing the number of surviving crypts. Pre-treatment with VND3207 significantly increased the number of Lgr5 intestinal stem cells (ISCs) and their daughter cells, the transient Ki67 proliferating cells. Mechanistically, VND3207 decreased oxidative DNA damage and lipid peroxidation and maintained endogenous antioxidant status by increasing the level of superoxide dismutase and total antioxidant capacity. In addition, VND3207 maintained appropriate levels of activated p53 that triggered cell cycle arrest but were not sufficient to induce NOXA-mediated apoptosis, thus ensuring DNA damage repair in the irradiated small intestinal crypt cells. Furthermore, VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure. In conclusion, VND3207 promoted intestinal repair following radiation injury by reducing reactive oxygen species-induced DNA damage and modulating appropriate levels of activated p53 in intestinal epithelial cells.
肠道是一种高度敏感的组织，由于全身和局部辐射暴露，容易受到结构和功能损伤。不幸的是，目前没有有效的预防或治疗药物可用于管理放射性肠损伤。我们观察到香草醛衍生物 VND3207 通过促进肠道再生和增加存活隐窝的数量来提高致死性辐射照射小鼠的存活率。VND3207 预处理显着增加了 Lgr5 肠道干细胞（ISCs）及其子细胞短暂 Ki67 增殖细胞的数量。在机制上，VND3207 通过增加超氧化物歧化酶和总抗氧化能力的水平来减少氧化 DNA 损伤和脂质过氧化作用，并维持内源性抗氧化状态。此外，VND3207 维持适当水平的激活 p53，触发细胞周期停滞，但不足以诱导 NOXA 介导的细胞凋亡，从而确保照射的小肠隐窝细胞中的 DNA 损伤修复。此外，VND3207 治疗可恢复 TBI 暴露改变的肠道细菌菌群结构。总之，VND3207 通过减少活性氧诱导的 DNA 损伤和调节肠道上皮细胞中适当水平的激活 p53 来促进辐射损伤后的肠道修复。
