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Abstract：
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.
摘要：
肠是一种高度辐射敏感的组织,由于全身和局部辐射暴露,其易受结构和功能损伤。不幸的是,目前尚无有效的预防或治疗药物可用于治疗辐射引起的肠损伤.我们观察到香草醛衍生物VND3207通过促进肠再生和增加存活隐窝的数量来改善致命性照射小鼠的存活率。用VND3207预处理显着增加了Lgr5肠干细胞（ISC）及其子细胞的数量，瞬时Ki67+增殖细胞。机械上,VND3207通过增加超氧化物歧化酶水平和总抗氧化能力来降低氧化DNA损伤和脂质过氧化并维持内源性抗氧化状态。此外,VND3207维持适当水平的活化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DNA损伤的修复。此外，VND3207治疗可恢复因TBI暴露而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损伤并调节肠上皮细胞中激活的p53的适当水平来促进辐射损伤后的肠修复。
