The vanillin derivative VND3207 protects intestine against radiation injury by modulating p53/NOXA signaling pathway and restoring the balance of gut microbiota

• Published in: Free radical biology & medicine Vol. 145; pp. 223 - 236
• Main Authors: Li, Ming, Gu, Meng-Meng, Lang, Yue, Shi, Jianming, Chen, Benjamin P.C., Guan, Hua, Yu, Lan, Zhou, Ping-Kun, Shang, Zeng-Fu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2019
• Subjects: Animals; Antioxidants - pharmacology; Benzaldehydes - chemistry; Benzaldehydes - pharmacology; Cell Lineage - drug effects; Cell Lineage - radiation effects; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - radiation effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - radiation effects; Humans; Intestinal flora; Intestines - drug effects; Mice; NOXA; Oxidative Stress - drug effects; p53; Proto-Oncogene Proteins c-bcl-2 - genetics; Radiation Exposure - adverse effects; Radiation Injuries - genetics; Radiation Injuries - prevention & control; Radiation Tolerance - genetics; Radiation-induced intestinal injuries; Reactive oxygen species (ROS); Receptors, G-Protein-Coupled - genetics; Signal Transduction - radiation effects; Stem Cells - drug effects; Tumor Suppressor Protein p53 - genetics; VND3207; VND3207; Intestinal flora; Radiation-induced intestinal injuries; NOXA; Reactive oxygen species (ROS); p53
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2019.09.035

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. [Display omitted] •VND3207 improves survival and mitigates intestinal injury in lethally irradiated mice.•VND3207 augments proliferation and survival of intestinal stem cells in irradiated mice.•VND3207 downregulates IR-induced activation of p53/Noxa signaling in intestinal crypts.•VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure.