Zhou Yan, Liu Jingwen, Li Xiong, Wang Luman, Hu Lirong, Li Aiping, Zhou Jianwei
Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China.
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China.
Antioxidants (Basel). 2022 May 27;11(6):1067. doi: 10.3390/antiox11061067.
Radiation-induced intestinal injury is one of the major side effects in patients receiving radiation therapy. There is no specific treatment for radiation-induced enteritis in the clinic. We synthesized a compound, named JAC4, which is an agonist and can increase JWA protein expression. JWA has been shown to reduce oxidative stress, DNA damage, anti-apoptosis, and anti-inflammatory; in addition, the small intestine epithelium showed dysplasia in JWA knockout mice. We hypothesized that JAC4 might exert a protective effect against radiation-induced intestinal damage. Herein, X-ray radiation models were built both in mice and in intestinal crypt epithelial cells (IEC-6). C57BL/6J mice were treated with JAC4 by gavage before abdominal irradiation (ABI); the data showed that JAC4 significantly reduced radiation-induced intestinal mucosal damage and increased the survival rate. In addition, radiation-induced oxidative stress damage and systemic inflammatory response were also mitigated by JAC4 treatment. Moreover, JAC4 treatment alleviated DNA damage, decreased cell apoptosis, and maintained intestinal epithelial cell proliferation in mice. In vitro data showed that JAC4 treatment significantly inhibited ROS formation and cell apoptosis. Importantly, all the above protective effects of JAC4 on X-ray radiation-triggered intestinal injury were no longer determined in the intestinal epithelium of JWA knockout mice. Therefore, our results provide the first evidence that JAC4 protects the intestine from radiation-induced enteritis through JWA-mediated anti-oxidation/inflammation signaling.
放射性肠损伤是接受放射治疗患者的主要副作用之一。临床上对于放射性肠炎尚无特异性治疗方法。我们合成了一种名为JAC4的化合物，它是一种激动剂，能够增加JWA蛋白的表达。研究表明，JWA可减轻氧化应激、DNA损伤、具有抗凋亡和抗炎作用；此外，JWA基因敲除小鼠的小肠上皮出现发育异常。我们推测JAC4可能对放射性肠损伤具有保护作用。在此，我们分别在小鼠和小肠隐窝上皮细胞（IEC-6）中建立了X射线辐射模型。C57BL/6J小鼠在腹部照射（ABI）前经口灌胃给予JAC4；数据显示，JAC4显著减轻了放射性肠黏膜损伤并提高了存活率。此外，JAC4治疗还减轻了放射性氧化应激损伤和全身炎症反应。而且，JAC4治疗减轻了小鼠的DNA损伤，减少了细胞凋亡，并维持了肠上皮细胞增殖。体外数据显示，JAC4治疗显著抑制了活性氧的形成和细胞凋亡。重要的是，JAC4对X射线辐射引发的肠损伤的所有上述保护作用在JWA基因敲除小鼠的肠上皮中不再存在。因此，我们的结果首次证明JAC4通过JWA介导的抗氧化/炎症信号通路保护肠道免受放射性肠炎的侵害。
