Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo
Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo
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香草醛衍生物 VND3207 激活 DNA-PKcs，从而在体外和体内提供针对辐射诱导的肠上皮细胞损伤的保护
DOI：
10.1016/j.taap.2019.114855
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发表时间：
2020
影响因子：
3.8
通讯作者：
Shang Zeng-Fu
中科院分区：
文献类型：
--
作者：
Li Ming;Lang Yue;Gu Meng-Meng;Shi Jianming;Chen Benjamin P. C.;Yu Lan;Zhou Ping-Kun;Shang Zeng-Fu
香兰素是一种天然化合物，具有抗氧化和抗突变性能。我们先前鉴定了香兰素衍生物VND3207具有很强的辐射防护和抗氧化作用，并发现VND3207对小鼠的存活有利，并对辐射诱导的肠道损伤(RIII)具有保护作用。我们还观察到，VND3207处理增强了人淋巴母细胞DNA依赖蛋白激酶催化亚单位(DNA-PKcs)的表达水平，无论是否有伽玛射线照射。DNA-PKcs是DNA双链断裂修复途径的重要组成部分，也通过稳定纺锤体的形成和防止DNA损伤引起的有丝分裂灾难来调节有丝分裂进程。在本研究中，我们发现VND3207通过促进细胞增殖和抑制细胞凋亡来保护体外培养的肠上皮细胞免受电离辐射的伤害。此外，VND3207还通过增加S2056位点的自磷酸化来促进DNA-PKcs的活性。与此一致的是，VND3207显著减少了辐射后伽马H_2AX焦点的数量和有丝分裂灾难。DNA-PKcs缺乏消除了这些VND3207的辐射保护作用，表明DNA-PKcs的激活对VND3207的活性是必不可少的。结论：VND3207通过调节DNA-PKcs通路促进辐射损伤后的肠道修复。
Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without gamma-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of gamma H2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.