College of Food Science and Nutritional Engineering, China Agricultural University, 17 Tsinghua East Road, Beijing 100083, China.
Nutrients. 2021 Aug 24;13(9):2910. doi: 10.3390/nu13092910.
It is urgent to seek new potential targets for the prevention or relief of gastrointestinal syndrome in clinical radiation therapy for cancers. Vitamin D, mediated through the vitamin D receptor (VDR), has been identified as a protective nutrient against ionizing radiation (IR)-induced damage. This study investigated whether VDR could inhibit IR-induced intestinal injury and explored underlying mechanism. We first found that vitamin D induced VDR expression and inhibited IR-induced DNA damage and apoptosis in vitro. VDR was highly expressed in intestinal crypts and was critical for crypt stem/progenitor cell proliferation under physiological conditions. Next, VDR-deficient mice exposed to IR significantly increased DNA damage and crypt stem/progenitor cell apoptosis, leading to impaired intestinal regeneration as well as shorter survival time. Furthermore, VDR deficiency activated the Pmaip1-mediated apoptotic pathway of intestinal crypt stem/progenitor cells in IR-treated mice, whereas inhibition of Pmaip1 expression by siRNA transfection protected against IR-induced cell apoptosis. Therefore, VDR protects against IR-induced intestinal injury through inhibition of crypt stem/progenitor cell apoptosis via the Pmaip1-mediated pathway. Our results reveal the importance of VDR level in clinical radiation therapy, and targeting VDR may be a useful strategy for treatment of gastrointestinal syndrome.
在癌症临床放射治疗中，迫切需要寻找新的潜在靶点来预防或缓解胃肠道综合征。维生素 D 通过维生素 D 受体（VDR）介导，已被确定为一种可预防电离辐射（IR）诱导损伤的保护性营养素。本研究探讨了 VDR 是否可以抑制 IR 诱导的肠道损伤，并探讨了潜在的机制。我们首先发现，维生素 D 诱导 VDR 表达，并抑制体外 IR 诱导的 DNA 损伤和细胞凋亡。VDR 在肠隐窝中高度表达，在生理条件下对隐窝干细胞/祖细胞增殖至关重要。接下来，暴露于 IR 的 VDR 缺陷型小鼠显著增加了 DNA 损伤和隐窝干细胞/祖细胞凋亡，导致肠道再生受损以及存活时间缩短。此外，VDR 缺乏会在 IR 处理的小鼠中激活 Pmaip1 介导的肠隐窝干细胞/祖细胞凋亡途径，而 siRNA 转染抑制 Pmaip1 表达则可防止 IR 诱导的细胞凋亡。因此，VDR 通过 Pmaip1 介导的途径抑制隐窝干细胞/祖细胞凋亡来保护肠道免受 IR 损伤。我们的研究结果揭示了 VDR 水平在临床放射治疗中的重要性，靶向 VDR 可能是治疗胃肠道综合征的一种有效策略。
