Oral administration of hydroxylated-graphene quantum dots induces intestinal injury accompanying the loss of intestinal stem cells and proliferative progenitor cells
Oral administration of hydroxylated-graphene quantum dots induces intestinal injury accompanying the loss of intestinal stem cells and proliferative progenitor cells
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口服羟基化石墨烯量子点会引起肠道损伤，并伴有肠道干细胞和增殖祖细胞的损失
DOI：
10.1080/17435390.2019.1668068
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发表时间：
2019
期刊：
影响因子：
5
通讯作者：
Zeng-Fu Shang
中科院分区：
文献类型：
--
作者：
Lan Yu;Xin Tian;Dexuan Gao;Yue Lang;Xiang-Xiang Zhang;Chen Yang;Meng-Meng Gu;Jianming Shi;Ping-Kun Zhou;Zeng-Fu Shang
摘要 石墨烯量子点（GQD）在各种生物医学应用中受到了广泛关注。这些纳米粒子的物理化学性质，包括毒性作用，很大程度上取决于它们的表面修饰。先前的研究已证明羟基化 GQD (OH-GQD) 具有较高的体外细胞毒性。本研究的重点是 OH-GQD 的肠道毒性。简而言之，C57BL/6J小鼠每天口服灌胃0.05、0.5或5mg/kg OH-GQD，持续7天，并评估肠道损伤指数。较高剂量的 OH-GQD 会导致严重的肠道损伤，例如肠道通透性增强、绒毛缩短和隐窝损失。暴露于 OH-GQD 后，Lgr5+ 肠道干细胞的数量也显着减少，这也抑制了 Ki67+ 增殖祖细胞。此外，在 OH-GQD 处理的小鼠肠道中还检测到含有氧化 DNA 碱基 8-OHdG 和 γH2AX 焦点的隐窝细胞数量增加。从机制上讲，OH-GQD 上调总 p53 和磷酸化 p53。与此一致的是，OH-GQD 处理后，TUNEL+ 和裂解的 caspase-3+ 凋亡肠上皮细胞的平均数量显着增加。最后，使用分离的隐窝建立了 3 维类器官培养物，并且 OH-GQD 处理显着减小了存活的肠道类器官的大小。综上所述，在生物医学应用过程中应考虑 OH-GQD 的肠道毒性。
Abstract Graphene quantum dots (GQDs) have gained significant attention in various biomedical applications. The physicochemical properties of these nanoparticles, including toxic effects, are largely determined by their surface modifications. Previous studies have demonstrated high in vitro cytotoxicity of the hydroxylated GQDs (OH-GQDs). The focus of this study was on the intestinal toxicity of OH-GQDs. Briefly, C57BL/6J mice were given daily oral gavage of 0.05, 0.5 or 5 mg/kg OH-GQD for 7 days, and the indices of intestinal damage were evaluated. Higher doses of the OH-GQDs caused significant intestinal injuries, such as enhanced intestinal permeability, shortened villi and crypt loss. The number of Lgr5+ intestinal stem cells also decreased dramatically upon OH-GQDs exposure, which also inhibited the Ki67+ proliferative progenitor cells. In addition, an increased number of crypt cells harboring the oxidized DNA base 8-OHdG and γH2AX foci were also detected in the intestines of OH-GQD-treated mice. Mechanistically, the OH-GQDs up-regulated both total and phosphorylated p53. Consistent with this, the average number of TUNEL+ and cleaved caspase-3+ apoptotic intestinal epithelial cells were significantly increased after OH-GQDs treatment. Finally, a 3-dimensional organoid culture was established using isolated crypts, and OH-GQDs treatment significantly reduced the size of the surviving intestinal organoids. Taken together, the intestinal toxicity of the OH-GQDs should be taken into account during biomedical applications.