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新型含依达拉奉类似物和 3-正丁基苯酞开环衍生物的杂合化合物的合成及辐射防护作用。

Synthesis and radioprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives.

机构信息

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China.

出版信息

J Cell Mol Med. 2021 Jun;25(12):5470-5485. doi: 10.1111/jcmm.16557. Epub 2021 May 8.

Abstract

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC-6 and HFL-1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)-induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)-induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5 intestinal stem cells, lysozyme Paneth cells and Ki67 transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase-9 and caspase-3, and upregulated the expression of Bcl-2, suggesting that it could prevent irradiation-induced intestinal damage through the p53-dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.

摘要

随着辐射暴露的潜在风险不断增加,辐射防护剂的研究变得越来越重要。在这项研究中,合成了含有依达拉奉类似物和 3-正丁基苯酞开环衍生物的新型杂合化合物,并评估了它们的辐射防护作用。在这些化合物中,化合物 10a 在 IEC-6 和 HFL-1 细胞中表现出最高的辐射防护活性。口服给药可提高受照射小鼠的存活率,并通过减轻骨髓抑制和提高造血干/祖细胞频率来缓解全身照射(TBI)诱导的造血损伤。此外,10a 治疗可预防腹部照射(ABI)引起的小肠结构损伤。实验结果表明,10a 可增加 Lgr5 肠干细胞、溶菌酶 Paneth 细胞和 Ki67 短暂扩增细胞的数量,并减少受照射小鼠肠上皮细胞的凋亡。此外,体内外研究表明,10a 的辐射防护活性与降低氧化应激和抑制 DNA 损伤有关。此外,化合物 10a 下调了 p53、Bax、caspase-9 和 caspase-3 的表达,上调了 Bcl-2 的表达,表明它可以通过 p53 依赖性凋亡途径预防辐射诱导的肠道损伤。总之,这些发现表明 10a 有利于预防辐射损伤,具有成为辐射防护剂的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f922/8184683/5f5996b2681b/JCMM-25-5470-g003.jpg

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