Protective mechanism of a novel aminothiol compound on radiation-induced intestinal injury

Abstract

Purpose

With the development of nuclear technology and radiotherapy, the risk of radiation injury has been increasing. Therefore, it is important to find an effective radiation-protective agent. In this study, we designed and synthesized a novel compound called compound 8, of which the radioprotective effect and mechanism were studied.

Materials and methods

Before being exposed to ionizing radiation, mice were pretreated with compound 8. The 30-day mortality assay, hematoxylin–eosin staining, and immunohistochemistry staining assay were performed to evaluate the anti-radiation effect of the compound 8. TUNEL and immunofluorescence assays were conducted to study the anti-radiation mechanism of compound 8.

Results

Compared to the IR + vehicle group, the 30-day survival rate of mice treated with 25 mg/kg of compound 8 was significantly improved after 8 Gy total body irradiation. In the morphological study of the small intestine, we found that compound 8 could maintain crypt-villus structures in the irradiated mice. Further immunohistochemical staining displayed that compound 8 could improve the survival of Lgr5⁺ cells, ki67⁺ cells, and lysozyme⁺ cells. The results of TUNEL and immunofluorescence assays showed that compound 8 could decrease the expression of apoptosis-related caspase-8/-9, γ-H2AX, Bax, and p53.

Conclusions

These results indicate that compound 8 exerts its effects by maintaining structure and function of small intestine. It also reduces DNA damage, promotes crypt proliferation and differentiation. Moreover, it may enhance the anti-apoptotic ability of small intestinal tissue by inhibiting the activation of p53 and blocking the caspase cascade reaction. Compound 8 can protect the intestinal tract from post-radiation damage, it is thus a new and effective protective agent of radiation.

Keywords:

• Aminothiol
• radiation intestinal injury
• radioprotector
• DNA damage
• p53

Acknowledgements

The authors express our sincere gratitude to the reviewers and their comments.

Disclosure statement

No conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Tianjin Major Scientific and Technological Projects of Drug Creation [17ZXXYSY00090], Key Scientific and Technological Support Projects of Tianjin Key R&D Program, 2019 [19YFZCSY00350], and the Technology Development Project from the Chinese Academy of Medical Sciences & Peking Union Medical College [IRMQT2020045].

Notes on contributors

Xinxin Wang

Xinxin Wang, MS, was a postgraduate student at 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.

Renbin Yuan

Renbin Yuan, BD, is a postgraduate student at 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.

Longfei Miao

Longfei Miao, PhD, was a PhD student at 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.

Xuejiao Li

Xuejiao Li, BD, is a PhD student at 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.

Yuying Guo

Yuying Guo, BD, is a PhD student at 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.

Hongqi Tian

Hongqi Tian, PhD, is a professor at 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.