Isofraxidin alleviated radiation-induced testicular damage via the Nrf2/HO-1-NLRP3/ASC axis

Abstract

Objective: Radiotherapy is used to treat patients with tumors; however, radiation (IR)-induced testicular injury, which has no effective treatment approved in clinical practice, significantly influences their prognosis and quality of life. The protective effects and underlying mechanisms of action of isofraxidin (IF) against IR-induced testicular injury were investigated.
Methods: A mouse testis injury model was established using 5 Gy irradiation. Hematoxylin and eosin (H&E) staining, immunofluorescence staining, and enzyme-linked immunosorbent assay were used to measure DNA damage, apoptosis, inflammatory reactions, and oxidative stress in the testes of mice after irradiation. The effectiveness of IF irradiation on testicular injury was evaluated, and the mechanisms of the related oxidative stress and inflammatory response pathways were discussed.
Results: IF can improve IR-induced testicular injury by inhibiting the increased levels of DNA damage, apoptosis rate, oxidative stress, and inflammatory factors. The radioprotective effects of IF on testicular injury are mediated by the stimulation of nuclear factor E2-related factor 2 (Nrf2)/heme oxidase-1 (HO-1) or suppression of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathways. In addition, crosstalk between the Nrf2/HO-1 and NLRP3 inflammasome signaling pathways was elucidated, in which the inhibition of the NLRP3 inflammasome was mediated by the activation of Nrf2 signaling with IF upon IR exposure.
Conclusion: IF can be a potent radioprotective agent to mitigate testicular damage, and may provide a new therapeutic option to alleviate the side effects of radiotherapy in male patients with tumors.

Keywords

Isofraxidin / Radiation / Testicular

Conflict of interest statement

Yue Gao is the editorial board member of this journal and other authors declare no conflicts of interest.

Funding

National Natural Science Foundation of China (82192911, 82103776). Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202207).

Author contributions

Zengchun Ma, Zebin Liao, and Yue Gao contributed to the study concept and design, manuscript review, experiments, and funding. Changkun Hu performed the experiments and data analyses, prepared the manuscript, and prepared the figures. Liangliang Zhang and Zekun Wu performed the experiments and data analysis.

Ethical approval of studies and informed consent

All animal experiments were approved by the Animal Care and Use Committee of the Animal Center in Academy (IACUC-DWZX-2021-557).

Acknowledgments

None.

Data availability

All data generated or analyzed during this study are included in this published article.

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Acupuncture and Herbal Medicine