Evaluating a novel protective agent against radiation-induced acute intestinal injury

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To develop and synthesize a novel derivative of ethyl pyruvate, named TZC02, and investigate its radioprotective effects against ionizing radiation (IR)-induced intestinal injury in mice. Male C57BL/6J mice weighing (20 ± 2) g in the survival experiment were randomly divided into five groups (n = 10 per group): a control group, an IR group, an IR + TZC02 (50 mg/kg) group, an IR + TZC02 (100 mg/kg) group, and an IR + TZC02 (200 mg/kg) group. The mice's survival was monitored for 7 d. In the other experiment, the male mice were randomly divided into three groups (n = 5 per group): a control group, an IR group, and an IR + TZC02 (200 mg/kg) group. TZC02 (100 mg/kg body weight) was intragastrically administered to the mice 1 h before 12 Gy abdominal irradiation (ABI) and for 2 d after irradiation. Three days after IR exposure, small intestinal tissues were collected and the number of small intestinal crypts was determined using hematoxylin & eosin (H&E) staining. To assess the regenerative capacity of the small intestine (SI) and radiation-induced damage, stemness markers or DNA repair surrogates, including Ki67, lysozyme, and villus, were employed for immunohistochemical analysis. The expression of histone H2AX phosphorylation (gH2AX) and caspase-3 were evaluated through immunofluorescence analyses. Additionally, in vitro cultured small intestinal organoids were employed to investigate the effects of TZC02 on SI regeneration after γ -radiation. The administration of TZC02 significantly improved the 7 d survival rate of mice exposed to 12 Gy ABI (p = 0.0001), attenuated Ki67-positive cells (37.7 ± 7.82/five crypts, 59.6 ± 6.33/five crypts, 11.89/five crypts, p < 0.0001) and Paneth cells (5.5 ± 1.71/five crypts, 9.9 ± 1.37/five crypts, t = 6.021, p = 0.0008), and reduced structural damage to the SI (villus height: 294.72 ± 40.09 μm, 349.49 ± 60.17 μm; t = 3.387; p = 0.0017). TZC02 also significantly decreased the crypt apoptosis detected by caspase-3 (29.83 ± 2.56, 10.75 ± 1.26, t = 13.39, p < 0.0001) and DNA damage detected by gH2AX, (29.6 ± 2.70, 10.4 ± 1.14, t = 10.13, p < 0.0001). The organoid survival 7 d post-irradiation further confirmed the protective effects of TZC02 (area of organoids: 0.080 ± 0.037 mm2, 0.119 ± 0.081 mm2; t = 2.304; p = 0.0261). The findings of this study demonstrate that TZC02 can offer effective protection against IR-induced intestinal injury, suggesting its potential as a promising protective compound for patients treated with radiotherapy.