Xu Fei-Fei, Shang Yue, Wei Hui-Qiang, Zhang Wei-Ying, Wang Li-Xing, Hu Tong, Zhang Shu-Qin, Li Yan-Li, Shang Hai-Hua, Hou Wen-Bin, Gou Wen-Feng, Fan Sai-Jun, Li Yi-Liang
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
Department of Biochemistry and Molecular Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin, 300071, China.
Acta Pharmacol Sin. 2025 Apr 28. doi: 10.1038/s41401-025-01564-0.
The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6 Gy of γ-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 µM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 µM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.
电离辐射（IR）造成的生物损伤不仅取决于组织成分的暴露时间和剂量，还取决于细胞的发育状态。目前，氨磷汀是唯一用于与放射治疗相关临床指征的辐射防护剂，但这种化合物有多个缺点，包括高毒性、半衰期短以及对神经系统无保护作用。熊果酸（UA）是一种天然的五环三萜类化合物，具有多种保护作用，包括抗炎、抗癌和抗氧化作用。由于其溶解性和生物利用度差，UA大多与脂质体一起给药。在本研究中，我们研究了UA的优化衍生物UA312对斑马鱼胚胎和幼体辐射诱导的发育毒性的影响。在受精后4、24、48和72小时观察胚胎和幼体的存活情况。UA312在受精后3小时给药，而胚胎在受精后4小时接受6 Gy的γ射线照射（剂量率：0.88 Gy/min），然后将胚胎转移到新鲜缓冲液中。我们确定40 μM的UA312对斑马鱼胚胎和幼体是安全浓度。我们发现用UA312（40 μM）处理可恢复IR诱导的斑马鱼胚胎和幼体早期发育异常。转录组分析显示，暴露于IR会抑制斑马鱼中与神经发育和心肌细胞功能相关的多种途径，这通过评估心脏形态异常、神经递质水平变化和运动行为改变得到验证；并且UA312处理改善了这些改变。我们证明UA312处理通过靶向胆碱能受体α3（chrna3）和谷氨酸离子型受体红藻氨酸5（grik5）显著逆转了相关信号通路。总之，本研究确定了一种有前景的辐射防护药物UA312，它通过靶向chrna3和grik5减轻IR诱导的斑马鱼心脏毒性和神经发育毒性。UA312可能被开发为一种针对人类急性IR损伤的新型辐射防护剂。
