Yan Tao, Guo Shun, Zhang Tian, Zhang Zhimin, Liu An, Zhang Song, Xu Yuan, Qi Yuhong, Zhao Weihe, Wang Qinhui, Shi Lei, Liu Linna
Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China.
Department of Cardiology, General Hospital of Xinjiang Military Command, Urumqi, China.
Front Pharmacol. 2021 Apr 22;12:629125. doi: 10.3389/fphar.2021.629125. eCollection 2021.
There is a high incidence of radiation enteritis (RE) after abdominal radiotherapy. The occurrence of RE seriously affects the treatment and quality of life of patients; however, its pathogenesis is complex and there are no effective drugs for its prevention or treatment. Intestinal ischemia plays an important role in the occurrence of enteritis. Previous studies have shown that targeting GTP-cyclohydrolase 1 (Gch1) to improve intestinal ischemia could be a new strategy to prevent and treat RE. A high content of the naturally occurring phthalide derivative ligustilide (LIG) has been found in the plant drug Rhizoma Ligustici Chuanxiong for the treatment of cardiovascular diseases. The purpose of this study was to evaluate the protective effects of LIG on RE. Ionizing radiation (IR) rat and endothelial cell models were used to observe and record rat body weights and stool morphologies, measure intestinal blood perfusion by laser Doppler blood flow imaging, determine the diastolic functions of mesenteric arteries, detect the levels of Gch1/BH/eNOS pathway-related proteins and regulatory molecules in the mesenteric arteries and endothelial cells, and predict affinity by molecular docking technology. The results showed that LIG significantly improved the body weights, loose stools, intestinal villi lengths, intestinal perfusion and vasodilatory functions of IR rats. LIG also significantly improved Gch1 protein and BH levels in the mesenteric arteries and endothelial cells after IR, increased the NO content, reduced superoxide accumulation, and improved p-eNOS (Ser1177) levels in endothelial cells. LIG has good affinity for Gch1, which significantly improves its activity. These results indicate that LIG is the preferred compound for the prevention and treatment of RE by improving intestinal ischemia through the Gch1/BH/eNOS pathway. This study provides a theoretical basis and new research ideas for the development of new drugs for RE.
腹部放疗后放射性肠炎（RE）的发病率较高。RE的发生严重影响患者的治疗和生活质量；然而，其发病机制复杂，尚无有效的预防或治疗药物。肠道缺血在肠炎的发生中起重要作用。先前的研究表明，靶向鸟苷三磷酸环化水解酶1（Gch1）以改善肠道缺血可能是预防和治疗RE的新策略。在用于治疗心血管疾病的植物药川芎中发现了高含量的天然存在的苯酞衍生物藁本内酯（LIG）。本研究的目的是评估LIG对RE的保护作用。使用电离辐射（IR）大鼠和内皮细胞模型来观察和记录大鼠体重及粪便形态，通过激光多普勒血流成像测量肠道血流灌注，测定肠系膜动脉的舒张功能，检测肠系膜动脉和内皮细胞中Gch1/BH/eNOS途径相关蛋白和调节分子的水平，并通过分子对接技术预测亲和力。结果表明，LIG显著改善了IR大鼠的体重、稀便、肠绒毛长度、肠道灌注和血管舒张功能。LIG还显著提高了IR后肠系膜动脉和内皮细胞中的Gch1蛋白和BH水平，增加了NO含量，减少了超氧化物积累，并提高了内皮细胞中p-eNOS（Ser1177）的水平。LIG对Gch1具有良好亲和力，可显著提高其活性。这些结果表明，LIG是通过Gch1/BH/eNOS途径改善肠道缺血来预防和治疗RE的首选化合物。本研究为RE新药的开发提供了理论依据和新的研究思路。
