Abstract
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/BH4/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 BH4 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/BH4/eNOS pathway. This study provides a theoretical basis and new research ideas for the development of new drugs for RE.
Highlights
Radiotherapy is a commonly used cancer treatment method, and approximately 50–60% of cancer patients need to receive radiation therapy
The results showed that the weights of the rats in the control group increased by approximately 20 g per week
The effects of LIG on GTP cyclohydrolase 1 (Gch1) protein levels in human umbilical vein endothelium cells (HUVECs) were investigated by western blot, and the results showed that LIG could significantly improve the protein level of Gch1 compared with the control group
Summary
Radiotherapy is a commonly used cancer treatment method, and approximately 50–60% of cancer patients need to receive radiation therapy. During intraperitoneal or pelvic radiotherapy, radiation enteritis (RE) may occur in more than half of patients. The blood supply to tissues and organs is a key factor in maintaining organ function. We found that ionizing radiation (IR) could lead to a significant reduction in the intestinal blood supply, causing mesenteric vascular ischemia and inducing RE. We found that targeting the downregulation of GTP-cyclohydrolase 1 caused by IR to prevent endothelial dysfunction could be a new strategy for the prevention of RE (Yan et al, 2020). There is a lack of drugs that can improve this reduction in Gch observed after IR
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