Abstract：
Acute pancreatitis (AP) is an acute inflammatory gastrointestinal disease, the mortality and morbility of which has been on the increase in the past years. Spermidine, a natural polyamine, has a wide range of pharmacological effects including anti-inflammation, antioxidation, anti-aging, and anti-tumorigenic. This study aimed to investigate the reliable targets and molecular mechanisms of spermidine in treating AP. By employing computational biology methods including network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we explored the potential targets of spermidine in improving AP with dietary supplementation. The computational biology results revealed that spermidine had high degrees (degree: 18, betweenness: 38.91; degree: 18, betweenness: 206.41) and stable binding free energy (ΔGbind: - 12.81 ± 0.55 kcal/mol, - 15.00 ± 1.00 kcal/mol) with acetylcholinesterase (AchE) and serotonin transporter (5-HTT). Experimental validation demonstrates that spermidine treatment could reduce the necrosis and AchE activity in pancreatic acinar cells. Cellular thermal shift assay (CETSA) results revealed that spermidine could bind to and stabilize the 5-HTT protein in acinar cells. Moreover, spermidine treatment impeded the rise of the expression of 5-HTT in pancreatic tissues of caerulein induced acute pancreatitis mice. In conclusion, serotonin transporter might be a reliable target of spermidine in treating AP. This study provides new idea for the exploration of potential targets of natural compounds.
摘要：
急性胰腺炎(AP)是一种急性炎症性胃肠道疾病,在过去的几年里，这种疾病的死亡率和死亡率一直在上升。亚精胺,一种天然多胺,具有广泛的药理作用，包括抗炎，抗氧化，抗衰老,和抗肿瘤。本研究旨在探讨亚精胺治疗AP的可靠靶点及分子机制。通过采用包括网络药理学在内的计算生物学方法，分子对接,和分子动力学(MD)模拟，我们探讨了亚精胺在膳食补充剂改善AP方面的潜在作用靶点.计算生物学结果表明，亚精胺具有高度（度：18，介数：38.91；度：18，介数：206.41）和稳定的结合自由能（ΔGbind：-12.81±0.55kcal/mol，-15.00±1.00kcal/mol）与乙酰胆碱酯酶（AchE）和5-羟色胺转运蛋白（5-HTT）。实验验证表明亚精胺处理可以降低胰腺腺泡细胞的坏死和AchE活性。细胞热转移分析（CETSA）结果表明，亚精胺可以结合并稳定腺泡细胞中的5-HTT蛋白。此外，亚精胺治疗阻碍了5-HTT在caerulein诱导的急性胰腺炎小鼠胰腺组织中的表达升高。总之,5-羟色胺转运体可能是亚精胺治疗AP的可靠靶点。本研究为探索天然化合物的潜在靶标提供了新思路。
