Wang Xiaohong, Qian Jing, Meng Yun, Wang Ping, Cheng Ruizhi, Zhou Guoxiong, Zhu Shunxing, Liu Chun
Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng, 211900, Jiangsu, China.
Department of General Surgery, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng, 211900, Jiangsu, China.
Heliyon. 2023 Jan 28;9(2):e13225. doi: 10.1016/j.heliyon.2023.e13225. eCollection 2023 Feb.
Our previous studies showed that Salidroside (Sal), a glucoside of the phenylpropanoid tyrosol isolated from , alleviated severe acute pancreatitis (SAP) by inhibiting inflammation. However, the detailed mechanism remains unclear. Recent evidence has indicated a critical role of Sal in ameliorating inflammatory disorders by regulating pyroptosis. The present study aimed to explore the involvement of Sal and pyroptosis in the pathogenesis of SAP and investigate the potential mechanism. The effects of Sal on pyroptosis were first evaluated using SAP rat and cell model. Our results revealed that Sal treatment significantly decreased SAP-induced pancreatic cell damage and pyroptosis in vivo and in vitro, as well as reduced the release of lactate dehydrogenase (LDH), IL-1β and IL-18. Search Tool for Interacting Chemicals (STITCH) online tool identified 4 genes (CASP3, AKT1, HIF1A and IL10) as candidate targets of Sal in both rattus norvegicus and homo sapiens. Western blot and immunohistochemistry staining validated that Sal treatment decreased the phosphorylation levels of Akt and NF-κB p65, as well as cleaved caspase-3 and N-terminal fragments of GSDME (GSDME-N), suggesting that Sal might suppress pyroptosis through inactivating Akt/NF-κB and Caspase-3/GSDME pathways. Furthermore, overexpression of AKT1 or CASP3 could partially reverse the inhibitory effects of Sal on cell injury and pyroptosis, while downregulation of AKT1 or CASP3 promoted the inhibitory effects of Sal. Taken together, our data indicate that Sal suppresses SAP-induced pyroptosis through inactivating Akt/NF-κB and Caspase-3/GSDME pathways.
我们之前的研究表明，红景天苷（Sal）是从红景天中分离出的苯丙醇酪醇的糖苷，可通过抑制炎症来缓解重症急性胰腺炎（SAP）。然而，具体机制仍不清楚。最近的证据表明，Sal在通过调节细胞焦亡改善炎症性疾病方面起关键作用。本研究旨在探讨Sal和细胞焦亡在SAP发病机制中的作用，并研究其潜在机制。首先使用SAP大鼠和细胞模型评估Sal对细胞焦亡的影响。我们的结果显示，Sal治疗显著降低了体内和体外SAP诱导的胰腺细胞损伤和细胞焦亡，同时减少了乳酸脱氢酶（LDH）、IL-1β和IL-18的释放。在线工具化学物质相互作用搜索工具（STITCH）确定了4个基因（CASP3、AKT1、HIF1A和IL10）作为Sal在大鼠和人类中的候选靶点。蛋白质免疫印迹和免疫组织化学染色验证了Sal治疗降低了Akt和NF-κB p65的磷酸化水平，以及裂解的caspase-3和GSDME的N端片段（GSDME-N），这表明Sal可能通过使Akt/NF-κB和Caspase-3/GSDME途径失活来抑制细胞焦亡。此外，AKT1或CASP3的过表达可部分逆转Sal对细胞损伤和细胞焦亡的抑制作用，而AKT1或CASP3的下调则增强了Sal的抑制作用。综上所述，我们的数据表明，Sal通过使Akt/NF-κB和Caspase-3/GSDME途径失活来抑制SAP诱导的细胞焦亡。
