Laboratory of Ethnopharmacology, Tissue-Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
Nutrients. 2022 Jun 22;14(13):2591. doi: 10.3390/nu14132591.
Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.
急性胰腺炎（AP）是最常见的胃肠道疾病住院原因之一，具有较高的发病率和死亡率。内质网应激（ERS）和 Gasdermin D（GSDMD）介导 AP，但它们之间相互影响的机制知之甚少。薯蓣皂苷元具有出色的抗炎和抗氧化作用。本研究旨在探讨薯蓣皂苷元衍生物 D（药物 D）是否通过调节内质网（ER）中的 GSDMD 来抑制 L-精氨酸诱导的急性胰腺炎。我们在 L-精氨酸诱导的 AP 小鼠模型以及体外小鼠胰腺腺泡细胞模型中进行了研究。本研究发现 GSDMD 在 ER 中积累，导致腺泡细胞发生 ERS。GSDMD 抑制剂 Disulfiram（DSF）显著降低了 ER 中 GSDMD 的表达以及 TXNIP/HIF-1α 信号。分子对接研究表明，药物 D 与 GSDMD 之间存在潜在的相互作用。结果表明，药物 D 显著抑制了胰腺腺泡细胞的坏死，呈剂量依赖性，我们还发现药物 D 通过抑制腺泡细胞 ER 中 GSDMD 的积累，通过 TXNIP/HIF-1α 通路，缓解胰腺坏死和全身炎症。此外，药物 D 还可在 AP 中剂量依赖性地下调 p-IRE1α（ERS 的标志物）的水平。我们还发现药物 D 可减轻 AP 中的 TXNIP 上调和氧化应激。此外，我们的结果表明，GSDMD 通过抑制 TXNIP/HIF-1α 减轻 AP。因此，从盾叶薯蓣中提取的药物 D 可能通过 TXNIP / HIF-1α 途径调节 ER 中的 GSDMD 来抑制 L-精氨酸诱导的 AP。
