Zhou Jun, Yan Shan, Guo Xu, Gao Yanguo, Chen Shiqi, Li Xiaohan, Zhang Yonghong, Wang Qibin, Zheng Tao, Chen Li
School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Institute of Wudang Traditional Chinese Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Institute of Wudang Traditional Chinese Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Int Immunopharmacol. 2023 Jan;114:109543. doi: 10.1016/j.intimp.2022.109543. Epub 2022 Dec 9.
The NACHT, LRP, and PYD domains-containing protein 3 (NLRP3) inflammasome-evoked chronic inflammation is involved in the pathogenesis of diabetes mellitus (DM), and the NLRP3/gasdermin D (GSDMD)-mediated canonical pathway of pyroptosis leads to the loss of pancreatic β-cells and failure of pancreatic function in DM. A previous study demonstrated that salidroside (SAL) alleviates the pathological hyperplasia of pancreatic β-cells in db/db mice. However, it is not clear whether the NLRP3/GSDMD pathway-mediated pyroptosis can be regulated by SAL. In addition, the action of SAL on pancreatic β-cells in DM remains poorly understood. Thus, this study aimed to investigate the effects and underlying mechanisms of SAL on pancreatic β-cell pyroptosis. Rat insulinoma (INS-1) cells were cultured in a medium containing either high glucose (HG) or HG plus high insulin (HG-HI), and the effects of SAL on cell viability, AMP-activated protein kinase (AMPK) activity, reactive oxygen species (ROS) generation, NLRP3/GSDMD activation, and pyroptotic body formation were assessed. Streptozocin-induced DM mice were used to further investigate the effects of SAL on pancreatic pyroptosis. The results revealed aberrances on cell viability, AMPK activity, ROS generation, NLRP3/GSDMD activation, and pyroptotic body formation in HG- and HG-HI-exposed INS-1 cells; these abnormal effects were corrected by SAL in both a concentration- and AMPK-dependent manner. Moreover, SAL administration activated AMPK, suppressed NLRP3/GSDMD signaling, and protected pancreatic β-cells against pyroptosis in DM mice. These findings suggest that SAL promotes AMPK activation to suppress NLRP3/GSDMD-related pyroptosis in pancreatic β-cells under DM conditions.
含NACHT、LRP和PYD结构域的蛋白3（NLRP3）炎性小体引发的慢性炎症参与了糖尿病（DM）的发病机制，且NLRP3/ Gasdermin D（GSDMD）介导的经典细胞焦亡途径导致DM中胰腺β细胞丢失和胰腺功能衰竭。先前的一项研究表明，红景天苷（SAL）可减轻db/db小鼠胰腺β细胞的病理性增生。然而，尚不清楚SAL是否能调节NLRP3/GSDMD途径介导的细胞焦亡。此外，SAL对DM中胰腺β细胞的作用仍知之甚少。因此，本研究旨在探讨SAL对胰腺β细胞焦亡的影响及其潜在机制。将大鼠胰岛素瘤（INS-1）细胞培养于含高糖（HG）或HG加高胰岛素（HG-HI）的培养基中，评估SAL对细胞活力、AMP激活的蛋白激酶（AMPK）活性、活性氧（ROS）生成、NLRP3/GSDMD激活及细胞焦亡小体形成的影响。使用链脲佐菌素诱导的DM小鼠进一步研究SAL对胰腺细胞焦亡的影响。结果显示，暴露于HG和HG-HI的INS-1细胞在细胞活力、AMPK活性、ROS生成、NLRP3/GSDMD激活及细胞焦亡小体形成方面存在异常；SAL以浓度和AMPK依赖性方式纠正了这些异常效应。此外，给予SAL可激活AMPK，抑制NLRP3/GSDMD信号传导，并保护DM小鼠的胰腺β细胞免受细胞焦亡。这些发现表明，在DM条件下，SAL通过促进AMPK激活来抑制胰腺β细胞中NLRP3/GSDMD相关的细胞焦亡。
