College of Pharmacy, Xinjiang Medical University, No. 567 North Shangde Road, Urumqi, Xinjiang 830017, PR China.
Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Int Immunopharmacol. 2022 Apr;105:108582. doi: 10.1016/j.intimp.2022.108582. Epub 2022 Feb 3.
Pyroptosis mediated by nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome is implicated in cerebral ischemia/reperfusion (I/R) injury. Ginsenoside Rd (Rd), a monomer component of Panax ginseng and Panax notoginseng, is reported to confer neuroprotection in brain injury models. However, the role of pyroptosis in Rd-mediated neuroprotection following cerebral I/R has not been investigated. We aimed to confirm the neuroprotective function and underlying mechanisms of Rd on pyroptosis after cerebral I/R using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male C57BL/6 mice, and oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary cortical neurons. MicroRNA-139-5p (miR-139-5p) downregulation, forkhead box transcription factor O1 (FOXO1) and Kelch-like ECH-associated protein 1 (Keap1) upregulation, nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant pathway inactivation, reactive oxygen species (ROS)-driven thioredoxin-interacting protein (TXNIP) over-expression, and NLRP3 inflammasome activation-induced pyroptosis were observed in ischemic cortical tissues and primary neurons under MCAO/R and OGD/R induction. More importantly, Rd upregulated miR-139-5p to inhibit FoxO1 which regulates Keap1 transcriptional activity, and subsequently activates the Nrf2 antioxidant pathway, resulting in attenuation of ROS/TXNIP/NLRP3 inflammasome axis-driven pyroptosis in these animal and cell models. In summary, an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis may be the mechanism by which Rd attenuates ischemic stroke.
核苷酸结合寡聚化结构域（NOD）样受体 3（NLRP3）炎性小体介导的细胞焦亡与脑缺血/再灌注（I/R）损伤有关。人参皂苷 Rd（Rd）是人参和三七的单体成分，据报道在脑损伤模型中具有神经保护作用。然而，Rd 介导的脑 I/R 后细胞焦亡的神经保护作用的机制尚未得到研究。我们旨在使用雄性 C57BL/6 小鼠大脑中动脉闭塞/再灌注（MCAO/R）模型和原代皮质神经元氧葡萄糖剥夺/再氧合（OGD/R）模型，证实 Rd 对脑 I/R 后细胞焦亡的神经保护作用及其潜在机制。在 MCAO/R 和 OGD/R 诱导下，缺血性皮质组织和原代神经元中观察到 microRNA-139-5p（miR-139-5p）下调、叉头框转录因子 O1（FOXO1）和 Kelch 样 ECH 相关蛋白 1（Keap1）上调、核因子红细胞 2 相关因子 2（Nrf2）抗氧化途径失活、活性氧（ROS）驱动的硫氧还蛋白相互作用蛋白（TXNIP）过表达以及 NLRP3 炎性小体激活诱导的细胞焦亡。更重要的是，Rd 上调 miR-139-5p 以抑制 FoxO1，FoxO1 调节 Keap1 的转录活性，随后激活 Nrf2 抗氧化途径，从而减轻这些动物和细胞模型中 ROS/TXNIP/NLRP3 炎性小体轴驱动的细胞焦亡。总之，通过 miR-139-5p/FoxO1/Keap1/Nrf2 轴的抗细胞焦亡作用可能是 Rd 减轻缺血性中风的机制。
