1. Academic Validation
  2. Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis

Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis

  • Int Immunopharmacol. 2022 Apr;105:108582. doi: 10.1016/j.intimp.2022.108582.
Yiqin Yao 1 Sheng Hu 1 Chunxue Zhang 2 Qun Zhou 3 Hui Wang 2 Ya Yang 1 Chao Liu 4 Haiyan Ding 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Xinjiang Medical University, No. 567 North Shangde Road, Urumqi, Xinjiang 830017, PR China.
  • 2 Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China.
  • 4 Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China. Electronic address: liuchaogermany@126.com.
  • 5 College of Pharmacy, Xinjiang Medical University, No. 567 North Shangde Road, Urumqi, Xinjiang 830017, PR China. Electronic address: dinghaiyan79@163.com.
Abstract

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.

Keywords

Cerebral ischemia/reperfusion injury; Ginsenoside Rd; NLRP3 inflammasome; Pyroptosis; miR-139-5p.

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