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.
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Authors | Yiqin Yao, Sheng Hu, Chunxue Zhang, Qun Zhou, Hui Wang, Ya Yang, Chao Liu, Haiyan Ding |
Journal | International immunopharmacology
(Int Immunopharmacol)
Vol. 105
Pg. 108582
(Apr 2022)
ISSN: 1878-1705 [Electronic] Netherlands |
PMID | 35124564
(Publication Type: Journal Article)
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Copyright | Copyright © 2022. Published by Elsevier B.V. |
Chemical References |
- Forkhead Box Protein O1
- Foxo1 protein, mouse
- Ginsenosides
- Keap1 protein, mouse
- Kelch-Like ECH-Associated Protein 1
- MIRN139 microRNA, mouse
- MicroRNAs
- NF-E2-Related Factor 2
- Nfe2l2 protein, mouse
- ginsenoside Rd
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Topics |
- Animals
- Brain Ischemia
(drug therapy, metabolism)
- Forkhead Box Protein O1
(genetics, metabolism)
- Ginsenosides
(pharmacology)
- Kelch-Like ECH-Associated Protein 1
(genetics, metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs
(genetics, metabolism)
- NF-E2-Related Factor 2
(genetics, metabolism)
- Reperfusion Injury
(drug therapy, metabolism)
- Signal Transduction
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