Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.750815
Keywords
dihydrotanshinone I; NLRP3 inflammasome; caspase-1; IL-1 beta; septic shock
Categories
Funding
- Beijing Natural Science Foundation [7214296]
- National Natural Science Foundation of China [82003984, 81874368, 8163000655]
- Beijing Nova Program (China) [Z181100006218001]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program [2017ZX09301022]
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The study revealed that DHT specifically inhibits the activation of the NLRP3 inflammasome, has no effect on AIM2 or NLRC4 inflammasome activation, and does not influence potassium or calcium flux. Additionally, DHT suppresses the assembly of the NLRP3 inflammasome and shows significant therapeutic effects on NLRP3-mediated sepsis in mice.
The abnormal activation of the NLRP3 inflammasome is closely related to the occurrence and development of many inflammatory diseases. Targeting the NLRP3 inflammasome has been considered an efficient therapy to treat infections. We found that dihydrotanshinone I (DHT) specifically blocked the canonical and non-canonical activation of the NLRP3 inflammasome. Nevertheless, DHT had no relation with the activation of AIM2 or the NLRC4 inflammasome. Further study demonstrated that DHT had no influences on potassium efflux, calcium flux, or the production of mitochondrial ROS. We also discovered that DHT suppressed ASC oligomerization induced by NLRP3 agonists, suggesting that DHT inhibited the assembly of the NLRP3 inflammasome. Importantly, DHT possessed a significant therapeutic effect on NLRP3 inflammasome-mediated sepsis in mice. Therefore, our results aimed to clarify DHT as a specific small-molecule inhibitor for the NLRP3 inflammasome and suggested that DHT can be used as a potential drug against NLRP3-mediated diseases.
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