Title : Artesunate ameliorate inflammasome-induced pyroptosis via inhibition of TLR4/NF-?B signaling trajectory in hepatic ischemia/ reperfusion injury
Abstract:
Artesunate (Art), an antimalarial drug, has demonstrated its protective effects against ischemia/reperfusion (I/R) injury in various organs, but its potential function against hepatic I/R is still unknown. This study, hence, examined whether treatment with Art alone or in combination with rapamycin (Rapa), an mTOR inhibitor, can ameliorate hepatic I/R injury via targeting the NLRP3 inflammasome signaling pathway. Rats were allocated into sham-operated (SO), I/R, ART post-treated group, Rapa treated group , and combination group. Hepatic I/R was induced via occlusion of the hepatic pedicle using microvascular clamp for 30 min followed by 24 h reperfusion.
On the molecular level, all treatment regimens succeeded to hinder inflammasome assembly and activation which was associated by the inhibition of HMGB1/RAGE and TLR4/MyD88/TRAF6 signaling pathway to inactivate NF-κB and the production of its pro-inflammatory cytokines. Furthermore, this impact also involved a reduction in pyroptosis, necrosis, and apoptosis. Notably, Art's impact on each parameter greatly surpassed that of Rapa, and in the combination group, Art actually enhanced Rapa's influence.In conclusion, Art displays novel therapeutic potential in the management of hepatic I/R injury via inhibition on TLR4/NLRP3 signaling trajectory.
Key words Artesunate, TLR4, NF-?B, oxidative stress, pyroptosis
Audience Take Away:
- Artesunate (Art) has a hepatoprotective role in hepatic ischemia/reperfusion injury
- Art alleviates hepatic I/R injury via inhibition TLR4/NF-?B/NLRP3 inflammasome
- The hepatoprotective effect was mediated by their anti-inflammatory, anti-oxidant, anti-apoptotic, anti-pyroptotic, anti-necrotic, and immunomodulatory characters
- It is noteworthy to mention that the add-on of Art has augmented the therapeutic benefit of Rapa in the hepatic I/R experimental setting
