Daprodustat reduces skeletal muscle ischemia-reperfusion injury in mice.

PURPOSE: The purpose of the present work was to assess the specific effects and underlying mechanisms of Daprodustat (GSK1278863) on skeletal muscle injury induced by ischemia reperfusion (I/R). METHODS: C57BL/6 mice were randomized into the skeletal muscle I/R injury (I/R), Daprodustat (GSK1278863) pretreatment and I/R (I/R + GSK) and sham operation (Sham) groups. The skeletal muscle I/R injury model was established by placing an orthodontic rubber band at the left hip joint for 3 h and releasing it for 3 h. H&E staining, wet weight/dry weight ratio assessment, TUNEL assay, ELISA, qRT-PCR and immunoblot were utilized to assess the effects of Daprodustat. RESULTS: Daprodustat pretreatment significantly ameliorated apoptosis in skeletal muscle cells, reduced oxidative damage and suppressed inflammatory cytokines. Mechanistically, Daprodustat positively affected NF-κB signaling activation. CONCLUSION: These data demonstrated that Daprodustat may provide a potential clinical approach for preventing or treating skeletal muscle injury induced by I/R.

MG53 protects against Coxsackievirus B3-induced acute viral myocarditis in mice by inhibiting NLRP3 inflammasome-mediated pyroptosis via the NF-κB signaling pathway.

Pyroptosis, a novel programmed cell death mediated by NOD-like receptor protein 3 (NLRP3) inflammasome, is a critical pathogenic process in acute viral myocarditis (AVMC). Mitsugumin 53 (MG53) is predominantly expressed in myocardial tissues and has been reported to exert cardioprotective effects through multiple pathways. Herein, we aimed to investigate the biological function of MG53 in AVMC and its underlying regulatory mechanism in pyroptosis. BALB/c mice and HL-1 cells were infected with Coxsackievirus B3 (CVB3) to establish animal and cellular models of AVMC. As inflammation progressed in the myocardium, we found a progressive decrease in myocardial MG53 expression, accompanied by a significant enhancement of cardiomyocyte pyroptosis. MG53 overexpression significantly alleviated myocardial inflammation, apoptosis, fibrosis, and mitochondrial damage, thereby improving cardiac dysfunction in AVMC mice. Moreover, MG53 overexpression inhibited NLRP3 inflammasome-mediated pyroptosis, reduced pro-inflammatory cytokines (IL-1ß/18) release, and suppressed NF-κB signaling pathway activation both in vivo and in vitro. Conversely, MG53 knockdown reduced cell viability, facilitated cell pyroptosis, and increased pro-inflammatory cytokines release in CVB3-infected HL-1 cells by promoting NF-κB activation. These effects were partially reversed by applying the NF-κB inhibitor BAY 11-7082. In conclusion, our results suggest that MG53 acts as a negative regulator of NLRP3 inflammasome-mediated pyroptosis in CVB3-induced AVMC, partially by inhibiting the NF-κB signaling pathway. MG53 is a promising candidate for clinical applications in AVMC treatment.