ABSTRACT
@#Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale. Graphical abstract
ABSTRACT
@#Caspases are a group of structurally related cysteine proteases present in cytosol. One of their important common points is that the active sites contain cysteine and can specifically break the peptide bonds after the aspartic acid residues. Caspases are broadly divided into two groups based on their functions, including inflammatory Caspases and apoptotic Caspases. Inflammatory Caspases include Caspase-1, Caspase-4, Caspase-5, Caspase-11 and Caspase-12, which play important roles in the process of innate immune defense. Unlike inflammatory Caspases, apoptotic Caspases(2/3/6/7/8/910)initiate and execute an immunologically silent form of programmed cell death known as apoptosis. However, ongoing investigations have uncovered essential functions of Caspase-8 in the regulation of immunity in cells and organisms. Accumulated studies have shown that Caspases play important roles in the occurrence and development of various immunity-related diseases. In order to comprehensively elucidate the relationship between Caspases and innate immunity, and to provide some scientific basis and theoretical reference for the treatment of various diseases, this article reviews the regulation of activity and inflammation mechanism of innate immunity-related Caspase-1/4/5/11/8/12.