Activation of Inflammasomes and Relevant Modulators for the Treatment of Microglia-mediated Neuroinflammation in Ischemic Stroke.

As the brain's resident immune patrol, microglia mediate endogenous immune responses to central nervous system injury in ischemic stroke, thereby eliciting either neuroprotective or neurotoxic effects. The association of microglia-mediated neuroinflammation with the progression of ischemic stroke is evident through diverse signaling pathways, notably involving inflammasomes. Within microglia, inflammasomes play a pivotal role in promoting the maturation of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), facilitating pyroptosis, and triggering immune infiltration, ultimately leading to neuronal cell dysfunction. Addressing the persistent and widespread inflammation holds promise as a breakthrough in enhancing the treatment of ischemic stroke.

Breviscapine protects against pathological cardiac hypertrophy by targeting FOXO3a-mitofusin-1 mediated mitochondrial fusion.

Forkhead box O3a (FOXO3a)-mediated mitochondrial dysfunction plays a pivotal effect on cardiac hypertrophy and heart failure (HF). However, the role and underlying mechanisms of FOXO3a, regulated by breviscapine (BRE), on mitochondrial function in HF therapy remain unclear. This study reveals that BRE-induced nuclear translocation of FOXO3a facilitates mitofusin-1 (MFN-1)-dependent mitochondrial fusion in cardiac hypertrophy and HF. BRE effectively promotes cardiac function and ameliorates cardiac remodeling in pressure overload-induced mice. In addition, BRE mitigates phenylephrine (PE)-induced cardiac hypertrophy in cardiomyocytes and fibrosis remodeling in fibroblasts by inhibiting ROS production and promoting mitochondrial fusion, respectively. Transcriptomics analysis underscores the close association between the FOXO pathway and the protective effect of BRE against HF, with FOXO3a emerging as a potential target of BRE. BRE potentiates the nuclear translocation of FOXO3a by attenuating its phosphorylation, other than its acetylation in cardiac hypertrophy. Mechanistically, over-expression of FOXO3a significantly inhibits cardiac hypertrophy and mitochondrial injury by promoting MFN-1-mediated mitochondrial fusion. Furthermore, BRE demonstrates its ability to substantially curb cardiac hypertrophy, reduce mitochondrial ROS production, and enhance MFN-1-mediated mitochondrial fusion through a FOXO3a-dependent mechanism. In conclusion, nuclear FOXO3a translocation induced by BRE presents a successful therapeutic avenue for addressing cardiac hypertrophy and HF through promoting MFN-1-dependent mitochondrial fusion.