Compound C (Merck Research Laboratories)

Microglial activation driving neuroinflammation is a key factor in secondary brain injury after intracerebral hemorrhage (ICH); however, the regulatory mechanisms remain unknown. This study investigates how corin influences microglial inflammatory activation and its underlying mechanisms. Corin expression in rat ICH brain tissue was assessed at multiple time points. To assess corin's effect on neurological function and microglial inflammation, ICH rats and oxygen-glucose deprivation plus hemin (OGD/H)-stimulated HAPI microglia were treated with corin-encoding lentivirus. Neurobehavioral performance was evaluated using the Morris water maze (MWM). Microglial activation was assessed via Iba-1, iNOS, and Arg-1 expression, cytokine secretion, and migration assays. To determine whether AMPK mediates corin's effects, cells were co-treated with Compound C (an AMPK inhibitor) and corin lentivirus. Corin expression decreased in ICH rat brain tissue, reaching its lowest level on day 3 post-ICH. Corin overexpression protected against ICH-induced neuronal apoptosis and improved neurological deficits as confirmed by MWM. Moreover, corin overexpression reduced microglial activation and inflammation in both ICH rats and OGD/H-stimulated microglial cells, ameliorated mitochondrial dysfunction, and increased the p-AMPK/AMPK ratio. The protective effects of corin on cell migration, inflammation, and mitochondrial function were reversed by Compound C, indicating AMPK is a downstream mediator of corin. Targeting corin offers a promising therapeutic strategy for ICH by reducing neuroinflammation and mitochondrial damage through AMPK activation and modulation of microglial inflammatory phenotype polarization. [BMB Reports 2026; 59(2): 143-150].

This study aims to investigate the efficacy of SGLT2i in mitigating DOX-associated ventricular arrhythmias and explore the underlying molecular mechanisms.

Rats received DOX(5 mg/kg/week i.p., 4 weeks) to model cardiotoxicity; saline-injected rats served as controls. DOX-treated rats were orally administered empagliflozin(EMPA, 10 mg/kg/day) or losartan (Los, 20 mg/kg/day). Cardiac structure and function were assessed. Then left ventricles were prepared for histology, the whole-cell patch clamp, and Western blot measurements. The direct impact of EMPA on neonatal rat ventricular cardiomyocytes (NRVCMs) were also investigated.

Left ventricular (LV) remodeling and dysfunction in DOX-treated rats were alleviated with EMPA. BNP, cTnT, and BP were reduced by EMPA. Cardiomyocyte hypertrophy, fibrosis, apoptosis, and LV conduction were improved by EMPA and Los, while Los was inferior to that of EMPA. DOX suppressed L-type calcium current (I_Ca,L) and prolonged action potential duration (APD) both in rats and NRVCMs. EMPA increased I_Ca,L, shorted APD, and reduced levels of Cav1.2, BNP, and fibrosis proteins(COL1A1, COL3A1, MMP-2, MMP-9). Activation of AMPK and inactivation of mTOR were induced by EMPA in DOX-treated rats and NRVCMs. These effects of EMPA were attenuated when treatment with compound C, an AMPK inhibitor. EMPA restored autophagic flux in DOX-treated rats and NRVCMs in an AMPK-dependent manner. The cardio-protective effects of EMPA were attenuated when treatment with 3-MA, an autophagy inhibitor.

Our research demonstrated for the first time that EMPA reduced the incidence of ventricular arrhythmia by regulating AMPK/mTOR signaling and restored autophagic flux in DOX-treated rats and NRVCMs.