Ischemia-reperfusion injury (IRI) significantly impacts liver surgeries and transplantation due to oxidative stress, inflammation, and apoptosis. This study examines the protective effects of 2-cyano-3-5-(2,5-dichlorophenyl)- 2-furanyl-N-5-quinolinyl-2-propenamide (AGK2), a Sirtuin 2 (SIRT2) inhibitor, in hepatic IRI using in vitro and in vivo models. In vitro, HepG2 cells underwent hypoxia (1% oxygen for 45 minutes) followed by reoxygenation (21% oxygen for 2 hours) to simulate IRI. AGK2 was administered either 30 minutes before hypoxia (pre-treatment) or immediately after reoxygenation (post-treatment). Western blot analysis showed that IRI reduced SIRT2 expression to 50–60% of baseline levels, while AGK2 pre-treatment restored it to 130–150%, and post-treatment to 110–120%. Pre-treatment significantly reduced NF-κB activation and cleaved Caspase-3 levels, correlating with improved cell viability, as assessed by MTT assay. In vivo, a murine model of hepatic IRI (45 minutes ischemia, 2 hours reperfusion) was used, with AGK2 (20 mg/kg) administered pre- or post-treatment. IRI reduced hepatic SIRT2 expression to 50–60% of baseline, while AGK2 pre-treatment elevated it to 140–160%, and post-treatment to 110–130%. AGK2 pre-treatment significantly decreased NF-κB activation and cleaved Caspase-3 levels in liver tissues, indicating reduced inflammation and apoptosis. These findings suggest that AGK2 protects against hepatic IRI by modulating SIRT2 expression and attenuating inflammatory and apoptotic pathways. Pre-treatment consistently demonstrated superior efficacy compared to post-treatment, highlighting the importance of administration timing. This study supports the potential therapeutic application of AGK2 in mitigating hepatic ischemia-reperfusion injury.
He et al. (Wed,) studied this question.