ABSTRACT
Glycyrrhizic acid (GA) has effects on anti-hepatic fibrosis, anti-tumor and prevention from hepatocellular carcinoma (HCC) progression. Yet, the capacity of GA to ameliorate the advance of HCC pertinent to nonalcoholic fatty liver disease (NAFLD) remains to be clarified. We used the CCK-8 method to detect the optimal treatment concentration and time for L-02 cells, palmitic acid (PA)-induced L-02 cells and HepG2 cells, and selected 40 µM and 48 h to treat PA-induced L-02 cells and 60 µM for 24 h to treat HepG2 cells. Moreover, functional associations of HepG2 cells were elucidated through various assays. The results showed that GA demonstrated enhances lipid deposition and alleviates the inflammatory response in L-02 cells induced by palmitic acid. Simultaneously, we found that GA inhibits the proliferation, migration, and invasion while promoting apoptosis in HepG2 cells. In pursuit of constructing of HCC model rats, a combination of high-fat diets and diethylnitrosamine was utilized. The results showed that GA significantly decreased the liver index, body weight, liver weight, and the number of nodules in HCC model rats. Moreover, GA mitigated infiltration and heightened apoptosis in these rats. Mechanistically, GA notably attenuated the KKß/NF-κB pathway in both HepG2 cells and the HCC model rats. In conclusion, GA functions as an inhibitor in the progression of NAFLD-related HCC cells, which might be relevant to the KKß/NF-κB pathway. Therefore, GA is a potential drug for NAFLD-related HCC treatment.
ABSTRACT
Loss of E3 ubiquitin ligase RING finger protein 8 (RNF8) may lead to neuronal DNA damage and apoptosis. In order to expand on our knowledge on the mechanistic basis underlying neuronal death in ischemic stroke, the present study sought to investigate the potential role of E3 ubiquitin ligase RNF8 on ischemic stroke and explore the underlying downstream mechanism. Middle cerebral artery occlusion (MCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in neurons were induced to simulate an ischemic stroke environment. It was found that downregulation of RNF8 and Reelin occurred in MCAO mice and OGD/R-exposed neurons. Silencing of RNF8 enhanced the MCAO-induced neuronal apoptosis and oxidative stress. Mechanistically, RNF8 enhanced the ubiquitination and degradation of HDAC2, thus attenuating OGD/R-induced neuronal apoptosis and oxidative stress. Moreover, HDAC2 inhibited Reelin expression through deacetylation of H3K27me3 in its promoter, causing reduced glycogen synthase kinase-3beta (GSK3ß)-Ser9 phosphorylation and the resultant elevated GSK3ß activity. By this mechanism, RNF8 alleviated ischemic stroke. Coherently, this study suggests that RNF8 plays a neuroprotective effect against ischemic stroke by downregulating HDAC2 expression and inducing Reelin-induced GSK3ß inhibition.