Yiqi Weng

Background . The neuronal injury and cognitive dysfunction after liver transplantation have severe effects on the prognosis and life quality of patients. Accumulating evidence suggests that both exosomes and pyroptosis could participate in hepatic ischemia-reperfusion injury (HIRI) and play key roles in neuronal death. However, the link between exosomes and neuronal pyroptosis in HIRI awaits further investigation. Methods. After establishing the HIRI rat models, we primarily studied the role of pyroptosis in hippocampal and cortical neuron injury through detecting NOD-like receptor protein 3 (NLRP3), pro-caspase-1, cleaved-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), gasdermin D (GSDMD), interleukin-1beta (IL-1 β ), and interleukin-18 (IL-18) expressions with western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Then, we intravenously injected normal male rats with exosomes isolated from the sera of HIRI-challenged rats and pretreated rats with MCC950, a specific inhibitor of NLRP3, and carried out the same assay. We also detected the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in the hippocampal and cortical tissues. Results. The results indicated that NLRP3 inflammasome and caspase-1-dependent pyroptosis were activated in the hippocampus and cortex of HIRI rats. Furthermore, serum-derived exosomes from HIRI-challenged rats not only had the ability to cross the blood-brain barrier (BBB) but also had the similar effects on neuronal pyroptosis. Moreover, ROS and MDA productions were induced in the HIRI and exosome-challenged groups. In addition, to some degree, MCC950 could alleviate HIRI-mediated hippocampal and cortical neuronal pyroptosis. Conclusion . This study experimentally demonstrated that circulating exosomes play a critical role in HIRI-mediated hippocampal and cortical injury through regulating neuronal pyroptosis.

BACKGROUND: Acute kidney injury (AKI) impacts the survival of liver transplant recipients severely. To date, the related mechanism and effective therapy have not been rigorously explored. The present study aimed to explore the role of p53-mediated autophagy in the protective effect of hydrogen-rich saline (HRS) on AKI after orthotropic liver transplantation (OLT). METHODS: Adult male Sprague-Dawley rats were randomly allocated into four groups: sham, OLT, OLT with HRS (6 ml/kg) pretreatment (HS), OLT with HRS and chloroquine pretreatment (60 mg/kg) group (CQ). All the samples were collected 6 hours after reperfusion. The renal function and oxidative stress level were measured by biochemical and histopathologic examinations. The formation of autophagosome was observed by transmission electron microscopy. The apoptotic rate was determined by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis. The expression of caspase-3, cytochrome c, p53, damage-regulated autophagy modulator, Becline-1, microtubule-associated protein light 3-II, p62, lysosome-associated membrane protein-2, and the phosphorylation of p53 were assayed by western blot assay. RESULTS: Compared with the OLT group, HRS dramatically attenuated the histopathologic damage, restored the renal function, and decreased the oxidative stress level. Simultaneously, HRS significantly ameliorated apoptosis by decreasing the apoptotic rate and inhibiting the expression of caspase-3 and cytochrome c in rats subjected to OLT. The expression of Becline-1 and microtubule-associated protein light 3-II were upregulated with the inhibition of p62 and lysosome-associated membrane protein-2. The inhibition of autophagy by chloroquine counteracted the renoprotective effects of HRS. CONCLUSIONS: HRS is able to protect against AKI after liver transplantation partly by reducing apoptosis, which is possibly involved in the modulation of p53-mediated autophagy.