Hepatoprotective effects of sevoflurane against hepatic ischemia-reperfusion injury by regulating microRNA-124-3p-mediated TRAF3/CREB axis

Abstract

The purpose of the present study is to define the role of sevoflurane (SEV) in hepatic ischemia-reperfusion (I/R) injury as well as its underlying mechanism. Initially, hepatic I/R animal models and I/R hepatocyte models were established in C57BL/6 mice and normal mouse hepatocytes (BNL CL.2) after SEV preconditioning, respectively, followed by detection of microRNA-124-3p (miR-124-3p), TRAF3, and CREB expression by RT-qPCR and Western blot analysis. In addition, miR-124-3p, TRAF3 and CREB expression in hepatocytes was altered to identify their roles in modulating the levels of glutathione transferase (GST), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and inflammation-related factors and hepatocyte apoptosis by ELISA and flow cytometry respectively. The effects of SEV on the miR-124-3p/TRAF3/CREB axis were also verified in vitro and in vivo. IP assay was performed to verify the effect of TRAF3 on CREB ubiquitination in BNL CL.2 cells, and the cycloheximide (CHX) intervention experiment to detect the stability of CREB protein. SEV augmented the miR-124-3p expression in I/R animal and cell models. Moreover, SEV was observed to suppress I/R-induced liver damage, GST, ALT, and AST levels, hepatocyte apoptosis and inflammation. Overexpression of miR-124-3p resulted in alleviation of hepatic I/R injury, which was countered by TRAF3 overexpression. miR-124-3p targeted TRAF3, while TRAF3 promoted CREB ubiquitination and reduced protein stability of CREB. SEV could impede I/R-induced liver damage, GST, ALT, and AST levels, hepatocyte apoptosis and inflammation via mediation of the miR-124-3p/TRAF3/CREB axis in vitro and in vivo. Collectively, SEV may upregulate miR-124-3p to inhibit TRAF3 expression, thereby reducing the ubiquitination and degradation of CREB, alleviating hepatic I/R injury.

Sevoflurane blocks KLF5‐mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury

“…Sevo has been extensively studied to mitigate hepatic I/R injury through the alleviation of cell inflammatory response and oxidative stress, as well as apoptosis 14,18,19 . Here, we also found the downregulation of TUNEL‐positive cells, Bax expression, and TNF‐α, IL‐6 and IL‐1β levels upon Sevo treatment in both liver tissues of mice with hepatic I/R injury and in AML12 cells insulted with OGD/R.…”

“…17 Sevo has been extensively studied to mitigate hepatic I/R injury through the alleviation of cell inflammatory response and oxidative stress, as well as apoptosis. 14,18,19 Here, we also found the downregu- a positive feedback loop, and that curcumol may break this feedback loop, thereby alleviating liver fibrosis. 21 These results suggested a possible link between KLF5 dysregulation and liver fibrosis.…”

The Effect of Sevoflurane and Fullerenol C 60 on the Liver and Kidney in Lower Extremity Ischemia-Reperfusion Injury in Mice with Streptozocin-Induced Diabetes

“…They stated that this might be related to the inhibition of the IR-mediated down-regulation of miR-124-3p. 29 In another study, sevoflurane preconditioning was observed to decrease MDA and MPO levels and increase SOD and CAT activity in a kidney IR mouse model. It has been stated that this is due to the upregulation of Nrf2 expression.…”

Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases

“…Recombinant RANKL ameliorates HIRI [55]. TRAF3 plays an essential role in HIRI [56,57]. Hepatocytespecific knockout of TRAF3 ameliorates cell death and immune responses both in vitro and in vivo hepatic I/R models, whereas myeloid cell-specific deletion of TRAF3 does not affect HIRI [58].…”

“…Hepatic ischemia/reperfusion disturbs liver function, leading to irreversible damage and even multiple organ failure [86]. In HIRI, CD40 [48][49][50][51][52][53], OX40 [54], RANKL [55], TRAF2 [87,88], TRAF3 [56][57][58], cIAP1 [89], RELB [59] are upregulated in the liver. CD40, as an M1 macrophage marker gene, is increased in purified Kupffer cells in mice under IR conditions [53].…”