Abstract
Liver ischemia-reperfusion injury (IRI) is a common clinical event with high morbidity in patients undergoing complex liver surgery or having abdominal trauma. Inflammatory and oxidative stress responses are the main contributing factors in liver IRI. The iridoid glucoside aucubin (AU) has good anti-inflammatory and antioxidative effects; however, there are no relevant reports on the protective effect of glucosides on hepatic IRI. The purpose of this study was to determine whether AU pretreatment could prevent liver IRI and to explore the mechanism. Sprague–Dawley rats were randomly divided into five groups. The sham operation and IRI control groups were given intraperitoneal injections of normal saline, while the AU low-dose (AU-L) group, AU medium-dose (AU-M) group, and AU high-dose (AU-H) group were given intraperitoneal injections of AU at doses of 1, 5, and 10 mg/kg/day, respectively. After 10 d, liver IRI (70% liver ischemia for 1 h, reperfusion for 6 h) was surgically established in all groups except the sham group. Our results confirmed that liver injury was significantly aggravated after hepatic ischemia-reperfusion. AU alleviated the increase of transaminase and pathological changes induced by ischemia-reperfusion and improved liver damage. AU could also ameliorate the inflammatory and oxidative stress responses induced by ischemia-reperfusion and reduced expression of high mobility group protein (HMG)B1, receptor for advanced glycation end-products (RAGE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and reactive oxygen species (ROS). Moreover, AU reduced ischemia-reperfusion-induced mitochondrial dysfunction and cells apoptosis, increased peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and uncoupling (UCP)2 protein expression, and reduced caspase-3, cleaved caspase-3, and Cytochrome P450 proteins (CYP) expression. To determine expression levels of the Toll-like receptor (TLR)-4/nuclear factor-κB (NF-κB) pathway-related proteins in vitro and in vivo, we also measured TLR-4, myeloid differentiation factor88 (MyD88), NF-κB P65, p-P65, I-kappa-B-alpha (IκB-α), and p-IκB-α levels. The results showed that AU effectively inhibited activation of the TLR-4/NF-κB signaling pathway. In conclusion, we showed for the first time a hepatoprotective effect for AU in liver IRI, which acted by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, oxidative stress, and apoptosis. Pretreatment with AU may be a promising strategy for preventing liver IRI.
Highlights
Liver ischemia–reperfusion injury (IRI) is a type of liver injury caused by reperfusion after ischemic injury (JimenezCastro et al, 2019; Taner and Heimbach, 2019)
Compared with serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the IRI group, levels were significantly reduced in the AU low-dose (AU-L), AU medium-dose (AU-M), and AU high-dose (AU-H) groups (P < 0.05) with the most significant reduction being in the AU-M group (P < 0.01)
Serum levels of tumor necrosis factor alpha (TNF-a), IL-1b, and High mobility group protein B1 (HMGB1) were significantly reduced in the AU-L, AU-M, and AU-H groups compared with those in the IRI group (P < 0.05) with the most significant reduction being in the AU-M group (P < 0.01)
Summary
Liver ischemia–reperfusion injury (IRI) is a type of liver injury caused by reperfusion after ischemic injury (JimenezCastro et al, 2019; Taner and Heimbach, 2019). The pathogenesis of IRI is closely related to aseptic inflammatory response, oxidative stress level, energy metabolism disorder, and cell apoptosis and autophagy (Go et al, 2015; Li et al, 2015; Olthof et al, 2017; Kan et al, 2018; Xu et al, 2019). High mobility group protein B1 (HMGB1) is a highly conserved nuclear protein that is widely distributed in mammalian cells. When the body is injured, nuclear HMGB1 is acetylated and transferred to the cytoplasm (Liu et al, 2011). HMGB1 has been regarded as a potential target for the treatment of inflammatory responses and infection (Andersson and Tracey, 2011)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
