Search

Hepatic ischemia/reperfusion (I/R) injury is a major cause of high morbidity and mortality after liver resection, transplantation, and hemorrhagic shock. Paeoniflorin (PF), the main substance of glucosides in Radix Paeoniae Alba, has been widely used to treat various hepatic inflammatory diseases including I/R injury. However, the underlying mechanisms of PF on hepatic I/R injury remain further investigated. In this study, the liver I/R model was performed by clamping the portal vein and hepatic artery with an atraumatic clamp for 90 min followed by 6 hr reperfusion. PF (100 mg/kg) was given three times a day by gavage before I/R. The blood and hepatic samples were collected to evaluate liver injury and molecular indexes. The results showed that PF pretreatment significantly inhibited I/R-induced serum ALT and AST activities (40.3% and 53.8% those of I/R group, respectively), hepatic pathological damages and hepatic apoptosis (P < 0.01), and infiltration of neutrophils into liver. In addition, PF suppressed the production of pro-inflammatory cytokines (P < 0.01), decreased the expression of high mobility group box-1 (HMGB1), and down-regulated toll-like receptors 4 (TLR4) and phosphorylated ERK1/2, JNK1/2, p38, and NF-κB signal molecules expression in the I/R-operated mice. These findings indicated that PF played a protective role in liver I/R injury, and this protection was associated with inhibition of I/R-activated HMGB1-TLR4 signaling pathway to attenuate hepatic inflammation responses., (© 2018 John Wiley & Sons, Ltd.)

Acetaminophen (APAP) is a widely used antipyretic and analgesic drug, which is safe and effective at the therapeutic dose. Unfortunately, excessive dosage of APAP could cause severe liver injury due to lack of effective therapy. Successful therapeutic strategies are urgently requested in clinic. Glycyrrhetinic acid (GA), derived from a traditional medicine licorice, has been shown to exert anti-inflammatory and antioxidant actions. In this study, the effect and the underlying mechanism of GA on APAP-induced hepatotoxicity were explored. Our results showed that pretreatment with GA significantly reduced serum ALT and AST activities, alleviated hepatic pathological damages with hepatocellular apoptosis, down-regulated expression of CYP2E1 mRNA and protein, increased GSH levels, and reduced reactive oxygen species (ROS) productions in the liver of APAP-exposed mice. Furthermore, GA obviously inhibited APAP-induced HMGB1-TLR4 signal activation, as evaluated by reduced hepatic HMGB1 release, p-IRAK1, p-MAPK and p-IκB expression as well as the productions of TNF-α and IL-1β. In addition, GA attenuated hepatic neutrophils recruitment and macrophages infiltration caused by APAP. These findings reflected that GA could alleviate APAP-induced hepatotoxicity, the possible mechanism is associated with down-regulation of CYP2E1 expression and deactivation of HMGB1-TLR4 signal pathway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glycyrrhetinic acid (GA), the main bioactive substances of glycyrrhiza uralensis Fisch, has been reported to exhibit hepatoprotective and anti-inflammatory properties. However, the effects and underlying mechanisms of GA in liver ischemia/reperfusion (I/R) injury remain elusive. In this study, mice were pretreated with GA (100 mg/kg) three times a day by gavage prior to I/R injury, and then hepatic histopathological damages, biochemical parameters and inflammatory molecules were evaluated. We found that mice performed with liver I/R showed a significantly increase in plasma aminotransferase (ALT), aspartate aminotransferase (AST), liver cell apoptosis and infiltration of neutrophils compared with the control group. GA pretreatment notably improved liver function, histopathology of liver tissues, and lowered liver cell apoptosis and infiltration of neutrophils. Besides, further analysis indicated that GA pretreatment reduced I/R-induced expression of extracellular HMGB1, inhibited activation of TLR4 and following phosphorylation of IRAK1, ERK, P38 and NF-κB, and attenuated TNF-α and IL-1β production. These data suggested that GA protected against liver I/R injury through a HMGB1-TLR4 signaling pathway and it might be a promising drug for future clinical use in liver transplantation. • The therapeutic effect of glycyrrhetinic acid on hepatic ischemia-reperfusion injury was confirmed. • Glycyrrhetinic acid alleviates hepatic ischemia reperfusion injury mainly by inhibiting innate immune inflammatory response. • Glycyrrhetinic acid protects against liver ischemia-reperfusion injury through a HMGB1-TLR4 signaling pathway. • Oral administration may be an effective route for administration of glycyrrhetinic acid. [ABSTRACT FROM AUTHOR]