Paeoniflorin protects against liver ischemia/reperfusion injury in mice via inhibiting HMGB1‐TLR4 signaling pathway

Abstract

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.

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

“…8 a-c). Effects of SSB extract on HMGB1, TRAF6, TLR4, IκB, p-IκBα, and NF-κB65 protein expression in LPS/D-GalN-induced acute liver injury in mice HMGB1/TLR4/NF-κB65 is a crucial inflammatory pathway that may be involved in LPS/D-GalN-induced acute liver injury [31]. We explored the effects of SSB extract on HMGB1, TRAF6, TLR4, IκB, p-IκB-α, and NF-κB65 protein expression in LPS/D-GalN-induced acute liver injury in mice.…”

Paeoniflorin, a Natural Product With Multiple Targets in Liver Diseases—A Mini Review

“…Therefore, a reduction in the innate immune response might contribute to this process. This research finally found that inhibiting the HMGB1-TLR4 signaling pathway is the crucial mechanism of paeoniflorin in hepatic I/R injury (Xie et al, 2018). Another study also supported this conclusion.…”

Efficacy, Chemical Constituents, and Pharmacological Actions of Radix Paeoniae Rubra and Radix Paeoniae Alba

“…Experiments have shown that paeoniflorin can inhibit ischemia/reperfusion (I/R)-induced hepatocyte apoptosis and cysteinyl aspartate specific proteinase 3 (caspase-3) activation, as well as dampening I/R-induced neutrophil infiltration and pro-inflammatory cytokine production. The protective effect on the liver is associated with the inhibition of the I/R-activated high mobility group box-1 (HMGB1)-toll-like receptors 4 (TLR4) signaling pathway to attenuate hepatic inflammatory response (Xie et al, 2018). In the CCl4-induced acute liver injury model, RPR water extracts protect the liver from CCl4-induced oxidative damage in rats, which was associated with antioxidant and free radical scavenging activity (Li et al, 2011;Wang et al, 2012).…”