Sesamin Protects against APAP-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Inflammatory Response via Deactivation of HMGB1/TLR4/NFκB Signal in Mice.

Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1ß, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.

Chrysin and its nanoliposome ameliorated non-alcoholic steatohepatitis via inhibiting TLR4 signalling pathway.

OBJECTIVES: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease histologically characterized by liver steatosis, hepatocellular injury, inflammation and fibrosis, resulting in cirrhosis and hepatocellular carcinoma, but effective measures and obvious pathogenesis for NASH remain elusive. Chrysin (CH) has been reported to have anti-inflammatory effects but shows lower bioavailability. METHODS: In this study, a chrysin nanoliposome (CH-NL) was first prepared and characterized. Then, we used the methionine-choline-deficient (MCD) diet to induce a mouse model of NASH. Finally, the effects of CH and CH-NL on NASH were evaluated in the liver of NASH mice. KEY FINDINGS: The results showed that CH or CH-NL significantly reduced the accumulation of lipids in hepatocytes, alleviated liver injury, decreased the generation of radical oxygen species, and attenuated the accumulation of collagen fibre in the liver of NASH mice. In addition, CH and its nano-liposomes markedly inhibited the production of inflammatory cytokines and inflammatory cell infiltration in the liver of NASH mice. Further studies found that CH-NL and CH-NL downregulated the MCD diet-induced activation of Toll-like receptor 4 (TLR4) signalling pathway in the liver of mice. CONCLUSIONS: CH and its nanoliposome alleviated MCD diet-induced NASH in mice, which might be through inhibiting TLR4 signalling pathway.

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells.

Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.

Glycyrrhetinic acid pretreatment attenuates liver ischemia/reperfusion injury via inhibiting TLR4 signaling cascade in mice.

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-1ß 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.

Geniposide protected hepatocytes from acetaminophen hepatotoxicity by down-regulating CYP 2E1 expression and inhibiting TLR 4/NF-κB signaling pathway.

Acetaminophen (APAP) is a widely used over-the-counter drug for antipyretic and analgesic, but an overdose will induce acute liver injury. APAP hepatotoxicity has been the most common cause of acute liver failure in western countries with high morbidity and mortality. Geniposide (GP), an iridoid glycoside extracted from the fruit of Gardenia jasminoides, has been reported to exert a profound anti-inflammatory activity on acute and chronic diseases. However, it is never demonstrated whether GP can protect hepatocytes from APAP hepatotoxicity. In this study, we investigated the protective effect and underlying mechanism of GP against AILI. The results showed that GP pretreatment reduced the levels of ALT and AST in a dose-dependent manner and alleviated hepatocyte necrosis and apoptosis in mice exposed at APAP. Moreover, it suppressed the expression of CYP 2E1 and attenuated the exhaustion of GSH and accumulation of MDA in the liver. Furthermore, GP remarkably inhibited inflammatory cells infiltration and mitigated the release of IL-1ß and TNF-α, and inhibited Toll-like receptor 4 (TLR4) expression and nuclear factor kappa (NF-κB) activation. These data suggested that GP could effectively protect hepatocytes from APAP hepatotoxicity through the down-regulation of CYP 2E1 expression and the inhibition of TLR4/NF-κB signaling pathway.

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

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.