Ge Kuang

Sesamin ameliorates lipopolysaccharide/d-galactosamine-induced fulminant hepatic failure by suppression of Toll-like receptor 4 signaling in mice.

Sesamin has been described to exert anti-oxidant and anti-inflammatory properties. In present study, we investigated the potential effects and mechanisms of sesamin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in d-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with sesamin dose-dependently improved LPS/D-GalN-induced mortality and liver injury as indicated by reduced serum levels of aminotransferases and alleviated pathological damage as well as hepatocyte apoptosis in mice. Additionally, sesamin markedly attenuated LPS/D-GalN-induced adhesion molecules expression, and decreased neutrophils recruitment. Furthermore, sesamin inhibited LPS-induced tumor necrosis factor-alpha (TNF-α) production, p38 mitogen-activated protein kinases (MAPK) and NF-κB activation, and Toll like receptor (TLR) 4 expression in mice and in RAW264.7 macrophage cells. In summary, these results demonstrate that sesamin protects mice from LPS-induced FHF and the molecular mechanisms may down-regulate the expression of TLR4, block MAPK and NF-κB activation, decrease the production of TNF-α.

Mangiferin attenuates renal ischemia-reperfusion injury by inhibiting inflammation and inducing adenosine production.

AIM Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury, which is associated with high morbidity. The aims of the present study were to examine whether mangiferin attenuates renal IRI in an animal model and to identify the underlying mechanism(s). METHODS Male mice were subjected to right renal ischemia for 30min followed by reperfusion for 24h or to a sham operation during which the left kidney was removed. After the 24h reperfusion, all mice were humanely euthanized and kidney tissues collected. Renal damage and apoptosis were investigated by examining hematoxylin and eosin-stained tissues, and by TUNEL assay and immunohistochemistry. Renal function was examined by measuring the concentrations of creatinine, blood urea nitrogen, and potassium (K(+)) in the serum. MPO activity, the levels of NO, TNF-α, IL-1β, and adenosine, and CD73 expression in renal tissue were also examined. RESULTS Mangiferin reduced ischemia reperfusion-induced injury, improved kidney function, and inhibited both proinflammatory responses and tubular apoptosis. In addition, treatment with mangiferin increased adenosine production and CD73 expression in kidneys suffering IRI. CONCLUSION Mangiferin appears to attenuate renal IRI by inhibiting proinflammatory responses and tubular apoptosis and by increasing adenosine production. These effects are associated with the adenosine-CD73 signaling pathway.

Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice

Emodin has been reported to possess anti-inflammatory and anti-oxidant activities. The aim of this study was to explore the effect and mechanism of emodin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with emodin inhibited the elevation of plasma aminotransferases, alleviated the hepatic histopathological abnormalities and improved the survival rate of LPS/D-GalN-primed mice. Moreover, emodin markedly attenuated the increased serum and hepatic tumor necrosis factor-α (TNF-α) production, and activated hepatic p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signal pathways in LPS/D-GalN-challenged mice. Furthermore, using an in vitro experiment, we found that emodin dose-dependently suppressed TNF-α production, dampened AP-1 and NF-κB activation, and blocked toll-like receptor (TLR) 4/myeloid differentiation factor (MD) 2 complex expression in LPS-elicited RAW264.7 mouse macrophage cells. Taken together, these data suggested that emodin could effectively prevent LPS-induced FHF, which might be mediated by inhibition of TNF-α production, deactivation of MAPKs and NF-κB, and blockade of TLR4/MD2 complex expression.

Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice

Abstract 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‐I&kgr;B expression as well as the productions of TNF‐&agr; and IL‐1&bgr;. 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. HighlightsGlycyrrhetinic acid attenuates APAP‐induced liver injury.Glycyrrhetinic acid down‐regulates APAP‐induced hepatic CYP2E1 expression.Glycyrrhetinic acid promotes GSH content and inhibits ROS production in the liver of APAP‐primed mice.Glycyrrhetinic acid inhibits APAP‐activated HMGB1‐TLR4 signal pathway.Glycyrrhetinic acid alleviates APAP‐primed sterile inflammation.

Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M.

ABSTRACT Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti‐inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100 mg/kg) 1 h before lipopolysaccharide (LPS)/d‐galactosamine (D‐GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Toll like receptor 4 (TLR4), interleukin‐1 receptor‐associated kinases (IRAKs), activation of mitogen‐activated protein kinases (MAPKs) and NF‐&kgr;B, and production of TNF‐&agr; were assessed by flow cytometry, western blotting, and enzyme‐linked immunosorbent assay (ELISA), respectively. Our results showed that pretreatment with GA protected mice against LPS/D‐GalN‐induced fulminant hepatic failure (FHF), including a dose‐dependent alleviation of mortality and ALT/AST elevation, ameliorating hepatic pathological damage, and decreasing TNF‐&agr; release. Moreover, GA inhibited LPS‐induced activation of MAPKs and NF‐&kgr;B in response to LPS, but the expression of TLR4 was not affected in vivo and in vitro. Notably, GA pretreatment in vivo suppressed IRAK‐1 activity while inducing IRAK‐M expression. Silencing of IRAK‐M expression with siRNA blocked these beneficial effects of GA on the activation of MAPKs and NF‐&kgr;B as well as TNF‐&agr; production in LPS‐primed macrophages. Taken together, we conclude that GA could prevent LPS/D‐GalN‐induced FHF. The underlying mechanisms may be related to up‐regulation of IRAK‐M, which in turn caused deactivation of IRAK‐1 and subsequent MAPKs and NF‐&kgr;B, resulting in inhibiting TNF‐&agr; production. HIGHLIGHTSGlycyrrhetinic acid protected from LPS/D‐GalN‐induced liver injury in mice.Glycyrrhetinic acid inhibited LPS‐induced TNF‐&agr; production in vivo and in vitro.Glycyrrhetinic acid alleviated LPS‐activated TLR4 signal pathway in vivo and in vitro.Glycyrrhetinic acid upregulated the expression of IRAK‐M in vivo and in vitro.IRAK‐M mediated the protective effect of Glycyrrhetinic acid on LPS‐induced inflammation.

Baicalin inhibits the metastasis of highly aggressive breast cancer cells by reversing epithelial-to-mesenchymal transition by targeting β-catenin signaling

Metastasis is the main cause of death in breast cancer patients, which is due partly to the lack of effective treatment. Baicalin, a flavonoid compound isolated from the roots of Scutellaria lateriflora Georgi (Huang Qin), has recently been confirmed as an effective agent for the treatment of a variety of cancers. Yet, the effects and underlying molecular mechanisms of baicalin in regards to the metastasis of breast cancer remain unclear. In the present study, we found that baicalin had the potential to suppress the migration and invasion of highly aggressive breast cancer cells in a dose-dependent manner but had no impact on the viability of these cancer cells. Additionally, baicalin reversed the epithelial-to-mesenchymal transition (EMT) process, as evaluated by EMT markers in breast cancer cell lines with a change from a mesenchymal feature to an epithelial type. At the same time, the expression of β-catenin mRNA and protein was dose-dependently downregulated by baicalin in highly invasive breast cancer cell lines, and overexpression of β-catenin by adenoviruses abolished these beneficial effects of baicalin in regards to the migration and invasion, and EMT of breast cancer cells. Furthermore, using a xenograft mouse model, baicalin markedly reduced liver and lung metastasis of breast cancer, inhibited expression of β-catenin, and degraded the EMT molecules vimentin and Slug in the orthotopic tumor tissues. Taken together, all these results indicate that baicalin effectively suppresses the metastasis of breast cancer by reversing EMT, which may be mediated by downregulation of β-catentin expression.

Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice

Abstract Acute hepatic failure involves in excessive oxidative stress and inflammatory responses, leading to a high mortality due to lacking effective therapy. Resolvin D1 (RvD1), an endogenous lipid mediator derived from polyunsaturated fatty acids, has been shown anti-inflammatory and anti-oxidative actions, however, whether RvD1 has protective effects on hepatic failure remains elusive. In this study, the roles and molecular mechanisms of RvD1 were explored in carbon tetrachloride (CCl4)-induced acute liver injury. Our results showed that RvD1 protected mice against CCl4-induced hepatic damage, as evaluated by reduced aminotransferase activities and malondialdehyde content, elevated glutathione and superoxide dismutase activities, and alleviated hepatic pathological damage. Moreover, RvD1 significantly attenuated serum tumor necrosis factor-α and interleukin-6 levels as well as hepatic myeloperoxidase activity, whereas enhanced serum IL-10 level in CCl4-administered mice. Further, RvD1 markedly up-regulated the expression and activity of heme oxygenase-1 (HO-1). However, inhibition of HO-1 activity reversed the protective effects of RvD1 on CCl4-induced liver injury. These results suggest that RvD1 could effectively prevent CCl4-induced liver injury by inhibition of oxidative stress and inflammation, and the underlying mechanism may be related to up-regulation of HO-1.