Manyun Dai

Geniposide Inhibits Alpha-Naphthylisothiocyanate-Induced Intrahepatic Cholestasis: The Downregulation of STAT3 and NFκB Signaling Plays an Important Role

Traditional medicinal formulation of Yin-zhi-huang (YZH) is widely used in the clinic for the treatment of jaundice and chronic liver diseases in East Asian countries. However, the pharmacologically active components of YZH and the underlying mechanism are still unknown. Geniposide (GEN) was recently identified as one of the most abundant circulating components in YZH. In this study, we investigated the protective effect of GEN against liver injuries induced by alpha-naphthylisothiocyanate (ANIT). 50[Formula: see text]mg/kg of GEN was administered to ICR mice once daily for 5 days, and challenge of ANIT 75[Formula: see text]mg/kg was performed on the 4th day. Blood and liver tissues were collected on day 6 and subjected to biochemical, histopathological and pathway analyses. The biochemical and pathological findings showed that GEN almost totally attenuated ANIT-induced cholestasis and liver injury compared with the vehicle/ANIT group. The altered gene transcription related to bile acid metabolism and transport was normalized by co-treatment with GEN. The expressions of tumor necrosis factor-[Formula: see text] and the suppressor of cytokine signaling 3 were significantly decreased in the GEN/ANIT group. Western blot revealed that GEN inhibited the activation and expression of STAT3 and NF[Formula: see text]B. These data suggest GEN inhibits ANIT-induced hepatotoxicity. The protective effect is associated with the downregulation of STAT3 and NF[Formula: see text]B signaling.

Oral administration of nano-titanium dioxide particle disrupts hepatic metabolic functions in a mouse model

TiO2 nano-particle (TiO2 NP) is widely used in industrial, household necessities, as well as medicinal products. However, the effect of TiO2 NP on liver metabolic function has not been reported. In this study, after mice were orally administered TiO2 NP (21nm) for 14days, the serum and liver tissues were assayed by biochemical analysis, real time quantitative polymerase chain reaction, western blot and transmission electron microscopy. The serum bilirubin was increased in a dose dependent manner. Deposition of TiO2 NP in hepatocytes and the abnormality of microstructures was observed. Expression of metabolic genes involved in the endogenous and exogenous metabolism was modified, supporting the toxic phenotype. Collectively, oral administration of TiO2 NP (21nm) led to deposition of particles in hepatocytes, mitochondrial edema, and the disturbance of liver metabolism function. These data suggested oral administration disrupts liver metabolic functions, which was more sensitive than regular approaches to detect material hepatotoxicity. This study provided useful information for risk analysis and regulation of TiO2 NPs by administration agencies.

Inhibition of JNK signalling mediates PPARα‐dependent protection against intrahepatic cholestasis by fenofibrate

Fenofibrate, a PPARα agonist, is the most widely prescribed drug for treating hyperlipidaemia. Although fibrate drugs are reported to be beneficial for cholestasis, their underlying mechanism has not been determined.

Chlorogenic acid inhibits cholestatic liver injury induced by α-naphthylisothiocyanate: involvement of STAT3 and NFκB signalling regulation

Chlorogenic acid (CGA) is one of the most widely consumed polyphenols in diets and is recognized to be a natural hepatoprotective agent. Here, we evaluated the protective effect and the potential mechanism of CGA against ɑ‐naphthylisothiocyanate (ANIT)‐induced cholestasis and liver injury.

Basal PPARα inhibits bile acid metabolism adaptation in chronic cholestatic model induced by α-naphthylisothiocyanate

Cholestasis is one of the most challenging diseases to be treated in current hepatology. However little is known about the adaptation difference and the underlying mechanism between acute and chronic cholestasis. In this study, wild-type and Pparα-null mice were orally administered diet containing 0.05% ANIT to induce chronic cholestasis. Biochemistry, histopathology and serum metabolome analysis exhibited the similar toxic phenotype between wild-type and Pparα-null mice. Bile acid metabolism was strongly adapted in Pparα-null mice but not in wild-type mice. The Shp and Fxr mRNA was found to be doubled in cholestatic Pparα-null mice compared with the control group. Western blot confirmed the up-regulated expression of FXR in Pparα-null mice treated with ANIT. Inflammation was found to be stronger in Pparα-null mice than those in wild-type mice in chronic cholestasis. These data chain indicated that bile acid metabolism and inflammation signaling were different between wild-type and Pparα-null mice developing chronic cholestasis, although their toxic phenotypes could not be discriminated. So basal PPARα cross-talked with FXR and inhibited bile acid metabolism adaptation in chronic cholestasis.

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high‐density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established.

PPARα-dependent increase of mouse urine output by gemfibrozil and fenofibrate

While gemfibrozil and fenofibrate are prescribed for anti-dyslipidemia treatment, a rational basis for the use of these drugs for treatment of dyslipidemia with concurrent metabolic syndrome has not been established. In this study, wild-type and Pparα-null mice were fed gemfibrozil- or fenofibrate-containing diets for 14 days. Urine output (24 h) was monitored, and urine, serum, and liver and kidney tissues were subjected to toxicity assessment. A 2-month challenge followed by a 2-week wash-out was performed for gemfibrozil to determine urine output and the potential toxicity. A therapeutically equivalent dose of gemfibrozil was more effective than fenofibrate in increasing urine output. This regulatory effect was not observed in Pparα-null mice. In contrast, hepatomegaly induced by fenofibrate was more pronounced than that of gemfibrozil. No significant toxicity was observed in liver or kidney in the 2-month treatment with gemfibrozil. These data demonstrated PPARα mediates the increased urine output by fibrates. Considering the relative action on hepatomegaly and the regulatory effect on urine output, gemfibrozil may be the preferable drug to increase urine output. These results revealed a new pharmacodynamic effect of clinically prescribed PPARα agonists and suggested the potential value of gemfibrozil in modification of blood pressure.

Species-related exposure of phase II metabolite gemfibrozil 1-O-β-glucuronide between human and mice: a net induction of mouse P450 activity was revealed

Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1‐O‐β‐glucuronide (gem‐glu) are involved in drug–drug interaction (DDI). But the DDI risk caused by gem‐glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem‐glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail‐based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem‐glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem‐glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6‐ to 9‐fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem‐glu concentration was high. These data suggested species difference of relative gem‐glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model.

Peroxisome Proliferator‐Activated Receptor α Activation Suppresses Cytochrome P450 Induction Potential in Mice Treated with Gemfibrozil

Gemfibrozil, a peroxisome proliferator‐activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug–drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild‐type mice were first fed gemfibrozil‐containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose–response relationship for CYP induction. Then, wild‐type mice and Pparα‐null mice were treated with a 0.75% gemfibrozil‐containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose‐dependent manner by gemfibrozil. In Pparα‐null mice, their mRNA level, protein level and activity were induced more than those in wild‐type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug–drug interactions and metabolic diseases treated with fibrates.