Plasma ALT Levels Research Articles

Antioxidative effects of aqueous extract of broccoli sprouts against Triazophos induced hepatic and renal toxicity in female Wistar rats

Oxidative stress (OS) is a major cause of hepatic and renal disorders, so present investigation was designed to evaluate the antioxidative efficacy of aqueous broccoli extract (BE) via three different doses – 10, 20 and 30mmol – of glucosinolates against toxic effects of triazophos (TZ), an organophosphorous pesticide, in female rats during 30days experiment. Six groups of rats were made and were orally intubated with TZ and BE as per experimental design. TZ and BE induced OS biomarkers of hepatic and renal toxicity – ALT, AST, urea and creatinine – were noticed in plasma, while catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), lipid peroxidation (LPO) were estimated in liver and kidney along with histological and apoptotic observation. Plasma ALT, AST, urea and creatinine levels along with organ OS parameters as CAT, SOD, GST and GPx were subtly improved in all BE+TZ treated rats. Decreased LPO and reduced apoptosis along with improved histoarchitecture was observed in all BE+TZ treated rats. Present study suggest that the administration of broccoli extract and TZ combination in rats can prevent severe alterations of hepatic and renal biochemical markers and disruptions of histological structure by antioxidative potential of BE from sprouts.

Dietary butylated hydroxytoluene improves lipid metabolism, antioxidant and anti-apoptotic response of largemouth bass (Micropterus salmoides)

A 10-week growth trail was conducted to investigate the efficacy and tolerance of dietary butylated hydroxytoluene (BHT) by evaluating inflammation, apoptosis and hepatic disease related to oxidative stress in largemouth bass (Micropterus salmoides). Four experimental diets were prepared with BHT supplement levels of 0 (B0), 150 (B150), 300 (B300) and 1500 (B1500) mg/kg, in which B150 was at the maximum recommended level established by European Union Regulation, and the B300 and B1500 levels were 2 and 10-fold of B150, respectively. Each diet was fed to 6 replicates with 30 largemouth bass (initial body weight, IBW = 6.20 ± 0.01 g) in each tank. The BHT inclusion level did not affect the specific growth rate, but fish in the B150 group showed the lowest feed conversion rate (P < 0.05). BHT inclusion significantly decreased the levels of plasma TC, TG, LDL, ALT and AKP, and increased the (HDL-C)/TC ratio (P < 0.05). Plasma MDA was significantly decreased in the B150 group and GSH-Px was extremely enhanced in each BHT inclusion group (P < 0.05). Hepatic T-AOC was significantly enhanced and O2− was significantly decreased in each BHT inclusion group compared to the B0 group (P < 0.05), as well as hepatic MDA was significantly decreased in B1500 group (P < 0.05). Dietary BHT inclusion down-regulated the hepatic mRNA levels of inflammation, apoptosis and fibrosis related genes, including TNFα, TGF-β1, α-SMA, IL8, IL11β and caspase-9. Moreover, BHT could improve hepatic lipid metabolism via up-regulating the mRNA levels of APOA1, CYP7A1, CYP8B1, and down-regulating the mRNA levels of PPAR-γ and APOB. Histological examination of the liver morphology with H&E and Sirius Red staining showed that BHT inclusion decreased necrotic degenerative changes and collagen deposition in largemouth bass. An immunofluorescence examination revealed significantly decreased cleaved caspase-3 signals in the BHT groups. In conclusion, the results demonstrated that ROS induces hepatic cell apoptosis and fibrosis via the intrinsic pathway of apoptosis by activating caspase-9 in the mitochondria and then initiates apoptosis by activating caspase-3. Consuming 2.32–23.80 mg/kg·bw/d (150–1500 mg/kg in diet) of BHT effectively improved the plasma and hepatic lipid metabolism, antioxidant response as well as reduced ROS production, protecting hepatic cells from injury. It is implied that even a 10-fold increase of the maximum level of BHT (150 mg/kg) is safe for the largemouth bass.

Exhaust system for a compression ignition engine comprising a water adsorbent material

The liver performs a variety of essential functions; hence drug-induced liver injury (DILI) is a serious concern that can ultimately lead to the withdrawal of a drug from the market or discontinuation of drug development. However, the mechanisms of drug-induced liver injury are not always clear. We hypothesized that drugs may inhibit the liver recovery process, especially bile canalicular (BC) network reformation, leading to persistent liver injury and deterioration, and tested this hypothesis in the present work. The BC structure disappeared in mice following treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or thioacetamide (TAA) for 4 weeks, then reappeared after 4 weeks of receiving a normal diet. By contrast, reconstruction of the BC structure was suppressed in mice fed a diet containing 0.3% benzbromarone (BBR; which can induce fatal liver injury in clinical settings) after liver injury. Plasma ALT levels were increased significantly in mice treated with BBR after DDC or TAA treatment, compared with BBR alone. To confirm whether BBR has a direct inhibitory effect on hepatocytes, we also examined BC reformation in primary cultured mouse hepatocytes with a sandwich configuration. Under these culture conditions, the BC network rapidly reformed from days 2 and 3 after seeding. During the reformation period, BBR inhibited BC reformation significantly. These results suggest that BBR inhibits BC reconstruction and delays recovery from pre-existing liver injury.

Effects of Kamichunggantang on Lipoapoptosis and inflammation of NAFLD in db/db mice

Kamichunggantang (KCGT) is a decoction of 9 herb aqueous extract, which is already proved its effectiveness in non-alcoholic fatty liver disease (NAFLD) by ROS suppression and restrain HepG2 cell apoptosis as well as anti-fibrotic effect in liver. This study is designed to investigate the more specific effect of KCGT especially on NAFLD. This study was designed to investigate the effects of 30% ethanol KCGT extract on NAFLD in db/db mice. Nine-week-old male db/db mice were divided into four groups: saline-treated group, metformin-treated group, low dose KCGT-treated group, and high dose KCGT-treated group. The body weight, food intake, liver weight and white adipose tissue weight of the mice were checked as baseline characteristics. To identify the mechanism of the effect of KCGT, western blotting, which includes apoptosis-related protein (JNK, caspase 9) and inflammation-related protein (NFkB, iNOS, COX-2) were measured. Plasma AST and ALT levels of the KCGT-treated group were significantly decreased compared to those in other groups. In apoptosis-related proteins, p-JNK and cleaved caspase-9 expressions of the KCGT-treated groups were considerably decreased than that in the saline or metformin-treated group. In inflammation-related proteins, p-p65, iNOS and COX-2 expressions were noticeably decreased in the KCGT-treated groups than in the saline or metformin-treated group.

Resveratrol pretreatment reduces circulating inflammatory interleukins in CCl4-induced hepatotoxicity rats

Liver diseases represent one of major health burdens worldwide, both oxidative stress and inflammation play crucial roles in the development of liver diseases. Resveratrol (RSV), a naturally occurring compound, has recently been shown to exert anti-oxidative and anti-inflammatory actions. This work aimed to investigate the prophylactic effect of RSV against CCl4-induced hepatotoxicity in experimental rats in terms of inflammatory interleukins and histopathological changes. Twenty-four adult male rats were divided into three equal groups: group A: Negative control, received oral vehicle, group B: Positive control, received oral vehicle for 6 days and on 6th day injected with single dose of CCl4, and group C: RSV-treated group, received oral RSV (25 mg/kg/day) for 6 days and on 6th day injected with single dose of CCl4. 24 h after induction of hepatotoxicity by CCl4, all rats were sacrificed; liver was excised for histopathological studies and blood samples were collected. ALT, AST, ALP, total bilirubin, IL-1β, IL-6, and IL-10 were determined in plasma while total GSH, MDA, GPx, and SOD were assayed in liver homogenate. Plasma levels of ALT, AST, ALP, total-bilirubin, IL-1β, and IL-6 were significantly increased 24 h after induction of hepatotoxicity by CCl4 while IL-10 decreased. Pretreatment of rats with RSV prevented these changes. The histopathological changes were less obvious in livers of RSV-treated rats in comparative to positive control. In conclusion, RSV has a prophylactic effect against hepatotoxicity induced by CCl4 through decreasing the inflammatory interleukins level.

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice

ObjectiveNonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. MethodsOCA and IP118 alone and in combination were sub-chronically administered to Lepob/Lepob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lepob/Lepob mice was graded using a customized integrated scoring system. ResultsOCA reduced liver weight and lipid in NASH mice (both by −17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (−21%), liver lipid (−15%), ALT (−29%), and AST (−27%). The combination of OCA + IP118 further reduced liver weight (−29%), liver lipid (−22%), ALT (−39%), and AST (−36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (−4.3% and −3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (−25.3%) to a greater degree than IP118 alone (−12.5%) and further improved glucose tolerance and reduced hepatic lipid. ConclusionOur data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.

Abstract P307: pNaKtide Attenuates Dyslipidemia and Atherosclerosis by Blocking Na/K- ATPase/Reactive Oxygen Species Amplification in ApoE -/- Mice

Background: We have previously reported that the α1 subunit of the sodium potassium adenosine triphosphatase (Na/K-ATPase) acts as an amplifier for reactive oxygen species (ROS) in addition to its ion pumping function. We have also shown that blockade of this amplification with a novel peptide, pNaKtide, ameliorates oxidative stress and obesity in mice subjected to a high-fat diet. Hypothesis: Given the importance of oxidative stress in the pathophysiology of atherosclerosis, we chose to examine whether pNaKtide might be effective in ameliorating dyslipidemia and atherosclerosis in ApoE -/- mice. Methods: pNaKtide was administered in ApoE -/- mouse fed western diet. 25 mg/Kg pNaKtide was administered intraperitoneally once every 7 days. Lipid profile, glucose insulin levels, and ROS levels were measured. Aortas were dissected and quantification of aortic lesions was done. Results: Our results show that pNaKtide improved glucose tolerance and HOMA-IR scores in ApoE-/- mice fed a western diet (p&lt;0.05). Also, pNaKtide administered to these mice significantly decreased plasma ALT, triglycerides, FFA, and LDL levels. Further, our results show that ApoE -/- mice fed a western diet had decreased plasma HDL levels and this decrease was reversed by pNaKtide. Plasma ROS levels were significantly attenuated by pNaKtide treatment. Mice fed a western diet had increased plaque size. Plaque size was significantly decreased by pNaKtide treatment. Conclusion: This study suggests that the Na/K-ATPase/ROS signaling cascade is a possible mechanism for the development of dyslipidemia and atherosclerosis associated with the metabolic syndrome phenotype and pNaKtide presents a potential novel treatment for these pathologies.

Anti-tumor activity of KNTC2 siRNA in orthotopic tumor model mice of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is still one of the major causes of cancer-related death. Kinetochore-associated protein 2 (KNTC2) is specifically upregulated in tumor tissues of HCC patients and recognized as a potential candidate target for the treatment of HCC. However, the relationship between KNTC2 and in vivo tumor growth of HCC is not yet fully understood. Here we encapsulated KNTC2 siRNAs into a lipid nanoparticle (LNP) and investigated their knockdown activity, target engagement marker, anti-tumor activity and hepatotoxicity in an orthotopic HCC model mice of Hep3B-luc cells. Single i.v. administration of KNTC2 siRNA-LNP specifically suppressed the expression levels of both human KNTC2 mRNA and mouse Kntc2 mRNA in tumor tissues. Phosphorylation levels of histone H3 (HH3) at serine 10 in tumor tissues were increased by KNTC2 siRNA-LNP. Repeated administration of KNTC2 siRNA-LNP (twice a week) specifically inhibited the growth of tumor tissues without increasing the plasma AST and ALT levels. Their growth inhibitory activities were consistent with knockdown activities. These data strongly indicated that KNTC2 is a promising target for the treatment of HCC and that phosphorylated HH3 at serine 10 is one of the target engagement markers for KNTC2.

Zinc and Selenium Co-supplementation Reduces Some Lipid Peroxidation and Angiogenesis Markers in a Rat Model of NAFLD-Fed High Fat Diet

Studies have shown that non-alcoholic fatty liver disease (NAFLD) patients are more prone to cardiovascular disease (CVD). Zinc and selenium deficiency are common in NAFLD. But the effects of zinc and selenium co-supplementation before and/or after disease progression on CVD markers are not clear in NAFLD patients. This study aimed to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on some of the CVD markers in an experimental model of NAFLD. Forty male Sprague Dawley rats (197±4g) were randomly assigned into four dietary groups: control group (C; received 9% of calorie as fat), model group (M; received 82% of calorie as fat), and supplementation before (BS) or after (AS) disease progression. Animals were fed diets for 20weeks in all groups. Fasting plasma glucose (FPG), insulin, HOMA-IR, ALT, AST, lipid profile, malondialdehyde (MDA) and vascular endothelial growth factor (VEGF) levels were measured as CVD indices. Serum ALT, AST, FPG, insulin, MDA, VEGF and HOMA-IR were significantly higher in the M than C group. Co-supplementation reduced serum ALT and AST levels in the BS and AS groups compared with the M group. FPG, insulin, HOMA-IR, VEGF, MDA, LDL/HDL-c and TC/HDL-c ratio were significantly reduced in the AS compared with the M group. TG/HDL-c ratio was significantly reduced in the BS and AS compared with the M group. Serum MDA, VEGF, Insulin and HOMA-IR were significantly lowered in the AS than BS group (p<0.05). Zinc and selenium co-supplementation after NAFLD progression reduced CVD risk indices in an experimental model.

Design, synthesis and metabolic regulation effect of farnesoid X receptor (FXR) antagonistic benzoxepin-5-ones

A series of benzoxepin-5-ones were designed and synthesized by the cyclization of chalcones which were previously found as FXR antagonists. The cellular FXR antagonism of benzoxepines was investigated, among which the most potent compound 10l was able to reduce the plasma and hepatic triglyceride and plasma ALT levels in mice.

Loss of CCR5 signaling results in early NK cell and neutrophil recruitment into the liver and increased hepatic inflammation in a mouse model of acute hepatitis B

Abstract Human genetic studies demonstrate that a non-functional CCR5 receptor sequence variant is associated with enhanced control of acute hepatitis B virus (HBV) infection. To better understand the role of CCR5 in immune responses to HBV, we employed a mouse model of acute HBV in which Ccr5 +/+(WT) or Ccr5 −/−(KO) C57BL/6 mice were intravenously infected with adenovirus containing an overlapping HBV1.3 construct (AdHBV) or vector control (AdShuttle). Mice (N=4–6/group) were euthanized at days 2, 3, 7, 10, and 14 post injection. Increased plasma ALT levels were observed in both Ccr5 WT and KO AdHBV mice at day 7, but levels were significantly higher in the Ccr5 KO compared to WT mice by day 14 (554 vs 274 U/L, p &amp;lt; 0.05). Plasma ALT levels were not significantly different between Ccr5 WT and KO AdShuttle mice. Analysis of intrahepatic leukocytes by flow cytometry revealed significantly increased intrahepatic CD11b+ NK cells (26.3 vs 6.9, % of live leukocytes, p&amp;lt; 0.01) and neutrophils (7.3 vs 1.3, % of live leukocytes, p&amp;lt; 0.05) at day 3 in Ccr5 KO compared to WT AdHBV mice. By day 7, these differences in cell populations were no longer present. At Day 14, significantly higher levels of intrahepatic Ly6c+ macrophages were detected in Ccr5 KO compared to WT AdHBV mice (17.0 vs 6.4, % of live leukocytes, p&amp;lt; 0.01). These differences in intrahepatic leukocytes were not observed in AdShuttle mice. Loss of Ccr5 function did not significantly alter intrahepatic CD4+ and CD8+ populations at the time points investigated. Taken together, these findings suggest that loss of Ccr5 signaling increases intrahepatic innate cells and inflammation during acute HBV infection, providing evidence for a role of CCR5 in regulation of innate immune responses to acute HBV infection.

Pregnenolone 16α-carbonitrile ameliorates concanavalin A-induced liver injury in mice independent of the nuclear receptor PXR activation

The pregnane X receptor (PXR) is well-known as a key regulator of drug/xenobiotic clearance. Upon activation by ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters. Recent studies have revealed that PXR also plays a role in regulating immune/inflammatory responses. Specific PXR activators, including synthetic ligands and phytochemicals, have been shown to ameliorate chemically induced colitis in mice. In this study, we investigated an anti-inflammatory effect of pregnenolone 16α-carbonitrile (PCN), a prototypical activator for rodent PXR, in concanavalin A (Con A)-induced liver injury, a model of immune-mediated liver injury, using wild-type and Pxr−/− mice. Unexpectedly, pretreatment with PCN significantly ameliorated Con A-induced liver injury in not only wild-type but Pxr−/− mice as well, accompanied with lowered plasma ALT levels and histological improvements. Pretreatment with PCN was found to significantly repress the induction of Cxcl2 and Ccl2 mRNA expression and neutrophil infiltration into the liver of both wild-type and Pxr−/− mice at the early time point of Con A-induced liver injury. Our results indicate that PCN has unexpected immunosuppressive activity independent of PXR activation to protect mice from immune-mediated liver injury induced by Con A.

Suv39h2 deficiency ameliorates diet-induced steatosis in mice

Steatosis is a prototypical metabolic disorder characterized by accumulation of lipid droplets in the liver, extensive hepatic inflammation, and, in advanced stages, accelerated liver fibrogenesis. The molecular mechanism underlying steatosis is not completely understood. In the present study we investigated the involvement of the histone methyltransferase Suv39h2 in the pathogenesis of steatosis. Expression of Suv39h2 was up-regulated in the liver in two different mouse models of steatosis. Suv39h2 knockout (KO) mice developed a less severe form of steatosis fed on a methione-and-choline deficient (MCD) diet, compared to wild type (WT) littermates, as evidenced by reduced levels of plasma ALT, down-regulated expression of pro-inflammatory mediators, and decreased infiltration of macrophages. In addition, Masson's trichrome staining as well as qPCR measurements of fibrogenic genes suggested that liver fibrosis was attenuated in MCD diet-fed KO mice compared to WT mice. Further analysis found that Suv39h2 repressed SIRT1 expression in the liver by stimulating histone H3K9 trimethylation surrounding the SIRT1 promoter and that Suv39h2 deficiency alleviated SIRT1 expression in MCD diet-fed mice. Therefore, our data support a role of Suv39h2 in promoting steatosis in mice likely through contributing to SIRT1 trans-reperssion.

The Effects of Onion Consumption on Prevention of Nonalcoholic Fatty Liver Disease.

It is well known that dietary intakes play a pivotal role in pathogenesis of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); however, the role of each component of diet has not yet been elucidated. Our objective was to evaluate the effects of onion consumption on prevention of NAFLD/NASH development. Sprague-Dawley rats were fed either high-fat, high sugar diet (model group), or high-fat, high sugar diet plus 7% onion powder (model+onion), or chow diet ad libitum for 7weeks. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by H&E stain. Model+onion group had significantly lower hepatic steatosis, ballooning, lobular inflammation, and portal inflammation (p<0.001), lower hepatic TNF-α gene expression (p<0.001), lower plasma levels of ALT (p=0.026), AST (p=0.041), insulin (p<0.001), TG (p=0.041), and glucose (p=0.009) compared with model group; however, weight gain, food intake, plasma total cholesterol and LDL levels were not significantly different between these two groups. Our data indicate that regular consumption of onion can prevent NAFLD even in the presence of the other risk factors such as obesity, hypercholesterolemia, and high energy, fat, and sugar intakes.

Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury

BackgroundHepatic ischemia/reperfusion (I/R) injury is characterized by hepatocellular damage, sterile inflammation, and compromised postoperative liver function. Generally used mouse I/R models are too severe and poorly reflect the clinical injury profile. The aim was to establish a mouse I/R model with better translatability using hepatocellular injury, liver function, and innate immune parameters as endpoints. MethodsMice (C57Bl/6J) were subjected to sham surgery, 30min, or 60min of partial hepatic ischemia. Liver function was measured after 24h using intravital microscopy and spectroscopy. Innate immune activity was assessed at 6 and 24h of reperfusion using mRNA and cytokine arrays. Liver inflammation and function were profiled in two patient cohorts subjected to I/R during liver resection to validate the preclinical results. ResultsIn mice, plasma ALT levels and the degree of hepatic necrosis were strongly correlated. Liver function was bound by a narrow damage threshold and was severely impaired following 60min of ischemia. Severe ischemia (60min) evoked a neutrophil-dominant immune response, whereas mild ischemia (30min) triggered a monocyte-driven response. Clinical liver I/R did not compromise liver function and displayed a cytokine profile similar to the mild I/R injury model. ConclusionsMouse models using ≤30min of ischemia best reflect the clinical liver I/R injury profile in terms of liver function dynamics and type of immune response. General significanceThis short duration of ischemia therefore has most translational value and should be used to increase the prospects of developing effective interventions for hepatic I/R.

5-lipoxygenase activation is involved in the mechanisms of chronic hepatic injury in a rat model of chronic aluminum overload exposure

We previously confirmed that rats overloaded with aluminum exhibited hepatic function damage and increased susceptibility to hepatic inflammation. However, the mechanism of liver toxicity by chronic aluminum overload is poorly understood. In this study, we investigated changes in the 5-lipoxygenase (5-LO) signaling pathway and its effect on liver injury in aluminum-overloaded rats. A rat hepatic injury model of chronic aluminum injury was established via the intragastric administration of aluminum gluconate (Al3+ 200mg/kg per day, 5days a week for 20weeks). The 5-LO inhibitor, caffeic acid (10 and 30mg/kg), was intragastrically administered 1h after aluminum administration. Hematoxylin and eosin staining was used to visualize pathological changes in rat liver tissue. A series of biochemical indicators were measured with biochemistry assay or ELISAs. Immunochemistry and RT-PCR methods were used to detect 5-LO protein and mRNA expression in the liver, respectively. Caffeic acid administration protected livers against histopathological injury, decreased plasma ALT, AST, and ALP levels, decreased TNF-α, IL-6, IL-1β and LTs levels, increased the reactive oxygen species content, and down-regulated the mRNA and protein expressions of 5-LO in aluminum overloaded rats. Our results indicate that 5-lipoxygenase activation is mechanistically involved in chronic hepatic injury in a rat model of chronic aluminum overload exposure and that the 5-LO signaling pathway, which associated with inflammation and oxidative stress, is a potential therapeutic target for chronic non-infection liver diseases.

The effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy on placental P-glycoprotein in mice: Implications in the individualized transplacental digoxin treatment for fetal heart failure

IntroductionPlacental P-glycoprotein (P-gp) plays a significant role in controlling transplacental digoxin transfer rate. Investigations on P-gp regulation in placenta of women with different pregnant pathological states are of great significance to individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy (ICP) on placental P-gp in mice. MethodsICP model in mice was induced by subcutaneous injection of 17α-ethynylestradiol dissolved in propylene glycol once daily from E12.5 to E16.5. Maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations were measured. HE staining was applied for observation of maternal liver cells degeneration, necrosis and intrahepatic cholestasis. Placental Abcb1a/Abcb1b/HIF-1α mRNA and P-gp/HIF-1α protein expression were determined by real-time quantitative PCR and western-blot. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay. ResultsThe ICP group showed higher levels of maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations, reduction in fetal survival rates, lower placental and fetal weights, and typical liver cells degeneration, necrosis and intrahepatic cholestasis. The placental Abcb1a mRNA and P-gp expression of ICP group were significantly elevated, while transplacental digoxin transfer rates were significantly decreased. Both placental HIF-1α mRNA and protein expression was significantly elevated in the ICP group, and there was a positive correlation between Abcb1a mRNA and HIF-1α mRNA. Conclusions17α-ethynylestradiol induced ICP could up-regulate placental P-gp expression and reduce transplacental digoxin transfer rate in mice, which might be partly associated with higher expression of HIF-1α.

Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model.

Aim: Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model.Methods: Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the anticoagulant activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks.Results: When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A activity. Under these conditions, 0.5% trans-resveratrol enhanced the anticoagulant activity of warfarin, although CYP2C activity increased. However, MSE did not affect the anticoagulant activity of warfarin.Conclusion: The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the anticoagulant activity of warfarin.

Association of rs5764455 and rs6006473 polymorphisms in PARVB with liver damage of nonalcoholic fatty liver disease in Han Chinese population

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and its prevalence is rapidly increasing in Han Chinese individuals. Several studies have demonstrated that polymorphisms of the PARVB gene may play crucial roles in the development of NAFLD. Therefore, the present study was designed to investigate the association of rs5764455 and rs6006473 polymorphisms in PARVB with the Han Chinese population's susceptibility to NAFLD. MethodsA total of 384 cases of NAFLD patients and 384 healthy controls were enrolled in this study. Their clinical information and serum biochemical indexes were analyzed. A sample (5ml) of fasting venous blood was taken from each subject for DNA extraction, after which SNP probes were customized, and real-time PCR was used to detect SNP in the PARVB gene. ResultsPatients with genotype AA of rs5764455 SNP locus in PARVB gene had a higher incidence of NAFLD than patients with genotypes AG and GG (62.1% vs. 50.3% and 46.9%, respectively, p-values=0.034). Patients with genotype TT of rs6006473 SNP had a higher incidence of NAFLD than patients with genotypes CT and CC (56.9% vs. 49.9% and 42.0%, respectively, p-values=0.017). The ORs of the A allele and AA genotype of rs5764455 for NAFLD were 1.30 and 1.62, respectively; those of the T allele and TT genotype of rs6006473 for NAFLD were 1.34 and 1.35, respectively. Further analysis revealed that patients with genotype AA of rs5764455 and genotype TT of rs6006473 had higher levels of plasma triglyceride, LDL-C, ALT and AST (p-values<0.05). Likewise, patients with genotype AA of rs5764455 had a higher incidence of moderate to severe NAFLD than patients with genotypes AG and GG (62.7% vs. 44.3% and 43.0%, respectively, p-values=0.026). Patients with genotype TT of rs6006473 had a higher incidence of moderate to severe NAFLD than patients with genotypes CT and CC (59.6% vs. 46.6% and 30.9%, respectively, p-values=0.001). ConclusionsOur study found polymorphisms of rs5764455 and rs6006473 in PARVB gene in the Han Chinese population, and these polymorphisms were associated with the occurrence and progression of NAFLD.

Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation.

BackgroundHepatic fibrosis is a dynamic process which ultimately leads to cirrhosis in almost patients with chronic hepatic injury. However, progressive fibrosis is a reversible scarring response. Activation of hepatic stellate cells (HSCs) is the prevailing process during hepatic fibrosis. Osthole is an active component majorly contained in the fruit of Cnidium monnieri (L.) Cusson. This present study investigated the therapeutic effects of osthole on rat liver fibrosis and HSC activation.ResultsWe established the thioacetamide (TAA)-model of Sprague–Dawley (SD) rats to induce hepatic fibrosis. Rats were divided into three groups: control, TAA, and TAA + osthole (10 mg/kg). In vivo, osthole significantly reduced liver injury by diminishing levels of plasma AST and ALT, improving histological architecture, decreasing collagen and α-SMA accumulation, and improving hepatic fibrosis scores. Additionally, osthole reduced the expression of fibrosis-related genes significantly. Osthole also suppressed the production of fibrosis-related cytokines and chemokines. Moreover, nuclear translocation of p65 was significantly suppressed in osthole-treated liver. Osthole also ameliorated TAA-induced injury through reducing cellular oxidation. Osthole showed inhibitory effects in inflammation-related genes and chemokines production as well. In vitro, we assessed osthole effects in activated HSCs (HSC-T6 and LX-2). Osthole attenuated TGF-β1-induced migration and invasion in HSCs. Furthermore, osthole decreased TNF-α-triggered NF-κB activities significantly. Besides, osthole alleviated TGF-β1- or ET-1-induced HSCs contractility.ConclusionsOur study demonstrated that osthole improved TAA-caused liver injury, fibrogenesis and inflammation in rats. In addition, osthole suppressed HSCs activation in vitro significantly.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0168-5) contains supplementary material, which is available to authorized users.