Plasma ALT Levels Research Articles

Epigallocatechin gallate attenuated non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet

Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease. In this study, we evaluated the effects of Epigallocatechin gallate (EGCG) on methionine- and choline-deficient (MCD) diet-induced NASH. Our data showed that EGCG significantly prevented MCD diet-induced liver and body weight loss. Histological analysis showed that EGCG inhibited MCD diet-induced steatohepatitis including fat accumulation and inflammatory cells infiltration. Biochemical analysis data showed that EGCG significantly reduced the elevation of plasma ALT and AST levels but increased plasma triglyceride and cholesterol contents. However, EGCG significantly inhibited hepatic triglyceride and cholesterol content in MCD diet fed mice. Consistent with histology results, EGCG treatment significantly inhibited MCD diet-induced IL-1β, IL-6, TNF-α and MCP-1 mRNA expression. As an antioxidant, EGCG treatment significant inhibited hepatic MDA contents and increased hepatic SOD contents. In addition, transforming growth factor (TGF)-β, collagen I-α1, tissue inhibitor of metalloproteinase 1 (TIMP-1) and α-smooth muscle actin (SMA) mRNA expression, which are markers of hepatic fibrosis, were markedly inhibited by EGCG treatment. Western blot data showed that EGCG inhibited Smad2 and Smad3 phosphorylation in the liver and LX-2 cells which were involved in TGF-β-induced pathway. Taken together, EGCG attenuated NASH induced by MCD diet associated with ameliorating fibrosis, oxidative stress, and hepatic inflammation. Our results indicate that EGCG has beneficial roles in the development of MCD diet-induced NASH.

Carnosic Acid as the Major Bioactive Component in Rosemary Extract Ameliorates High‐fat Diet‐induced Obesity and Metabolic Syndrome in Mice

Rosemary has been used as a natural alternative to synthetic antioxidants in Europe and the United States. In this study, we investigated the preventive effects of carnosic acid (CA) enriched rosemary extract on high‐fat diet‐induced obesity and metabolic syndrome in mice. The mice were given a low‐fat (LF) diet, a high‐fat (HF) diet or a high‐fat diet supplemented with 0.14% (w/w, RE#1L), or 0.28% (w/w, RE#1H) rosemary extract with 80% CA, 0.5% (w/w, RE#2) rosemary extract with 45% CA for a period of 16 weeks. RE#1H and RE#2 diets have the same level of CA. The dietary RE supplementation significantly and dose‐dependently reduced body weight gain, percent of fat, plasma ALT, AST, cholesterol, glucose, and insulin levels and liver weight, liver triglyceride and free fatty acid levels. RE administration also decreased the plasma and liver malondialdehyde, advanced glycation end products (AGEs) levels and the liver expression of receptor for AGEs (RAGE). Histological analyses of liver samples showed decreased lipid accumulation in hepatocytes in mice administrated with RE compared with HF diet fed mice. Meanwhile, RE administration enhanced fecal lipid excretion and increased the liver GSH/GSSG ratio. In conclusion, the present study demonstrated that long‐term dietary CA‐enriched rosemary administration could effectively and dose‐dependently attenuate the development of obesity, metabolic syndrome, and fatty liver in HF diet‐induced obese mice. These beneficial effects may be mediated by decreased lipid absorption, improved lipid, glucose and insulin metabolism, decreased inflammation and oxidative stress.

Sulforaphane protects against acetaminophen-induced hepatotoxicity

Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity in vitro and in vivo. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury.

Dietary methionine requirement of the pre-adult gibel carp (Carassius auratus gibeilo) at a constant dietary cystine level

A 62-day growth trial was conducted to determine the dietary Met requirement of the pre-adult gibel carp (Carassius auratus gibeilo) (initial weight of 51.0 ± 0.02 g). Six isonitrogenous and isoenergetic diets using fish meal, blood meal and pea protein concentrate as protein sources supplemented with crystalline amino acids were formulated to contain graded levels of dietary Met (4.44, 6.56, 8.55, 10.90, 12.79 and 15.05 g kg−1, respectively) at a constant dietary cystine level of 3.99 g kg−1. The results showed that weight gain rate and protein productive value significantly increased with the dietary Met levels from 4.44 to 8.55 g kg−1, then reached plateau at 10.90 g kg−1. Plasma HDL-C and TC were increased with dietary Met levels. Fish supplied with 4.44–8.55 g kg−1 Met showed lower plasma AST level than that of other groups. Plasma TG, LDL-C and ALT levels were stable for all treatments. The activity of intestinal γ-GT was increased with dietary Met levels. The optimal requirement of Met for pre-adult gibel carp (>50 g) was a range from 7.86 g kg−1 to 9.84 g kg−1 dry diet or 16.9 g kg−1 to 23.0 g kg−1 of dietary protein with the presence of 3.99 g kg−1 Cys for the satisfied lipid metabolism and maximum growth, respectively.

Celastrol prevents circulatory failure via induction of heme oxygenase-1 and heat shock protein 70 in endotoxemic rats

Ethnopharmacological relevanceCelastrol, a quinone methide extracted from the root of Tripterygium wilfordii Hook, possesses anti-oxidant and anti-inflammatory effects. Tripterygium wilfordii Hook is officially listed in the Chinese Pharmacopoeia and is used traditionally against rheumatoid arthritis, ankylosing spondylitis, and cancer. Furthermore, the circulatory protective effect of celastrol on an in vivo animal model of sepsis was investigated. Aim of the study: Sepsis is a systemic inflammatory disorder that increases tissue oxidative stress and leads to multiple organ injury. We evaluated the beneficial effects of celastrol on multiple organ failure induced by lipopolysaccharide (LPS) in rats. Materials and methodsCelastrol (0.5 and 1.0mg/kg, i.v.) was administered to anaesthetized rats 2h before and 30min after LPS challenge (10mg/kg, i.v.). Eight hours later, cardiac and aortic protein expressions related to inflammatory responses, superoxide anion production, and reduced glutathione (GSH) level were measured. ResultsTreatment with celastrol prevented circulatory failure (bradycardia and hypotension) 8h after LPS challenge. The plasma levels of ALT, LDH, TNF-α, and nitric oxide metabolites increased markedly during sepsis, which significantly reduced after celastrol treatments. Celastrol attenuated iNOS, TNF-α, NF-κB phospho-p65 expression, superoxide anion production, and caspase 3 activity in the cardiovascular system, all of which were markedly elevated after LPS challenge. Furthermore, celastrol induced HO-1 and HSP70 expressions increase in nuclear levels of Nrf2 and HSF-1, respectively, and increase cardiac GSH level 8h after LPS challenge. ConclusionAnti-inflammatory and anti-oxidant effects of celastrol contribute to prevent circulatory failure in sepsis. Induction of HO-1 and HSP70 by celastrol participates in these beneficial effects.

UPLC/Q-TOFMS-Based Metabolomics Studies on the Protective Effect of Panax notoginseng Saponins on Alcoholic Liver Injury.

Consistent, excessive alcohol consumption leads to liver injury. The aim of the present study is to evaluate the possible efficacy of Panax notoginseng saponins (PNS) against chronic alcohol-induced liver injury using LC-MS-based urinary metabolomics. Mice were fed a Lieber-DeCarli liquid diet containing alcohol or isocaloric maltose dextrin as a control diet with or without PNS (200 mg/kg/BW) for 4 weeks. Treatment with PNS significantly reduced the increases in plasma ALT and AST levels, hepatic levels of reactive oxygen species (ROS) and malondialdehyde (MDA), which induced by chronic alcohol exposure. Conversely, PNS was also found to restore the glutathione (GSH) depletion and increase the superoxide dismutase (SOD) activities. The end-point urine sample of each mouse was collected overnight (24 h) in metabolic cages and their metabolic profiling changes were analyzed using UPLC/Q-TOFMS followed by multivariate statistical analysis. After 4 week of Lieber-DeCarli alcohol diet feeding, the metabolic profile experienced great perturbation in PCA score plot, and the treatment of PNS could assist to regulate the disturbed metabolic profile induced by alcohol exposure. Additionally, sixteen potential biomarkers responsible for derivations of the metabolic profile induced by alcohol exposure were identified, and the alcohol-induced changes in these biomarkers, except hexanoylglycine, could be partially or nearly reversed by PNS treatment. Taken together, PNS protects against chronic alcohol-induced liver injury. Our findings demonstrated that the LC-MS-based metabolomics approach is a useful tool to investigate the efficacy of Chinese medicines.

Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats

Oleoylethanolamine (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor alpha (PPAR-α), has revealed the pharmacological properties in the treatment of obesity, atherosclerosis and other diseases through the modulation of lipid metabolism. To assess whether OEA can also regulate non-alcoholic fatty liver disease (NAFLD) caused by fat accumulation, we administrated OEA or fenofibrate in Sprague Dawley (SD) rats fed with a high fat diet (HFD). After 6 or 17 weeks treatment, OEA (5 mg/kg/day, i.p.) relieved the development of NAFLD compared with control groups by regulating the levels of plasma TG, TC, ALT and AST and liver inflammatory cytokines. Gene expression analysis of liver tissue and plasma from the animal models showed that OEA and fenofibrate both promoted the lipid β-oxidation by activating PPAR-α. Detailed research revealed that OEA inhibited the mRNA expression of lipogenesis in a PPAR-α-independant manner, while fenofibrate expressed an opposite effection. In summary, our research results suggested that as a potential lead compound, OEA could improve HFD-induced NAFLD with higher efficacy and safety than fenofibrate.

The incidence rate of hepatosteatose in virus carriers with inactive Hepatitis B

Objective — The aim of this study is to examine the data retrospectively from patients with inactive HBV whose livers were evaluated by ultrasonography and to investigate hepatosteatosis as well as related parameters in this patient group. Material and Methods — In our study, the data of 134 patients, who have applied to the Internal Disease Polyclinic of Elazığ Çağrı Private Medical Center between January 2010 and August 2013 being diagnosed as carriers for inactive HBV and then performed abdominal ultrasonography, were evaluated retrospectively. Information for each patient was accessed by means of both the internal disease polyclinic in our hospital and patient epicrisis reports. The observed levels of plasma trigliserides, LDL cholesterol, AST, ALT, GGT, and ALP were all recorded. Findings — Out of 134 subjects, 72 were male while 62 were female accounting for 54% and 46%, respectively. The mean age of the patients were found to be 44.8±10.6 years old. Hepatosteatosis was found in 92 patients accounting for 68.7 %. The mean of age in some patients diagnosed with steatosis was found 50.1±7.6 years, while the others without steatosis was 33.2±6.0 years suggesting a significant difference compared to the former (p=0.001). Furthermore, a consistency in difference was also found between these two groups with and without hepatosteatosis in terms of average triglyceride levels (p=0.001). The mean GGT levels were consistently higher in the group with hepotosteatosis (p=0.004). No significant difference was found between these two groups regarding their mean cholesterol levels of AST, ALT, ALP, and LDL. Conclusion — In patients with asymptomatically HBV infection, an increased risk for hepatosteatosis comes along with an increased levels of plasma triglycerides and GGT in the course of aging.

Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice

Lithocholic acid (LCA) supplementation in the diet results in intrahepatic cholestasis and bile infarcts. Previously we showed that an innate immune response is critical for cholestatic liver injury in the bile duct ligated mice. Thus, the purpose of this study was to investigate the role of neutrophils in the mechanism of liver injury caused by feeding mice a diet containing LCA. C57BL/6 mice were given control or 1% LCA containing diet for 24–96h and then examined for parameters of hepatotoxicity. Plasma ALT levels were significantly increased by 48h after LCA feeding, which correlated with both neutrophil recruitment to the liver and upregulation of numerous pro-inflammatory genes. The injury was confirmed by histology. Deficiency in intercellular adhesion molecule-1 (ICAM-1) expression or inhibition of neutrophil function failed to protect against the injury. Bile acid levels were quantified in plasma and bile of LCA-fed mice after 48 and 96h. Only the observed biliary levels of taurochenodeoxycholic acid and potentially tauro-LCA caused direct cytotoxicity in mouse hepatocytes. These data support the conclusion that neutrophil recruitment occurs after the onset of bile acid-induced necrosis in LCA-fed animals, and is not a primary mechanism of cell death when cholestasis occurs through accumulation of hydrophobic bile acids.

Effect of triptolide on reproduction of female lesser bandicoot rat, Bandicota bengalensis

Triptolide has been reported to cause antifertility in male rats and mice. However, studies on female rats have been limited. Present study was aimed to evaluate the effects of triptolide on reproduction of wild female rodent pest species, Bandicota bengalensis. Feeding of bait containing 0.1, 0.15 and 0.2% triptolide for a period of 15 days in bi-choice resulted in per day ingestion of 17.37, 23.54 and 27.49 mg/kg body weight of triptolide, respectively. Examination of vaginal smear of all the rats revealed a significant (p ≤ 0.05) increase in duration of estrous cycle due to increase in durations of metestrous and diestrous stages in rats of treated groups. Autopsy of rats after 15 and 30 days of treatment withdrawal revealed significant (p ≤ 0.05) reduction in weights of uterus and ovaries, non-significant reduction in weights of liver and levels of estradiol and progesterone and significant (p ≤ 0.05) reduction in levels of urea and BUN and increase in levels of plasma proteins, ALT, AST, ALP, ACP and LDH in rats of treated groups compared to untreated group. There was no significant (p ≤ 0.05) effect of treatment on body weight. Triptolide treatment affected the histomorphology of uterus by causing a decrease in lumen and columnar cell height and number of uterine glands and ovary by increasing the number of atretic follicles and decreasing the number of developing follicles. The present study suggests triptolide to be a strong candidate affecting reproduction of female B. bengalensis.

감비경신환(1)에 의한 고지방식이 비만동물모델에서 체중감량과 지질대사의 조절

Objectives : We investigated the effects of gambigyeongsinhwan(GGH)(1) on body weight and non-alcoholic fatty liver disease(NAFLD) examined whether blood total cholesterol, LDL-cholesterol, free fatty acid and triglyceride levels and hepatic lipid accumulation are inhibited by it in high fat diet-fed obese male mice. Methods : 8 weeks old, high fat diet-fed obese male mice were divided into 5 groups: C57BL/6N normal, control, GGH(1)-1, GGH(1)-2 and GGH(1)-3. After mice were treated with GGH(1) for 8 weeks, we measured body weight gain, food intake, feeding efficiency ratio, fat weight, plasma ALT, leptin and lipid levels. We also did histological analysis for liver and fat on the mice. Results : Compared with controls, GGH(1)-treated mice had lower body weight gain and adipose tissue weight, the magnitudes of which were prominent in GGH(1)-3. Compared with controls, GGH(1)-treated mice had lower feeding efficiency ratio and blood leptin level, the magnitudes of which was prominent in GGH(1)-3. Compared with controls, GGH(1)-treated mice had lower blood plasma total cholesterol, LDL-cholesterol, free fatty acid and triglyceride levels. Compared with controls, GGH(1)-3 treated mice had lower blood plasma ALT concentration. Consistent with their effects on body weight gain, the size of adipocytes were significantly decreased by GGH(1), whereas the adipocyte number per unit area was significantly increased, suggesting that GGH(1) decreased the number of large adipocytes. Hepatic lipid accumulation was decreased by GGH(1). Conclusions : In conclusion, these results suggest that GGH(1) exhibits anti-obesity effects through the modulation of feeding efficiency ratio and plasma obesity parameters. Moreover, it seems that GGH(1) also contributes to improve NAFLD through the regulation of plasma ALT and hepatic triglyceride accumulation.

Lipid Profile and Oxidative Stress Markers in Wistar Rats following Oral and Repeated Exposure to Fijk Herbal Mixture.

This study determined the effect of the oral and repeated administration of Fijk herbal mixture on rat biochemical and morphological parameters. Twenty-four Wistar rats were distributed into four groups of 6. Group A served as control and received oral administration of distilled water daily. The experimental groups B, C, and D were daily and orally exposed to Fijk herbal mixture at 15, 30, and 45 mg/kg, respectively. Treatments lasted for 21 days. The rats were sacrificed under mild diethyl ether anesthesia 24 hr after cessation of treatment. The blood and liver samples were collected and used for the biochemical and morphological analyses. Oral exposure to Fijk caused elevated levels of rat plasma ALT, AST, triglycerides, LDL, and MDA. In contrast, rat plasma HDL, GSH, and ALP levels were lowered by Fijk oral exposure. Also, the herbal remedy caused a dose-dependent elevation in the plasma atherogenic index. The histopathology examinations of rat liver sections revealed inimical cellular alterations caused by repeated exposure to Fijk. Study provides evidence that oral and repeated exposure to Fijk in rats raised the atherogenic index and potentiated oxidative stress as well as hepatic injury.

Abstract C287: Efficacy and safety of the TH-302, gemcitabine, and nab-paclitaxel combination in xenograft models of pancreatic cancer.

Abstract Background: Tumors often consist of hypoxic regions which are resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-targeted drug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. A randomized Phase 2 clinical trial in pancreatic ductal adenocarcinoma (PDAC) demonstrated a significant increase in progression-free survival from the addition of T to gemcitabine (G) vs. G only (NCT01144455). A Phase 3 trial of G + T compared to G + placebo is currently underway (NCT01746979). G + nab-Paclitaxel (nP) significantly prolonged overall survival in a recent Phase 3 trial (NCT00844649). We investigated the efficacy and safety profile of combining T with G and nP in PDAC xenograft models. Methods: Four PDAC xenograft models were established by s.c. implantation of Hs766t, MIA PaCa-2, PANC-1 and BxPC-3 cells into the flank of nude mice. A ‘same day’ administration of T, nP and G with a Q3Dx5 regimen was employed: T, 50mg/kg, ip; nP: 30mg/kg, iv; and G: 60mg/kg ip. Saline treated animals served as vehicle control (V). Antitumor activity of the G + nP + T triplet was assessed, and compared with the G + nP doublet. Hematological, blood chemistry, and immunohistochemical-based analyses were also performed in PANC-1 bearing nude and/or CD-1 mice. Samples were collected 24 hours after the last treatment. Neuropathy assays were performed in CD-1 mice. Results: Using tumor growth inhibition, and Kaplan-Meier analysis of median time to tumor size of 1000mm3 to evaluate antitumor activity, G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP in all four models. Of note, the complete response rate (CR) of G + nP + T in the PANC-1 model reached 100%, compared to 10% and 50% in the T-alone and G + nP, respectively. G + nP or T-alone treatment reduced neutrophils or lymphocytes compared with V, but there was no additional decrease in neutrophil or lymphocyte count when T was added to G + nP compared to G + nP. Plasma ALT and AST levels were elevated after G + nP treatment, and G + nP + T did not further increase the levels of these liver function parameters. By immunostaining, Ki67-positive cells (a marker of cell proliferation) were significantly reduced after the drug treatment in the PANC-1 xenograft, and to a greater magnitude in G + nP + T. The necrotic region in G + nP + T was increased compared with all other groups. Employing the von Frey neuropathy assay, G + nP treated mice exhibited mechanical allodynia in the hind paw 9 days after initiation of treatment whereas mice treated with T did not, and there was no additive neuropathy in G + nP + T. Conclusions: The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to G + nP. These studies provide a translational rationale for combining G, nP, and T in the clinical setting to assess efficacy and safety. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C287. Citation Format: Jessica D. Sun, Qian Liu, Dharmendra Ahluwalia, Wenwu Li, Yan Wang, Ayesha S. Ruprell, Charles P. Hart. Efficacy and safety of the TH-302, gemcitabine, and nab-paclitaxel combination in xenograft models of pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C287.

Effect of green tea and its polyphenols on mouse liver

Increased consumption of green tea (GT) without enough scientific data has raised safety concerns. Epigallocatechin 3-gallate (EGCG) is the most prominent polyphenol of GT that has antioxidant activity. However, higher doses of EGCG have been shown to cause liver injury. This study was initiated to determine the effect of GT extracts in a mouse model. We also investigated the effects of EGCG in normal and health-compromised mice. Different doses of GT fractions and EGCG were administered for 5days to mice. Also, a single dose of lipopolysaccharide (LPS) was combined with EGCG in order to investigate its effect in the presence of fever. Plasma ALT and ALP levels were determined along with liver histopathology. Combining a single high IG dose of EGCG with a single IP dose of LPS initiated liver injury. Furthermore, repeated administration of high IG doses of EGCG showed mild liver injury, but it was augmented under febrile conditions induced by LPS. This study confirms the safety of reasonable consumption of GT over a short term. However, it highlights a caution that high doses of EGCG can lead to mild liver injury, and this may be markedly enhanced under febrile conditions.

Ageing Fxr Deficient Mice Develop Increased Energy Expenditure, Improved Glucose Control and Liver Damage Resembling NASH

Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

Losartan Supports Liver Regrowth via Distinct Boost of Portal Vein Pressure in Rodents with 90 % Portal Branch Ligation

The study used a model of 90 % portal branch ligation (PBL) in rats to study the effect of losartan on portal vein pressure (PVP) and liver regeneration in rats after PBL. A total of 144 male Sprague-Dawley rats were arbitrarily designated into three treatment method groups: a sham operation group (Sham), a PBL treatment group (PBL), and a PBL plus losartan treatment group (PBL + L). Losartan (2 mg/day) was intragastrically gavaged 3 days before the PBL or sham operation to time points of study. Both the PBL and PBL + L groups showed an intense surge in PVP after PBL treatment, peaking at 12 h postsurgery, then lessening progressively afterwards. PVP was substantially greater in these two groups compared with the Sham group at 6-72 h postsurgery (p < 0.01). Compared with the PBL group, the PBL + L group showed a noticeable reduction in PVP 6-48 h postsurgery (p < 0.05); the PBL group showed considerably raised levels of plasma ALT and AST 6-72 h postsurgery (p < 0.01). Compared to the PBL group, the PBL + L group showed drastically reduced plasma ALT and AST levels 12-72 h postsurgery (p < 0.05). Losartan supports liver regeneration in 90 % of rats that underwent PBL. The mechanism may be related to losartan's ability to regulate PVP and increase serum hepatocyte growth factor levels.

Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress

Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice.

Effects of quercetin on LPS-induced disseminated intravascular coagulation (DIC) in rabbits

IntroductionQuercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC. Materials and MethodsLPS-induced DIC model in rabbits was established through continuous infusion of 100 ug·kg-1·h-1 LPS for a period of 6h. Six groups were divided: quercetin-treated groups (0.5, 1.0, and 2.0mg·kg-1·h-1, respectively), LPS-control group, heparin-control group (100IU·kg-1·h-1), and saline-control group. APTT, PT, and plasma FIB level were measured, the plasma levels of ALT, BUN, and TNF-α were detected, and the activity of Protein C and ATIII was recorded. ResultsA continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII. ConclusionQuercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.

Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice

Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75mg/kg bw DF by oral gavage and 24h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p<0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p<0.001 and p<0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p<0.001) and protein expression of PCNA (p<0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury.

Ameliorative Effects of Soya Bean Oil and Vitamin C on Liver Enzymes in Ethanol -Induced Oxidative Stress in Wistar Rats

The protective potential of soya bean oil and vitamin C on Ethanol-induced oxidative stress in Wistar rats was evaluated. Thirty five Wistar rats of both sexes weighing 120-200g were grouped into five groups of seven rats each. Oxidative stress was induced by administration of 20% ethanol (w/v) for 28 days, at the end of the period of administration, the rats were fasted over night and their blood was collected directly from the heart via cardiac puncture in EDTA sample bottles and the blood was centrifuged and the serum was used to determine the levels of of AST, ALT and ALP in all the groups . The result revealed that Ethanol significantly (p<0.05) increased plasma AST, ALT and ALP levels. Vitamin C significantly (p<0.05) decreased serum AST while soya bean oil produced no significant (p<0.05) effect on plasma AST. The serum levels of ALT and ALP were significantly reduced following vitamin C and Soya bean oil administration. The elevation of serum AST, ALT and ALP after alcohol administration is an indication oxidative stress. The decrease in plasma concentration of the liver enzymes after treatment with vitamin C and Soya bean oil reveals the ameliorative potential of vitamin C and soya bean oil against ethanol-induced oxidative stress in Wistar rats.