Aminotransferase Activity Levels Research Articles

Lactobacillus plantarum ST-III culture supernatant protects against acute alcohol-induced liver and intestinal injury.

The beneficial effects of probiotics have been studied in inflammatory bowel disease, nonalcoholic steatohepatitis, and alcoholic liver disease (ALD). Probiotic supplements are safer and more effective; however, their potential mechanisms are unclear. An objective of the current study was to examine the effects of extracellular products of Lactobacillus plantarum on acute alcoholic liver injury. Mice on a standard chow diet were supplemented with Lactobacillus plantarum ST-III culture supernatant (LP-cs) for two weeks and administered alcohol at 6 g/kg body weight by gavage. Alcohol-induced liver injury was assessed by measuring plasma alanine aminotransferase activity levels and triglyceride content determined liver steatosis. Intestinal damage and tight junctions were assessed using histochemical staining. LP-cs significantly inhibited alcohol-induced fat accumulation, inflammation, and apoptosis by inhibiting oxidative stress and endoplasmic reticulum stress. LP-cs significantly inhibited alcohol-induced intestinal injury and endotoxemia. These findings suggest that LP-cs alleviates acute alcohol-induced liver damage by inhibiting oxidative stress and endoplasmic reticulum stress via one mechanism and suppressing alcohol-induced increased intestinal permeability and endotoxemia via another mechanism. LP-cs supplements are a novel strategy for ALD prevention and treatment.

PREVENTION OF PATHOLOGICAL EFFECT OF ISCHEMIA-REPERFUSION IN LIVER RESECTION BY SEVOFLURANE PRECONDITIONING.

The intermittent Pringle maneuver remains the major technique for controlling hemorrhage during liver surgery. Nevertheless, this procedure involves a risk of triggering a cascade of pathological changes resulting in the ischemia-reperfusion injury (I/R) effect. The pharmacological prevention of this I/R injury represents a promising approach. The aim of the study was to compare the effects of pharmacological preconditioning with sevoflurane and propofol-based intravenous anesthesia on the postoperative function of the liver as the primary end-point. A prospective cohort study includes the analysis of the data of 73 patients who underwent liver surgery. In the study group (n = 41), preconditioning with sevoflurane inhalation was provided 30 minutes prior to liver resection. In the control group (n = 32), sevoflurane preconditioning was not provided. The primary endpoints were blood lactate concentration shortly after the surgery and one day later; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities on postoperative Days 1, 3, and 5 as markers of hepatocyte damage. On postoperative Day 1, in patients of the study group, lactate decreased to preoperative levels, while in the control group, lactate content increased as compared to both preoperative levels and the levels immediately after liver resection. A significant difference in AST activity levels between the groups was registered on Day 5, although this difference was not clinically relevant. The decrease in the prothrombin index in the study group on Day 3 was superior to that in the control group. The multiple regression analysis demonstrated a moderate positive association between the number of resected liver segments and the markers of the functional state of the liver in the study group while in the control group, such association was not significant. The protective effect of sevoflurane on the postoperative function of the liver is manifested by the lower level of blood lactate and the stable level of transaminase activity.

Biodegradation and Immunological Parameters of Polyurethane-Based Tissue Adhesive in Arterial Microvascular Anastomoses-A Long-Term In Vivo Study.

In microsurgical anastomosis, non-synthetic fibrin-based adhesives have predominantly shown superior properties to synthetic cyanoacrylates, but they have hardly any clinical application. This study aims to investigate the local and systemic effects of synthetically produced biodegradable adhesive VIVO when used in microsurgical anastomosis. VIVO is used in two different anastomosis procedures in the common carotid artery in a rat model: VIVO in addition to a temporary catheter (VIVO TC) and VIVO with a custom-shaped memory nitinol stent (VIVO SM). Conventionally sutured anastomoses serve as controls (C). Tissue response is assessed by in vivo fluorescence imaging and histological examination. The systemic effects of biodegradation are measured using hematologic parameters and serum levels of transaminase activity and lactate dehydrogenase. Finally, the degree of local adhesion of the different anastomotic procedures is evaluated. Fluorescence imaging shows reduced inflammatory blood flow in the VIVO TC group. Histological analysis of the anastomosed vessels also reveals significantly more inflammation in C than in the two adhesive groups. The severity of VIVO adhesions proves acceptable, and no histotoxic effects of VIVO are detected. The data demonstrate that the synthetic tissue adhesive VIVO is a reliable and-compared to sutures-tissue-friendly adhesive for microsurgical anastomoses.

Gastrodin Improves Nonalcoholic Fatty Liver Disease Through Activation of the Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway.

NASH is currently one of the most common causes of liver transplantation and hepatocellular carcinoma. Thus far, there is still no effective pharmacological therapy for this disease. Recently, Gastrodin has demonstrated hepatoprotective effects in a variety of liver diseases. The aim of this study is to investigate the function of Gastrodin in NASH. In our study, Gastrodin showed potent therapeutic effects on NASH both in vivo and in vitro. In high-fat diet or high-fat and high-cholesterol diet-fed mice, the liver weight, hepatic and serum triglyceride and cholesterol contents, and serum alanine aminotransferase and aspartate aminotransferase activity levels were markedly reduced by Gastrodin treatment as compared with the corresponding vehicle groups. Notably, Gastrodin showed minimal effects on the function and histological characteristics of other major organs in mice. We further examined the effects of Gastrodin on lipid accumulation in primary mouse hepatocytes and human hepatocyte cell line and observed that Gastrodin showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. Furthermore, RNA-sequencing analysis systemically indicated that Gastrodin suppressed the pathway and key regulators related to lipid accumulation, inflammation, and fibrosis in the pathogenesis of NASH. Mechanistically, we found that Gastrodin protected against NASH by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway, which was supported by the result that the AMPK inhibitor Compound C or AMPK knockdown blocked the Gastrodin-mediated hepatoprotective effect. Gastrodin attenuates steatohepatitis by activating the AMPK pathway and represents a therapeutic for the treatment of NASH.

Effects of caffeine on brain antioxidant status and mitochondrial respiration in acetaminophen-intoxicated mice.

Hepatic encephalopathy is a pathophysiological complication of acute liver failure, which may be triggered by hepatotoxic drugs such as acetaminophen (APAP). Although APAP is safe in therapeutic concentration, APAP overdose may induce neurotoxicity, which is mainly associated with oxidative stress. Caffeine is a compound widely found in numerous natural beverages. However, the neuroprotective effect of caffeine remains unclear during APAP intoxication. The present study aimed to investigate the possible modulatory effects of caffeine on brain after APAP intoxication. Mice received intraperitoneal injections of APAP (250mg/kg) and/or caffeine (20mg/kg) and, 4h after APAP administration, samples of brain and blood were collected for the biochemical analysis. APAP enhanced the transaminase activity levels in plasma, increased oxidative stress biomarkers (lipid peroxidation and reactive oxygen species), promoted an imbalance in endogenous antioxidant system in brain homogenate and increased the mortality. In contrast, APAP did not induce dysfunction of the mitochondrial bioenergetics. Co-treatment with caffeine modulated the biomarkers of oxidative stress as well as antioxidant system in brain. Besides, survival assays demonstrated that caffeine protective effects could be dose- and time-dependent. In addition, caffeine promoted an increase of mitochondrial bioenergetics response in brain by the enhancement of the oxidative phosphorylation, which could promote a better energy supply necessary for brain recovery. In conclusion, caffeine prevented APAP-induced biochemical alterations in brain and reduced lethality in APAP-intoxicated mice, these effects may relate to the preservation of the cellular antioxidant status, and these therapeutic properties could be useful in the treatment of hepatic encephalopathy induced by APAP intoxication.

Application infusion drugs based on sorbitol for normalization of aminotransferase activity blood cancer patients operated cardia of the stomach

Objective. To study the effect of intravenous infusions of Rheosorbilact on the activity of alanine aminotransferase and aspartate aminotransferase in the plasma of operated patients with gastric cardiac cancer after proximal gastrectomy.
 Materials and methods. Alanine aminotransferase and aspartate aminotransferase activity levels were studied in plasma of 40 operated patients with gastric cardiac cancer after proximal gastrectomy immediately after surgery, on the 1st, 2nd, 3rd, 5th day after intravenous infusions of the drug. The infusion of Rheosorbilact was administered intravenously, drip, for 5 days at a rate of 40 drops per minute. The daily dose of the drug was 1000.0 ml.
 Results. In patients with gastric cardiac cancer after proximal gastrectomy in the first days after surgery revealed changes in aminotransferases, which are accompanied by an increase in the activity of alanine aminotransferase and aspartate aminotransferase in blood plasma. To correct the activity of plasma aminotransferases in such patients, Rheosorbilact was administered intravenously immediately after surgery. After repeated intravenous infusions of Rheosorbilact for 5 days, a significant decrease in the activity of alanine aminotransferase and aspartate aminotransferase in blood plasma in the operated patients was revealed.
 Conclusions. In the first days after proximal gastrectomy in patients with gastric cardiac cancer, an increase in the activity of aminotransferases in blood plasma was revealed. Repeated intravenous infusions of Rheosorbilact normalize the activity of alanine aminotransferase and aspartate aminotransferase in the blood plasma of such patients in the early postoperative period. Infusion drug Rheosorbilact is recommended for widespread medical use in patients with cardiac gastric cancer after proximal gastrectomy, especially in the early postoperative period.

UDP‐glucuronosyltransferase polymorphisms affect diethylnitrosamine‐induced carcinogenesis in humanized transgenic mice

UDP‐glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case‐control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)‐induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15‐day‐old htgUGT1A‐WT and htgUGT1A‐SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver‐body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN‐treated htgUGT1A‐SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A‐SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case‐control studies implicating impaired UGT1A‐mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.

ITRAQ-based quantitative phosphoproteomics provides insights into the metabolic and physiological responses of a carnivorous marine fish (Nibea albiflora) fed a linseed oil-rich diet

The limited production of fish oil (FO) cannot meet the increasing demand of the aqua-feed industry. Accordingly, the replacement of FO with sustainable alternatives such as vegetable oils has become imperative. Linseed oil (LO), which has an abundance of α-linolenic acid (ALA), is a promising FO alternative. Nevertheless, high dietary LO inclusion generally causes abnormal hepatic lipid accumulation and growth retardation across carnivorous marine fish species. Previous studies have attempted to elucidate the mechanisms with regard to gene and protein levels; however, little is known about posttranslational modifications. In the present study, iTRAQ phosphoproteomics was conducted to investigate the metabolic and physiological responses of the yellow drum (Nibea albiflora) fed an LO-rich or FO-rich diet. Identification and analyses of differentially abundant phosphorylated proteins in hepatic tissue were conducted with parallel reaction monitoring (PRM) verification in reference to the genome sequences of the yellow drum. Among the specific peptides that passed the threshold, 203 hyperphosphorylated and 182 hypophosphorylated peptides were identified. Several functional categories and pathways were associated with these proteins that were mostly related to lipid, amino acid, and carbohydrate metabolism. In particular, the AMP-activated protein kinase (AMPK) pathway, mechanistic target of rapamycin (mTOR) pathway, and citrate (TCA) cycle are discussed. Statement of significanceDietary LO caused abnormal hepatic lipid accumulation and retarded growth performance. The abnormal hepatic lipid accumulation in the fish fed the LO-rich diet might have arisen from AMPK signaling pathway-mediated de novo synthesis of fatty acids and the synthesis of phospholipids. An mTOR signaling pathway-mediated reduction in ribosome protein synthesis could have been a factor in the growth retardation. Changes in UPS and autophagy proteins phosphorylation and aminotransferase activity levels were related to the flux of amino acids into the TCA cycle for ATP production. The results of PRM were highly correlated with the phosphoproteomics results. These findings will contribute to a better understanding of the mechanisms of abnormal hepatic lipid accumulation and retarded growth performance in carnivorous marine fish fed linseed oil-rich diets.

Hepatotoxic evaluation of Di-n-butyl phthalate in Wistar rats upon sub-chronic exposure: A multigenerational assessment

The extensive use of di--n-butyl phthalate (DBP) as a plasticizer in medical devices, personal care products, and industries, which is a major threat to humankind as it leaches out easily from the plastic matrix into the environment. Health risks posed to adults and children from the broad usage of DBP in cosmetics and infant toys observed predominantly due to repeated and prolonged exposure. Hence, this study was undertaken to evaluate the potential effect of DBP in the hepatic tissue of rats up to three generations. Wistar rats were induced at a dose of 500 mg DBP /kg body weight dissolved in olive oil by oral gavage throughout gestation (GD 6–21), lactation and post-weaning and reared by crossing intoxicated rats up to three generations. Results of the present study showed a significant increase in the relative weight of liver, while decreased levels of antioxidant enzymes viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) was evident in DBP treated rats at P < 0.05. Besides hepatic marker enzymes viz., alanine transaminase (ALT) and aspartate transaminase (AST) were elevated significantly in experimental rats compared to those of the control group. Furthermore, histological studies revealed congested central veins and dilated sinusoids in F1 progeny while mild to severe focal inflammatory infiltrations were evident in F2 & F3 rats. Negative correlation observed between the levels of antioxidant enzymes and transaminase activity. In brief, DBP exposure elicits oxidative stress and alters the transaminase activity levels causing damage in hepatic tissue. F3 progeny found to high vulnerability to the exposure of DBP than F2 & F1 rats.

Protective Effects of Ischemic Preconditioning Protocols on Ischemia-Reperfusion Injury in Rat Liver

Background: Hepatic ischemia reperfusion injury often leads to increased complications and mortality after surgery. Although ischemic preconditioning is used as a convenient and effective method to protect the liver from warm ischemia reperfusion injury, the optimal protocol is currently unclear. Therefore, in this study, we sought to identify ideal conditions and methods for ischemic preconditioning. Materials and methods: We compared several preconditioning protocols of the ischemia/reperfusion (I/R) cycle in 30 male Sprague-Dawley rats (5 groups, n = 6), including relevant sham and I/R injury (no preconditioning) controls. Experimental group conditions included: (1) ischemia for 5 min/reperfusion for 10 min (ischemic preconditioning 1, IPC-1); (2) ischemia for 5 min/reperfusion for 5 min, repeated three times (IPC-2); and (3) ischemia for 10 min/reperfusion for 10 min (IPC-3). Readouts included transaminase activity levels measured from collected sera, and histopathological changes, liver cell apoptosis, superoxide dismutase (SOD) activity, glutathione (GSH) levels, and malondialdehyde (MDA) levels measured from collected liver tissue segments subjected to warm ischemia (that is from the 70% of the liver mass that had been deprived from blood flow during the ischemia phase). Results: Compared to the I/R control group, the IPC-1, IPC-2, and IPC-3 groups all showed significant decreases in liver transaminase activity levels, alleviation of pathological injury-associated changes, and a decrease in liver cell apoptosis. Moreover, SOD activity and GSH content were increased while MDA content was decreased in the three experimental groups. Compared to the IPC-1 and IPC-3 groups, the changes in the IPC-2 group were the most significant (P < 0.05). Conclusions: Ischemic preconditioning can reduce hepatic warm ischemia reperfusion injury in rats. The IPC-2 protocol, involving ischemia for 5 min and reperfusion for 5 min, repeated three times, provided the optimal protection against hepatic ischemia reperfusion injury among the protocols studied.

Age-related differences in function and structure of rat livers subjected to ischemia/reperfusion.

IntroductionLiver function is affected during ischemia/reperfusion (IR). The current state of knowledge about liver aging processes during IR is incomplete. We evaluated the effects of aging on liver structure and function under IR conditions.Material and methodsAnimals were divided into control (C-2) and ischemia/reperfusion (IR-2) groups of young rats (2–4 months old) and C-12 and IR-12 groups of old rats (12–14 months old). The livers from IR-2 and IR-12 groups were subjected to partial ischemia (60 min), followed by global reperfusion (4 h). Blood samples were obtained during reperfusion (0, 30 and 240 min) to estimate the activity of aminotransferases (ALT, AST). After IR, tumor necrosis factor-α (TNF-α), interleukin-1b (IL-1b), malondialdehyde (MDA), and superoxide dismutase (SOD) were determined in liver homogenates.ResultsAt all points of reperfusion, an increase in aminotransferase activity levels in the ischemic groups was observed; mainly between IR-12 and C-12 rats. The concentration of TNF-α was significantly higher in young animals (in non-ischemic groups: p = 0.09, in ischemic groups: p = 0.05). Under IR conditions, the concentration of IL-1b dropped (p = 0.05). The concentration of MDA was significantly higher in mature animals (in non-ischemic groups: p = 0.09, in ischemic groups: p = 0.05). In ischemic groups an increase in necrosis rate was observed regardless of age. Rats in the IR-12 group showed the most pronounced changes in hepatic architecture, including increased micro- and macrosteatosis and parenchymal cell destruction.ConclusionsThe function and structure of mature livers slightly deteriorate with age and these differences are more noticeable under IR conditions.

Avaliação dos níveis das transaminases dos pacientes com infecção pelo Plasmodium vivax atendidos em um centro de referência para tratamento da malária no Estado de Mato Grosso

Objetivo: Analisar os marcadores hepáticos (transaminases) em pacientes com malária causada pelo Plasmodium vivax. Métodos: Trata-se de um estudo transversal retrospectivo, incluindo pacientes que apresentaram monoinfecção pelo P. vivax. O teste de Mann-Whitney U ou o teste t de Student foram utilizados para comparar a atividade média das transaminases de acordo com a classificação clínica e epidemiológica do paciente infectado. O teste de Kruskal-Wallis foi utilizado para comparar a média da atividade das transaminases de acordo com a classificação da infecção. Valores de p&lt;0,05 foram considerados significativos. Resultados: Indivíduos menores de 7 anos apresentaram maior atividade da transaminase glutâmico oxalacética (TGO) e da transaminase glutâmico pirúvica (TGP) — respectivamente, 68,7 U/L e 79,8 U/L — em relação a pacientes com idade de 8 a 59 anos (TGO 29,8 U/L e TGP 39,2 U/L) e acima de 60 anos (TGO 32,5 U/L e TGP 34 U/L). A média da dosagem sérica de TGO de todos os pacientes incluídos no estudo foi de 31,99 U/L e de TGP foi de 41,1 U/L. A atividade de TGP nos pacientes primoinfectados foi maior que nos reinfectados ou com recaída, sendo 65,6 U/L contra 36,2 U/L e 32,7 U/L, respectivamente. Conclusão: Crianças apresentam maior atividade de transaminases que os indivíduos maiores de sete anos de idade. Pacientes com infecção prévia pelo P. vivax apresentam menores valores séricos da atividade das transaminases do que os primoinfectados. Indivíduos com episódios de recaída apresentam menores valores das enzimas avaliadas do que aqueles com reinfecção ou primoinfecção.

Effect of phosphorus deficiency on erythrocytic morphology and function in cows.

The aim of this study was to evaluate the influence of phosphorus (P) deficiency on the morphological and functional characteristics of erythrocytes in cows. Forty Holstein-Friesian dairy cows in mid-lactation were randomly divided into two groups of 20 each and were fed either a low-P diet (0.03% P/kg dry matter [DM]) or a control diet (0.36% P/kg DM). Red blood cell (RBC) indices results showed RBC and mean corpuscular hemoglobin decreased while mean corpuscular volume increased significantly (p < 0.05) in P-deficient cows. Erythrocyte morphology showed erythrocyte destruction in P-deficient cows. Erythrocytes' functional characteristics results showed total bilirubin and indirect bilirubin concentrations and aspartate transaminase and alanine transaminase activity levels in the serum of P-deficient cows were significantly higher than those in control diet-fed cows. Activities of superoxide dismutase and glutathione peroxidase in erythrocytes were lower, while the malondialdehyde content was greater, in P-deficient cows than in control diet-fed cows. Na+/K+-ATPase and Mg2+-ATPase activities were lower in P-deficient cows than in control diet-fed cows; however, Ca2+-ATPase activity was not significantly different. The phospholipid composition of the erythrocyte membrane changed and membrane fluidity rigidified in P-deficient cows. The results indicate that P deficiency might impair erythrocyte integrity and functional characteristics in cows.

Polymannuronate 첨가에 의한 햄버거빵이 흰쥐의 지질대사에 미치는 영향

The dietary fiber alginic acid has no nutritional value; however, it decreases the utilization of nutrients by the body and can prevent obesity, hyperlipidemia, arteriosclerosis, constipation, and colon cancer. The low-molecular-weight alginic acid polymannuronate improves serum and liver lipid metabolism by decreasing cholesterol levels in high-cholesterol groups and may be used to control high blood pressure. Previously, we showed that polymannuronate, a physiologically active agent from seaweed, has a lipid-lowering effect and preventative role in colon cancer. In addition, the differentiation of polymannuronate-treated adipocytes was inhibited, triggering decreased leptin expression. This study examined ways to increase dietary satisfaction with and improve the nutritional quality of polymannuronate using hamburger buns supplemented with polymannuronate. Twenty male Sprague-Dawley rats were divided into two groups: the control group was fed hamburger buns containing 6% gluten, while the experimental group was fed hamburger buns containing 6% gluten and 10% polymannuronate. The serum triglyceride, phospholipid, and total and free cholesterol levels of the rats in the experimental group were decreased compared with those of the controls. The serum aspartate aminotransferase activity levels did not differ between the two groups. This study demonstrates that polymannuronate has beneficial effects on lipid metabolism and may be commercially useful.

Human hepatic stem cells transplanted into a fulminant hepatic failure Alb-TRECK/SCID mouse model exhibit liver reconstitution and drug metabolism capabilities.

IntroductionChimeric mice with humanized livers were recently established by transplanting human hepatocytes. This mouse model that is repopulated with functional human hepatocytes could be a useful tool for investigating human hepatic cell biology and drug metabolism and for other preclinical applications. Successfully transplanting human hepatocytes into mice requires that recipient mice with liver failure do not reject these human cells and provide a suitable microenvironment (supportive niche) to promote human donor cell expansion and differentiation. To overcome the limitations of current mouse models, we used Alb-TRECK/SCID mice for in vivo human immature hepatocyte differentiation and humanized liver generation.Methods1.5 μg/kg diphtheria toxin was administrated into 8-week-old Alb-TRECK/SCID mice, and the degree of liver damage was assessed by serum aspartate aminotransferase activity levels. Forty-eight hours later, mice livers were sampled for histological analyses, and the human donor cells were then transplanted into mice livers on the same day. Chimeric rate and survival rate after cell transplantation was evaluated. Expressions of human hepatic-related genes were detected. A human albumin enzyme-linked immunosorbent assay was performed after 50 days of transplantation. On day 60 after transplantation, drug metabolism was examined in mice.ResultsBoth human primary fetal liver cells and hepatic stem cells were successfully repopulated in the livers of Alb-TRECK/SCID mice that developed lethal fulminant hepatic failure after administering diphtheria toxin; the repopulation rate in some mice was nearly 100%. Compared with human primary fetal liver cells, human hepatic stem cell transplantation rescued Alb-TRECK/SCID mice with lethal fulminant hepatic failure, and human hepatic stem cell-derived humanized livers secreted more human albumin into mouse sera and also functioned as a “human liver” that could metabolize the drugs ketoprofen and debrisoquine.ConclusionOur model of a humanized liver in Alb-TRECK/SCID mice may provide for functional applications such as drug metabolism, drug to drug interactions, and promote other in vivo and in vitro studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0038-9) contains supplementary material, which is available to authorized users.

Importance of TLR2 on Hepatic Immune and Non-Immune Cells to Attenuate the Strong Inflammatory Liver Response During Trypanosoma cruzi Acute Infection

BackgroundToll-like receptors (TLR) and cytokines play a central role in the pathogen clearance as well as in pathological processes. Recently, we reported that TLR2, TLR4 and TLR9 are differentially modulated in injured livers from BALB/c and C57BL/6 (B6) mice during Trypanosoma cruzi infection. However, the molecular and cellular mechanisms involved in local immune response remain unclear.Methodology/Principal FindingsIn this study, we demonstrate that hepatic leukocytes from infected B6 mice produced higher amounts of pro-inflammatory cytokines than BALB/c mice, whereas IL10 and TGFβ were only released by hepatic leukocytes from BALB/c. Strikingly, a higher expression of TLR2 and TLR4 was observed in hepatocytes of infected BALB/c mice. However, in infected B6 mice, the strong pro-inflammatory response was associated with a high and sustained expression of TLR9 and iNOS in leukocytes and hepatic tissue respectively. Additionally, co-expression of gp91- and p47-phox NADPH oxidase subunits were detected in liver tissue of infected B6 mice. Notably, the pre-treatment previous to infection with Pam3CSK4, TLR2-agonist, induced a significant reduction of transaminase activity levels and inflammatory foci number in livers of infected B6 mice. Moreover, lower pro-inflammatory cytokines and increased TGFβ levels were detected in purified hepatic leukocytes from TLR2-agonist pre-treated B6 mice.Conclusions/SignificanceOur results describe some of the main injurious signals involved in liver immune response during the T. cruzi acute infection. Additionally we show that the administration of Pam3CSk4, previous to infection, can attenuate the exacerbated inflammatory response of livers in B6 mice. These results could be useful to understand and design novel immune strategies in controlling liver pathologies.

Change in dental pulp parameters in response to different modes of orthodontic force application

(1) To evaluate dental pulp sensitivity by electrical pulp testing and measure aspartate aminotransferase activity in the pulp after 14 days of orthodontic intrusion, and (2) to compare those measurements with measurements obtained in teeth after 7 days of intrusion and 7 days of rest. The study sample included 13 subjects (mean age = 16.5 +/- 2.7 years). For every subject, before extraction, two contralateral premolars were included in a spring and loaded by a force. Two study groups were formed: Group A, teeth with 14 days of mechanical load, and Group B, teeth with 7 days of mechanical load plus 7 days of rest. Electrical pulp testing and aspartate aminotransferase activity measurements were performed after 14 days in all tested teeth. After extraction, aspartate aminotransferase activity in the pulp was determined spectrophotometrically at 20 degrees C. Mean aspartate aminotransferase activity values were 0.21 U/mg (SD = 0.15) in Group A and 0.27 U/mg (SD = 0.17) in Group B. Mean electrical pulp testing readings were 38.92 microA (SD = 24.61) in Group A and 36.77 microA (SD = 26.84) in Group B. Mean values of the intrusive force magnitude did not differ in both groups. Different durations of orthodontic intrusion, defined as 14 days of load and 7 days of load followed by 7 resting days, were not reflected by electrical pulp testing or by aspartate aminotransferase activity levels in the pulp of the affected teeth. However, the response threshold to electrical pulp stimulation was elevated in all tested teeth.

Inactivation of NuRD Component Mta2 Causes Abnormal T Cell Activation and Lupus-like Autoimmune Disease in Mice

Dynamic changes in chromatin structure through ATP-dependent remodeling and covalent modifications on histones play important roles in transcription regulation. Among the many chromatin modifiers identified, the NuRD (nucleosome remodeling histone deacetylase) complex is unique because it possesses both nucleosome remodeling and histone deacetylase activities. To understand the biological function of the NuRD complex, we generated a knock-out mouse model of the Mta2 (metastasis-associated protein 2) gene, which encodes a NuRD-specific component. Mta2 null mice exhibited partial embryonic lethality. The surviving mice developed lupus-like autoimmune symptoms including skin lesions, bodyweight loss, glomerulonephritis, liver inflammation, and production of autoantibodies. Transplantation of bone marrow cells from Mta2 null mice recapitulated some of the symptoms including skin lesion and bodyweight loss in the recipient mice. Mta2 null T lymphocytes showed normal development but hyperproliferation upon stimulation, which correlates with hyperinduction of interleukin (IL)-2, IL-4, and interferon (IFN)-gamma. T cell hyperproliferation, but not other autoimmune symptoms, was observed in T cell-specific Mta2 knock-out mice. Mta2 null T cells produced more IL-4 and IFN-gamma under Th2 activation conditions, but normal levels of IL-4 and IFN-gamma under Th1 activation conditions. Furthermore, we found that IL-4 is a direct target gene of Mta2. Our study suggests that Mta2/NuRD is involved in modulating IL-4 and IFN-gamma expression in T cell immune responses, and gene expression in non-T cells plays an important role in controlling autoimmunity.

Altered activity of cytochrome P450 in alcoholic fatty liver exposed to ischemia/reperfusion

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality in liver surgery and transplantation, and fatty livers are susceptible to greater I/R injury and a higher incidence of primary graft nonfunction after transplantation. Because alcohol intake and obesity are major causes of fatty liver, this study was initiated to investigate the effect of chronic ethanol consumption on hepatic microsomal cytochrome P450 (CYP) activity after I/R. Rats were fed an alcohol liquid diet or a control isocaloric diet for 4 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. It was found that, chronic ethanol consumption significantly increased liver weight, serum triglyceride (TG), liver TG, and serum aminotransferase activities. Moreover, alcoholic fatty livers exposed to I/R showed significantly higher levels of aminotransferase activities than the controls. No significant differences in microsomal CYP content or CYP1A1 activity were found between I/R treated animals fed a control diet (the CD + I/R group) and I/R treated animals fed an ethanol containing diet (the ED + I/R group). Moreover, whereas CYP1A2 activity was decreased in the ED + I/R group versus the CD + I/R group, CYP2E1 activity was elevated. Additionally, chronic alcohol consumption up-regulated TNF-alpha and IL-6 mRNA levels immediately after I/R. In conclusion, chronic ethanol consumption was found to potentiate hepatocellular damage as indicated by abnormalities in microsomal drug metabolizing function during I/R.

Inhibitory effect of melatonin on diquat‐induced lipid peroxidation in vivo as assessed by the measurement of F2‐isoprostanes

Melatonin is a powerful antioxidant and free radical scavenger. A large body of in vivo and in vitro evidence shows that melatonin effectively inhibits membrane lipid peroxidation; this damage was based on the measurement of malondialdehyde and/or 4-hydroxynonenal levels. In the current study, for the first time using a more sensitive and specific biomarker, i.e. F2-isoprostanes, we investigate the effect of melatonin on diquat-induced lipid peroxidation in Fischer 344 rats. When diquat (40 mg/kg body weight) was intraperitoneally injected into rats, the levels of liver F2-isoprostanes were significantly increased at 1, 3, and 6 hr while plasma free F2-isoprostanes concentrations were augmented at 3, 6, and 12 hr after administration of the toxin. In addition, the plasma alanine aminotransferase activity level was measured as a parameter of hepatoxicity; the activity of this enzyme was augmented at 3, 6, and 12 hr after diquat administration when compared with levels of this constituent in untreated control rats. Pretreatment with melatonin (20 mg/kg) 30 min before diquat administration resulted in a significant reduction in both tissue and plasma F2-isoprostanes levels, and plasma alanine aminotransferase activity. These findings, using a sensitive and specific index of lipid peroxidation, show that the hepatoxicity of diquat, at least partially, is a consequence of reactive oxygen species-induced lipid damage. Melatonin's protective effects likely relate to its direct free radical scavenging ability and/or due to other antioxidative processes induced by the indole.