Measurement Of Liver Enzymes Research Articles

Effects of vitamin A and vitamin E on attenuation of titanium dioxide nanoparticles-induced toxicity in the liver of male Wistar rats.

The increasing application of titanium dioxide nanoparticles (NTiO2) in life and the toxicity potential of these nanoparticles have raised concerns about their detrimental effects on human health. This study was conducted to investigate the hepatoprotective effects of vitamin E and vitamin A against hepatotoxicity induced by NTiO2 in rats. Thirty-six male Wistar rats were randomly divided into six groups of six rats each. Intoxicated group received 300mg/kg NTiO2 for two weeks by gavage. Groups treated with vitamin E (100IU/kg), vitamin A (100IU/kg) and mixture of these vitamins were orally administered for 3weeks (started 7days before NTiO2 administration). In order to investigate the redox changes, total antioxidant capacity, total oxidant status, and lipid peroxidation were determined in liver tissue as well as activity of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase. In addition, inflammatory responses were assessed by measuring the expression of NF-κB (mRNA) and TNF-α (mRNA and protein). Histopathological analysis and measurement of liver enzymes (ALP, ALT, AST, and LDH in serum) were also done to determine hepatic injury. In liver, NTiO2 caused hepatic injury, redox perturbation, and reduction of antioxidant enzymes and elevation of inflammatory mediators, significantly. However, treatment with vitamins was able to significantly ameliorate these alterations. This study highlights the antioxidant and anti-inflammatory properties of vitamins A and E against toxicity of NTiO2 and poses the use of these vitamins to mitigate the toxic effects of this nanoparticles in NTiO2-contained products.

Liver enzymes in alcohol consumers with or without binge drinking.

While alcohol use is linked with a wide variety of health problems, the question of whether differences in drinking patterns could yield different outcomes has remained unclear. We measured liver enzymes (ALT, GGT) from alcohol consumers with or without binge drinking from a population-based sample in Finland, where binge-type drinking is common. Data on alcohol use, diet, body weight, lifestyle (smoking, coffee consumption, physical activity), and health status were collected from 19225 subjects (9492 men, 9733 women), aged 25-74 years. The participants were subsequently classified to subgroups, both according to the frequencies of binge drinking and the amounts of regular alcohol intake (low-, medium-, and high-risk drinking). The quantity of regular alcohol use was roughly linearly related with GGT and ALT activities. ANOVA analyses of the trends according to the frequency of binge drinking showed a significant GGT increase in both men (p<0.0005) and women (p<0.0005), and a significant increase of ALT in men (p<0.0005). In those with low-risk overall consumption, markedly higher GGT (p<0.0005) and ALT (p<0.0005) occurred in those with binge drinking more than once a month, compared with those with no such occasions. Binge drinking occurring ≤1/month also resulted in higher GGT (p<0.0005) and ALT (p<0.05) activities. These results emphasize possible adverse consequences of binge drinking on hepatic function even in those with low-risk overall consumption. The pattern of drinking should be more systematically implicated in clinical recommendations for drinking reduction.

Monosodium Glutamate Induced Hepatotoxicity and Oxidative Stress: Pathophysiological, Biochemical and Electron Microscopic Study

AbstractBackground: Monosodium Glutamate (MSG) is a widely used flavor enhancer with an umami taste.Aim of the Work: The present work was designed to study the potential hepatotoxic effect of monosodium glutamate as regard biochemical; pathophysiological and electron micro-scopic changes; besides whether these changes were due to oxidative stress process. In addition, the possibility of recovery after MSG cessation was studied.Material and Methods: The study was conducted on thirty-six adult male Sprague Dawley rats, classified into three groups (12/each). Distilled water was given orally to the control group for 90 days. Rats of MSG group administered daily oral dose of 4mg/Kg for 90 days and the recovery group received the same dose as group II then kept four weeks later for recovery. After rats were sacrificed; blood samples were taken to measure liver enzymes [(Alanine Transaminase (ALT) and Aspartate Aminotransaminase (ASAT)], cholesterol and TGs. The liver tissues were used to measure products of oxidative stress and examined for histopathological; immmuo-histochemical and Electron Microscopic (EM) changes.Results: The results revealed statistically highly significant increase in hepatic enzymes, cholesterol, TGs and product of lipid peroxidation (Malondialdehyde, MDA) in combination with decrease in antioxidant glutathione transferase and superoxide dismutase in MSG group compared to control group (p<0.001). The histopathological and immunohisto-chemical results showed steatosis; increased vacuolation; extensive fibrosis and apoptosis in the hepatic cells especially centrilobular in MSG group. EM confirms the previous changes.Conclusion: It could be concluded that MSG has hepato-toxic and oxidant effects and its use should be prohibited during treatment of liver disorders.

Monitoring Treatment of Childhood Tuberculosis and the Role of Therapeutic Drug Monitoring.

Most children tolerate the first-line antibiotics used to treat Mycobacterium tuberculosis (TB) very well. The most common adverse effect is gastrointestinal distress unrelated to hepatotoxicity; the latter is seen in less than 1% of children. Despite the infrequency of hepatotoxicity, the potential long-term impact of hepatic insufficiency dictates that all children receiving antimycobacterial therapy should be evaluated periodically by symptom screening and physical examination. Routine measurement of transaminases in previously healthy, asymptomatic children is discouraged, as up to 40% of children will have transient, asymptomatic transaminase elevation that should not alter clinical management; measurement of serum liver enzymes is reserved for children who develop symptoms and those with existing liver disease or taking other potentially hepatotoxic drugs. Caregivers and personnel distributing directly-observed therapy need to be cognizant of potential drug toxicities and have a clear understanding of what to do if a child develops symptoms. There are substantial inter-patient variations in serum antibiotic concentrations when the same milligram per kilogram dose is given to different children of varying ages and sizes, reflecting differences in drug absorption and metabolism. While these variations may not impact the outcome of previously healthy children with mild disease, outcomes for children with human immunodeficiency virus infection or severe disease can be worse if sub-therapeutic drug concentrations are achieved. Therapeutic drug monitoring, wherein serum drug concentrations are used to optimize medication doses, should be considered for children with severe disease or if there is concern about alterations in drug absorption or metabolism.

Therapeutic Effects of Green Tea on Nonalcoholic Fatty Liver Disease in 10-16-Year-Old Children

Introduction: Nonalcoholic Fatty Liver Disease (NAFLD) is characterised by fat accumulation in the liver. Treatment of NAFLD in children is an important issue but the options are limited. Green tea has antioxidant and anti-hyperlipidemic effects but studies; on the effect of green tea in children are limited. Aim: To investigate effect of green tea on NAFLD in children. Materials and Methods: In this study. 52 children aged 10-16 years with NAFLD were divided into two groups of 26 each: Intervention and control. For both groups, modification of diet and intensification of physical activity were prescribed for three months. Intervention group was also treated with green tea tablets. Sonography and measurements of liver enzymes {Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)}, lipid profile and Body Mass Index (BMI) were conducted before and after the intervention. The data were analysed by the Statistical Package for the Social Sciences (SPSS) version 19.0 using ANCOVA. Results: After treatment with green tea, fatty liver grade decreased significantly in the intervention group compared to control group (p<0.0001). In addition, this treatment caused significant decrease in ALT, AST, and triglyceride levels and significant increase in High-Density Lipoprotein (HDL) level (p<0.05), but Low-Density Lipoprotein (LDL) level did not decrease significantly in the intervention group compared to control. Conclusion: Oral prescription of green tea was effective in improving fatty liver grade, decreasing hepatic fat accumulation and improving liver function, weight loss and reducing ALT and AST without any side effects. These effects can be due to green tea compounds such as polyphenols especially catechin and antioxidant and anti-hyperlipidemic effects. Keywords Author Keywords:Alanine aminotransferase; Aspartate aminotransferase; Green tea extract; Nonalcoholic steatohepatitis

Study of Biochemical Criteria of Blood for Thalassemia Patients

This study was conducted for a samples of thalassemia patients who included males and females as well as healthy people as compared. We were measured liver enzymes(ALK, GOT, GPT), blood parameters such as WBCS count, RBCS count, hemoglobin deposition rate Erythrocyte Sedimentation Rate (ESR), hematocrit or packed red cell volume(PCV) and Quantity of iron.

Graves’ disease in children

R1 The diagnosis of Graves’ disease in children is based on detecting a suppression of serum TSH concentrations and the presence of anti-TSH receptor antibodies. 1/+++. R2 Thyroid ultrasound is unnecessary for diagnosis, but can be useful for assessing the size and homogeneity of the goiter. 2/+. R3. Thyroid scintigraphy is not required for the diagnosis of Graves’ disease. 1/+++. R4. The measurement of T4L and T3L levels is not necessary for the diagnosis of Graves’ disease in children but can be useful for the management and assessment of prognosis. 1/++. R5. In the absence of TSH receptor autoantibodies, the possibility of genetically inherited hyperthyroidism must be considered. 1/++. R6. Drug therapy is the primary line of treatment for children and consists of imidazole, carbimazole or thiamazole, with an initial dosage of 0.4 to 0.8mg/kg/day (0.3 to 0.6mg/kg/day for thiamazole) depending on the initial severity, up to maximum of 30mg. 1/++. R7. Propylthiouracil is contraindicated for children with Grave's disease. 1/+++. R8. Before starting treatment, it may be useful to perform a CBC in order to assess the degree of neutropenia caused by hyperthyroidism. It is not necessary to perform systematic CBCs during follow-up. 2/+. R9. An emergency CBC should be performed if symptoms include fever or angina. If neutrophil counts are <1000/mm3, synthetic antithyroid therapy should be discontinued or decreased and may be permanently contraindicated in severe (<500) and persistent neutropenia. Otherwise treatment may be resumed. 1/++. R10. Transaminases levels should be measured before initiating treatment. Systematic monitoring of liver function is not consensually validated. 2/+. R11. In cases of jaundice, digestive disorders or pruritus, measuring liver enzymes (AST, ALT), total and conjugated bilirubin and alkaline phosphatases is indicated. 1/++. R12. Patients and parents should be informed of the possible side effects of antithyroid agents. 1/+. R13. Therapeutic education of parents and children is important in ensuring the best possible treatment compliance. 2/++. R14. Given the specificities involved in the treatment of Graves’ disease in children, medical care should be provided by a specialist accustomed to treating endocrinopathies in pediatric patients. 2/+. R15. Depending on patient age, the severity of the disease at diagnosis and the persistence of anti-TSH receptor antibodies, the initial course of treatment must take place over an extended period of 3 to 6 years. R16.The anticipated success rates of medical treatment (50% of patients in remission following several years of treatment) should be explained to the family and the child. The possibility that radical treatment may be required in case of failure or intolerance of medical treatment should also be discussed. 1/++. R17.In females with Graves’ disease, it is important to explain that they must undergo an assessment by an endocrinologist before planning future pregnancies, from the start of pregnancy and during the course of pregnancy. This is true in all female patients, even those in remission after medical treatment, or those who have undergone radical treatment. R18.Indications for a radical treatment can arise in cases of: 1/+: contraindication to antithyroid agents; poorly controlled hyperthyroidism due to lack of compliance; relapse despite prolonged medical treatment; a request made by the family and child for personal reasons. R19.Surgery is the radical method of treatment used in children under 5 years of age, or in cases of very large, nodular, or compressive goiters. 2/++. R20. The surgeon's experience in dealing with thyroidectomies in children is likely to be the most significant determining factor in limiting the morbidity of the procedure (alongside any collaboration between a pediatric surgeon and an adult surgeon). 1/++. R21 When radical treatment is indicated, I-131 treatment may be discussed after 5 years (but more often after puberty), if the goiter is not too large. Experience from monitoring Graves’ disease in North American children is reassuring. 1/++.

Immunomodulatory effect of Stinging nettle (Urtica dioica) and Aloe vera (Aloe barbadensis) in broiler chickens

A study was conducted to identify the immunomodulatory effect of Stinging nettle (Urtica dioica) and Aloe vera (Aloe barbadensis) in broiler chicken. A total of 240 birds were divided into 4 treatment groups with 4 replications in each group, each replication containing 15 birds. Treatments were comprised of no Nettle and Aloe vera (T0); Nettle 5% (T1), Aloe vera @5 ml/lit drinking water (T2) and Nettle 5% and Aloe vera @5 ml/lit drinking water (T3). The study was conducted under a randomized design. The immunomodulating effect was evaluated by measuring antibody titer against NDV vaccine; and by estimating the albumin, globulin and total protein upto 40 days of age. The effect on liver was estimated by measuring liver enzymes alanine aminotransferase (ALT). The hypoglycemic effect was estimated by measuring glucose level in the serum, and morphological changes in the spleen and bursa were estimated by measuring the ratio score of the respective organs to the body weight. Throughout the experiment, the value for HI titer, albumin, globulin, total protein, spleen weight ratio score, bursa weight ratio score, liver function test and blood glucose of all treatment group were non significant (p > 0.05) except for albumin on 10th day, globulin on 0th day, total protein on 0th day and ratio score of spleen were found to be significant (p ≤ 0.05) at 30 days in all treatment compared to control group. Histopathology of spleen and bursa appeared normal in all treatment and control groups. Result thus suggests that nettle and Aloe vera have non-significant immunomodulatory effects.

Risk of Nonalcoholic Fatty Liver Disease (NAFLD)-Related Liver Complications in the Diabetic Population in Israel

In the absence of early non-invasive diagnostic tools, the burden of NAFLD and its related complications in the diabetic (DM) population remains unclear. Using longitudinal data and defined criteria to identify NAFLD patients, this study evaluated the incidence of NAFLD-related liver complication in DM vs. non-DM population. The study utilized the computerized database of a nationally representative payer-provider health fund, including all members enrolled in year 2000 (index) without viral hepatitis or excess alcohol intake. NAFLD was defined as at least 2 of the following criteria: 2+ measurements of elevated liver enzymes (&amp;gt;2 upper normal limit), NAFLD Fibrosis score&amp;gt;-1.455, coded NAFLD Diagnoses, or imaging evidence using natural language processing of 1 million ultrasonography text reports. Cirrhosis, liver transplant and hepatocellular carcinoma (HCC), were detected by diagnoses, procedures, and the national cancer registry. DM was defined using a previously validated registry. Incidence density rates based on person years (PY) since index were compared between NAFLD cases vs. age and sex matched controls (2:1 ratio). The incidence was further stratified by the presence of DM. The total population included 1,083,4subjects with a mean follow-up of 15.1 years (SD=4.2).Out of these, n=61,644 were identified as NAFLD, with a mean age of 52.1 years (SD=13.6) and 23.4% with DM when they met the criteria for NAFLD. The incidence of cirrhosis, HCC and liver transplant was substantially higher in NAFLD cases as compared with matched controls with rate ratios of 5.6 (95% CI: 5.2-6.0), 1.3 (1.2-1.4) and 3.9 (2.9-5.2) respectively. After stratification by DM, rate ratios were 2.2 (95% CI: 2.0-2.3) for cirrhosis, 2.1 (1.8-2.5) for HCC and 2.5 (1.7-3.5) for liver transplant in NAFLD with DM vs. NAFLD without DM. This study shows that patients identified with NAFLD had higher rates of liver complications and these rates were increased among patients with DM. Disclosure I. Goldshtein: None. G. Fernandes: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; Janssen Research &amp; Development. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Spouse/Partner; Janssen Research &amp; Development. G. Chodick: None. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc. A. Karasik: Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Merck &amp; Co., Inc., GlucoMe.

Monitoring liver damage using hepatocyte-specific methylation markers in cell-free circulating DNA.

Liver damage is typically inferred from serum measurements of cytoplasmic liver enzymes. DNA molecules released from dying hepatocytes are an alternative biomarker, unexplored so far, potentially allowing for quantitative assessment of liver cell death. Here we describe a method for detecting acute hepatocyte death, based on quantification of circulating, cell-free DNA (cfDNA) fragments carrying hepatocyte-specific methylation patterns. We identified 3 genomic loci that are unmethylated specifically in hepatocytes, and used bisulfite conversion, PCR, and massively parallel sequencing to quantify the concentration of hepatocyte-derived DNA in mixed samples. Healthy donors had, on average, 30 hepatocyte genomes/ml plasma, reflective of basal cell turnover in the liver. We identified elevations of hepatocyte cfDNA in patients shortly after liver transplantation, during acute rejection of an established liver transplant, and also in healthy individuals after partial hepatectomy. Furthermore, patients with sepsis had high levels of hepatocyte cfDNA, which correlated with levels of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Duchenne muscular dystrophy patients, in which elevated AST and ALT derive from damaged muscle rather than liver, did not have elevated hepatocyte cfDNA. We conclude that measurements of hepatocyte-derived cfDNA can provide specific and sensitive information on hepatocyte death, for monitoring human liver dynamics, disease, and toxicity.

The protective effect of selenium nanoparticles and selenium against paracetamol

Objective(s): Nanotechnology has enabled researchers to synthesize nanosize particles that possess increased surface areas. Compared to conventional microparticles, it has resulted in increased interactions with biological targets.The objective of this study was to determine the protective ability of selenium nanoparticles compared to selenium against parasetamol hepatotoxicity and GPX concentration. Materials and Methods: Seventy-two male rats were used in the study, and arbitrarily assigned to six groups. There were 12 rats in each group that six rat were tested in each period. Blood samples were collected from rats for measuring liver enzymes and GPX activity. Results: The present study shows that parasetamol has a toxic effect on the liver as a result of inducing a marked oxidative damage and release of reactive oxygen species. This was shown by the significant increases in ALP, AST, ALT and LDH activity which was accom­panied by significant decrease in GPX activity in the parasetamol -treated group compared to the control, selenium and selenium nanoparticles groups. There was no significant difference between selenium and selenium nanoparticles groups and two period time (15 and 30 day). Conclusion: selenium nanoparticles and selenium have protective against paracetamol.

Morin enhances hepatic Nrf2 expression in a liver fibrosis rat model.

AIMTo investigate whether morin can reduce hepatic fibrosis by activating the NF-E2-related factor 2 (Nrf2) signaling pathway.METHODSTwenty male Sprague-Dawley rats were randomly divided into four groups: control group, morin group, carbon tetrachloride (CCl4) group, and morin + CCl4 group. Rats in both the CCl4 and morin + CCl4 groups were injected intraperitoneally with CCl4 at a dose of 2 mL/kg twice a week. Rats in both the morin and morin + CCl4 groups were treated orally with morin at a dose of 50 mg/kg twice a week. Control rats were treated with vehicle only twice a week. At the end-point of the 8 wk of the experimental period, serum AST, ALT, and ALP were measured, and the liver specimens were obtained for pathological assessment. Real-time PCR and Western blot methods were used to analyze the expression of α-smooth muscle actin (α-SMA), collagen I, collagen III, Nrf2, heme oxygenase (HO-1), and quinone oxidoreductase 1 (NQO1) using frozen liver specimens.RESULTSMorin-treated rats in the morin + CCl4 group had less hyperplasia of fiber tissue, minimal inflammatory cells, and less body weight loss with favorable liver enzyme measurements compared to rats treated with CCl4 only. Additionally, morin-treated rats had significantly lower mRNA and protein expression of α-SMA, collagen I, and collagen III, but significantly higher mRNA and protein expression of Nrf2, HO-1, and NQO1 compared to rats treated with CCl4 only (P < 0.05).CONCLUSIONMorin could play a protective role by inducing the expression of Nrf2 and its downstream antioxidant factors (HO-1 and NQO1) and reducing the expression of α-SMA, collagen I, and collagen III in CCl4-induced liver fibrosis rats.

MANAGEMENT OF ACUTE ALUMINUM PHOSPHIDE TOXICITY IN RAT MODEL WITH A NOVEL INTERVENTION, A TRIAL OF BORIC ACID

Aluminum phosphide (AlP) or rice tablet is a cheap pesticide. When it comes in contact with acid (gastric acid) or moisture, it releases phosphine (PH3) gas. The heart, lungs, liver are the main targets in acute Aluminum phosphide (AlP) poisoning. Most deaths occur due to cardiovascular toxicity. Recently, boric acid has been proposed theoretically as an antidote for AlP poisoning. With the formula B (OH)3, boric acid can accept electrons as it is a Lewis acid with an empty p orbital. The aim of the present study was to investigate the possible protective role of boric acid in management of aluminum phosphide poisoning and its possible use as an effective antidote to reduce ALP poisoning mortality. Forty albino rats, all of which were adults and males were equally divided into four groups, group 1: control (given distilled water), group 2: given boric acid only (100mg/kg nontoxic dose), group 3: given aluminum phosphide (12.5 mg/kg), group 4: given aluminum phosphide followed by boric acid. Rats in group 1 and 2 was killed by cervical dislocation, while rats in group 3 and 4 were left to die, then all were dissected out. Fixation in situ was performed by perfusion technique then the chest and the abdomen were carefully incised to reveal the heart and the liver. The liver and the heart were washed with saline then quickly dissected, excised then blotted for histological preparation. Blood samples were collected from each rat (immediately after death) for measuring liver enzymes (SGOT, SGPT, ALK (alkaline phosphatase) and cardiac troponin. Rats treated with ALP followed by boric acid showed significant increase in their survival time, marked improvement in histopathological changes and also showed significant improvement in biochemical parameters including liver and cardiac markers (SGOT, SGPT, and cardiac troponin) compared with rats intoxicated with AlP. Conclusion: This study may increase the hope of using boric acid as a new effective antidote for ALP poisoning and opens the door of opportunity for larger experimental and then clinical trials to reevaluate the role of boric acid in acute ALP poisoning.

Determination of the Liver Enzymes Level and Kidney Functions in Pregnant Women in the Second Trimester of Pregnancy at Different Age Groups

The level of liver enzymes and kidney functions in pregnant women in the second trimester of pregnancy at different age groups was determined. This study is composed of fifty pregnant women in the second trimester of pregnancy and were classified into two subgroups; first group included twenty-five pregnant with an age between 22-30 years, a second group included twenty-five pregnant with an age 35-42 years. A control group included twenty-five non-pregnant, healthy women was also included. Blood samples were obtained from each group, centrifuged, serum was collected from each group to measure liver enzymes (AST, ALT and ALP) and kidney function tests (urea and creatinine) were measured using enzymatic kits. The results of present study illustrated significant elevation (P≤ 0.05) in AST and ALT means in the age group 35- 42 years, while there were no-significant differences in an age group 22- 30 compared with control healthy group. In addition, the ALP mean values are significantly increase(P≤0.05) in 22- 30 and 35- 42 years compared with non-pregnant women. The findings also demonstratedthat the means of blood urea is significantly declined (P≤0.05) in the age groups 22- 30 and 35- 42 years compared with healthy non-pregnant. This studyfoundsignificant decline(P≤0.05) in serum creatinine at an age group 22- 30 and significant increase(P≤0.05) in the other group (35- 42 years) compared with the control. The conclusion of the present study that hepatic and renal functions are more damaged in an age group 33- 42 years than an age group 22- 30 years through the values of parameters above. Therefore, pregnancy in the age 22- 30 years is more healthyfor both mother and fetus than an age 33- 42 years.

Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53.

Chemicals, toxicants, and environmental stressors mediate their biologic effect through specific modes of action (MOAs). These encompass key molecular events that lead to changes in the expression of genes within regulatory pathways. Elucidating shared biologic processes and overlapping gene networks will help to better understand the toxicologic effects on biological systems. In this study we used a weighted network analysis of gene expression data from the livers of male Sprague-Dawley rats exposed to chemicals that elicit their effects through receptor-mediated MOAs (aryl hydrocarbon receptor, orphan nuclear hormone receptor, or peroxisome proliferator-activated receptor-α) or non-receptor-mediated MOAs (cytotoxicity or DNA damage). Four gene networks were highly preserved and statistically significant in each of the two MOA classes. Three of the four networks contain genes that enrich for immunity and defense. However, many canonical pathways related to an immune response were activated from exposure to the non-receptor-mediated MOA chemicals and deactivated from exposure to the receptor-mediated MOA chemicals. The top gene network contains a module with 33 genes including tumor suppressor TP53 as the central hub which was slightly up-regulated in gene expression compared to control. Although, there is crosstalk between the two MOA classes of chemicals at the TP53 gene network, more than half of the genes are dysregulated in opposite directions. For example, Thromboxane A Synthase 1 (Tbxas1), a cytochrome P450 protein coding gene regulated by Tp53, is down-regulated by exposure to the receptor-mediated chemicals but up-regulated by the non-receptor-mediated chemicals. The regulation of gene expression by the chemicals within MOA classes was consistent despite varying alanine transaminase and aspartate aminotransferase liver enzyme measurements. These results suggest that overlap in toxicologic pathways by chemicals with different MOAs provides common mechanisms for discordant regulation of gene expression within molecular networks.

Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice.

Ischemia–reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-α and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen-activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver.

HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy-treated HIV/HCV-co-infected subjects.

The impact of hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viraemic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 ART-treated HIV/HCV genotype 1 co-infected) were studied. Clinical and liver enzyme measurements were performed. Whole blood was analysed for immune subset changes by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced signal transducer and activator of transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production. Statistical analysis was performed using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T-cell activation/exhaustion, and constitutive STAT-1 phosphorylation compared to HCV. In contrast, CD4+ FoxP3+ CD25+ frequency, IFN-αR expression on NK cells, as well as constitutive and IFN-α-induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load and CD4+ T-cell count had an opposite effect between the two groups on NK cell activity and T-cell activation, respectively. HCV viral load in ART-treated HIV/HCV co-infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono-infection. The more pronounced immune modulation noted in ART-treated HIV-co-infected/untreated HCV viraemic subjects may impact HCV disease progression and/or response to immunotherapy.

Prevalence of elevated liver enzymes in adults with type 1 diabetes: A multicentre analysis of the German/Austrian DPV database.

To assess the prevalence of elevated liver enzymes in adults with type 1 diabetes mellitus (T1DM) in routine clinical care and the association with cardiovascular risk profile in the Diabetes-Prospective-Documentation (DPV) network in Germany and Austria. This cross sectional observational study from the DPV registry includes data from 45 519 adults with T1DM at 478 centres up to September 2016. Liver enzyme measurements were available in 9226 (29%) patients at 270 centres and were analysed for increased alanine aminotransferase (ALT; men >50 U/L, women >35U/L) and/or aspartate aminotransferase (AST; men >50 U/L, women >35U/L) and/or gamma-glutamyltransferase (GGT; men >60U/L, women >40 U/L). A subgroup analysis in patients for whom 2 or more ALT measurements were available (n = 2335, 25%) and whose ALT was increased at least twice (men >30 U/L, women >19U/L) was performed. Associations with glycaemic control, cardiovascular risk factors and late complications were investigated with multiple regression analyses. Twenty percent (19.8%, n = 1824) had increased liver enzyme(s) on one or more occasions. Increased liver enzymes were associated with worse glycaemic control and higher BMI (both P < .0001), dyslipidemia (OR, 1.75; 95% CI, 1.54-2.0), hypertension (OR, 1.48; 95% CI: 1.31-1.68), myocardial infarction (OR, 1.49; 95% CI, 1.17-1.91) and end stage renal disease (OR, 1.59; 95% CI, 1.17-2.17). ALT was increased twice in 29% and was associated with worse glycaemic control (P < .0001), higher BMI (P < .0001), hypertension (OR, 1.58; 95% CI, 1.26-1.97) and dyslipidemia (OR, 1.89; 95% CI, 1.51-2.37). In this clinical audit in adults with T1DM, elevated liver enzymes on routine assessment were associated with a less favourable cardiovascular risk profile and with poorer glycaemic control.

Thiopurines and Methotrexate Use in IBD Patients in a Biologic Era.

Although we have been living in the era of biologic therapy for several decades, the use of immunomodulators (primarily thiopurines [azathioprine and mercaptopurine] and less so methotrexate) still remains an important component of the inflammatory bowel disease (IBD) pharmaceutical arsenal. Thiopurines as monotherapy exert corticosteroid-sparing effects and can maintain long-term remission in a considerable proportion of patients who have frequent relapses and are or have become mesalazine and/or corticosteroid intolerant or refractory. Withdrawal of thiopurines results in relapse of disease in a significant proportion of patients. Thiopurines enhance the induction effect of anti-TNFα biologics and can reinstate disease remission in patients who lose response to anti-TNF monotherapy. In thiopurine-naïve ulcerative colitis (UC) patients with iv corticosteroid-refractory disease, thiopurines offer an excellent maintenance strategy after cyclosporine rescue therapy. They also prevent the postoperative recurrence of Crohn's disease, especially in smokers, and can achieve response or remission in uncomplicated perianal fistulizing disease. Close monitoring of patients with sequential measurements of complete blood count, liver enzymes, serum and fecal biomarkers, and/or thiopurine metabolites is essential to assess efficacy, safety, and adherence to treatment. Adverse reactions are dose dependent or idiosyncratic. Idiosyncratic reactions to azathioprine, except pancreatitis, can be treated by switching to mercaptopurine or 6-thioguanine. Thiopurines increase the relative risk for skin, urinary tract, and lymphoid tissue malignancies but the absolute risk is low. Preventive measures include sunlight protection and annual Pap smears (females). The use of antimetabolite therapy in patients over the age of 65years is generally avoided. Methotrexate has advantages over thiopurines subsequent to its once weekly dosing, faster onset of action, and better safety profile relating to malignancies; however, its parenteral administration, contraindication in pregnancy and lactation, and its misconceptions particularly related to hepatotoxicity have reserved its use as a second-line therapy, i.e., when thiopurines fail. Yet, methotrexate in combination with a tapering dose of corticosteroids is an effective agent for active luminal Crohn's disease. In combination with infliximab is preferred for pediatric patients and adolescent IBD male patients who have not contracted the Epstein-Barr virus. Methotrexate also reduces the immunogenicity of infliximab. Folic acid supplementation and close monitoring with blood tests and renal and liver function tests are essential to prevent toxicity especially in patients with diabetes mellitus, non-alcoholic liver fatty disease (NAFLD), malnutrition, and renal function impairment.

Quercetin protects liver injury induced by bile duct ligation via attenuation of Rac1 and NADPH oxidase1 expression in rats

Bile duct ligation (BDL) and subsequent cholestasis are correlated with oxidative stress, hepatocellular injury and fibrosis. Quercetin is a flavonoid with antifibrotic, and hepatoprotective properties. However, the molecular mechanism underlying quercetin-mediated hepatoprotection is not fully understood. The current study was to evaluate mechanisms of hepatoprotective effect of quercetin in BDL rat model. We divided male Wistar rats into 4 groups (n=8 for each): sham, sham+quercetin (30 mg/kg per day), BDL, and BDL+quercetin (30 mg/kg per day). Four weeks later, the rats were sacrificed, the blood was collected for liver enzyme measurements and liver for the measurement of Rac1, Rac1-GTP and NOX1 mRNA and protein levels by quantitative PCR and Western blotting, respectively. Quercetin significantly alleviated liver injury in BDL rats as evidenced by histology and reduced liver enzymes. Furthermore, the mRNA and protein expression of Rac1, Rac1-GTP and NOX1 were significantly increased in BDL rats compared with those in the sham group (P<0.05); quercetin treatment reversed these variables back toward normal (P<0.05). Another interesting finding was that the antioxidant markers e.g. superoxide dismutase and catalase were elevated in quercetin-treated BDL rats compared to BDL rats (P<0.05). Quercetin demonstrated hepatoprotective activity against BDL-induced liver injury through increasing antioxidant capacity of the liver tissue, while preventing the production of Rac1, Rac1-GTP and NOX1 proteins.