Plasma Concentrations Of Alanine Aminotransferase Research Articles

Drinking magnetized water alters blood constituents, and structure of spleen and kidney in rabbits

This study aimed to investigate the effect of magnetic field on physicochemical properties of water and evaluating the effects of the magnetized water (MW ) on the productive performance, liver enzymes, spleen and kidney structure of rabbits. Water samples were collected to determine pH and electrical conductivity (EC), and water structure was investigated by Transmission Electron Microscopy (TEM). Twenty-four weaned Rex rabbits, 21 d old, were allotted into two experimental groups: the first group was assigned as control, received regular tap water (TW), and the treated group, received MW, for 5 weeks. Productive traits were recorded weekly and at the end of the experiment, blood samples, spleen and kidney were collected for examinations. Results showed that pH and EC of MW were higher than those of TW. In addition, the arrangement MW cluster showed a unique alteration on the nano-scale. Growth performance indicators were similar in both experimental treatments, except FCR of the MW rabbits was better than that of the TW rabbits. The MW had no significant effect on plasma concentration of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine in growing Rex rabbits received MW in comparison with those received regular TW. Spleen histological structure of rabbits of both groups was normal. However, the epithelial cells lining renal tubules of kidneys of rabbits in MW group appeared large with basophilic nuclei in comparison with TW group. Conclusively, magnetic field alters the physicochemical properties of water. The MW may consequently increase blood glucose level and spleen weight % and enhance kidney structure in growing rabbits. Moreover, more studies are still needed to know the benefits of providing the magnetized water to ‎animals. ‎

Status of some biochemical markers in Sprague dawley rats following sub-chronic consumption of alum- treated water

Alum is a double salt of aluminum and potassium sulfates. The aim of this study was to investigate the status of some biochemical markers in Sprague-dawley rats following sub-chronic consumption of alum- treated water. It consisted of 21 rats of 3–4 months old weighing roughly 122 ± 0.5 g. They were divided into three groups at random with 7 rats / group. The control group received 15 ml of distilled water daily for 30 days, while experimental groups one and two received 15ml of 0.04% concentration of alumtreated water for 15 days daily and 30 days respectively. Following this, 5 ml of blood specimen was withdrawn via cardiac puncture and introduced into corresponding lithium heparin anti-coagulated bottles. These specimens were spun at 1,500 revolutions per minute for 10 minutes using an 800 D macro centrifuge to extract the plasma that were utilized for the measurement of alanine aminotransferase, aspartate aminotransferase (colorimetric method), urea (urease Berthelot method), creatinine (Jaffe reaction method) and C-reactive protein (Latex turbidimetry method). Using SPSS 23.0 to perform statistical analysis on the study's findings, it was discovered that there were no significant differences between the experimental group one and the control group for all the measured biochemical parameters (p>0.05). However, in comparison to the control group, the results of the experimental group two revealed significant elevations (p<0.05) in revealed significant elevations (p<0.05) in plasma levels of alanine aminotransferase, aspartate aminotransferase and C-reactive protein. It is concluded that the plasma concentrations of alanine aminotransferase, aspartate aminotransferase and C-reactive protein may be altered in Sprague-dawley rats following consumption of 15 ml of 0.04% concentration of alum- treated water for 30 days. Thus, it is recommended that this study in a well guided manner be carried out in humans to ascertain if the findings will be consistent.

A Real-World Study on the Use of the Alcohol Use Disorders Identification Test (AUDIT) in Men Admitted to a Psychiatric Hospital.

BackgroundThis real-world study aimed to investigate the use of the Alcohol Use Disorders Identification Test (AUDIT) in men admitted to a psychiatric hospital.Material/MethodsThe AUDIT questionnaire (10 items) was consecutively administered for a period of 3 years to male patients admitted to a psychiatric hospital (n=636). Laboratory blood tests of biochemical parameters were measured as biomarkers of alcohol consumption. Data were evaluated using linear models with mixed effects in the case of continuous dependent variables and logistic regression models with mixed effects in the case of categorical dependent variables.ResultsWe found that 45.3% of the patients had a high risk of alcohol consumption or alcohol dependence and 54.7% had a low risk of alcohol consumption. The ICD-10 diagnoses of alcohol-related disorders (F1x), psychotic disorders (F2x), affective disorders (F3x), neurotic and psychosomatic disorders (F4x) were statistically significantly associated with total AUDIT score (P<0.001). There was a statistically significant association between the total AUDIT score and length of hospitalization (P=0.004) and the incidence of suicidal thoughts (P=0.003). Plasma concentrations of alanine aminotransferase (P=0.005), aspartate aminotransferase (P<0.001), gamma glutamyltransferase (P=0.001), total cholesterol (P=0.027) and mean corpuscular value of erythrocytes (P<0.001) were statistically significantly increased with a higher AUDIT score.ConclusionsThis real-world study showed that the AUDIT questionnaire evaluated the severity of disorders caused by alcohol and their impact on comorbid mental disorders. These results may be helpful in improving targeted interventions in this group of patients.

Resveratrol Reduces Glucolipid Metabolic Dysfunction and Learning and Memory Impairment in a NAFLD Rat Model: Involvement in Regulating the Imbalance of Nesfatin-1 Abundance and Copine 6 Expression.

Resveratrol (RES) is a polyphenolic compound, and our previous results have demonstrated its neuroprotective effect in a series of animal models. The aim of this study was to investigate its potential effect on a nonalcoholic fatty liver disease (NAFLD) rat model. The parameters of liver function and glucose and lipid metabolism were measured. Behavior performance was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST), and the Morris water maze (MWM). The protein expression levels of Copine 6, p-catenin, catenin, p-glycogen synthase kinase-3beta (GSK3β), GSK3β, and cyclin D1 in the hippocampus and prefrontal cortex (PFC) were detected using Western blotting. The results showed that RES could reverse nesfatin-1-related impairment of liver function and glucolipid metabolism, as indicated by the decreased plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), glucose, insulin, and nesfatin-1; increase the plasma level of high-density lipoprotein cholesterol (HDL-C); and reduce hepatocyte steatosis in NAFLD rats. Although there was no significant difference among groups with regard to performance in the OFT, EPM, and FST tasks, RES-treated NAFLD rats showed an increased sucrose preference index in the SPT and improved learning and memory ability in the MWM task. Furthermore, the imbalanced protein expression levels of Copine 6, p-catenin, and p-GSK3β in the hippocampus and PFC of NAFLD rats were also restored to normal by treatment with RES. These results suggested that four consecutive weeks of RES treatment not only ameliorated glucolipid metabolic impairment and liver dysfunction in the NAFLD rat model but also mitigated the attendant behavioral and cognitive impairments. In addition to the mediating role of nesfatin-1, the mechanism underlying the therapeutic effect of RES on NAFLD might be associated with its ability to regulate the imbalanced expression level of Copine 6 and the Wnt signaling pathway in the hippocampus and PFC.

Small heterodimer partner deficiency exacerbates binge drinking‑induced liver injury via modulation of natural killer T cell and neutrophil infiltration.

Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol-associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor small heterodimer partner (SHP), which is encoded by the NR0B2 gene, in acute binge drinking-induced liver injury was investigated. SHP-knockout (KO) and wild-type (WT) control mice were intragastrically administered single doses of alcohol. The plasma concentrations of alanine aminotransferase and aspartate aminotransferase in SHP-KO mice following alcohol treatment were significantly increased compared with WT mice. However, results of oil red O staining and 2′,7′-dichlorodihydrofluorescein diacetate staining indicated that levels of acute binge drinking-associated hepatic lipid accumulation and oxidative stress were not significantly different between WT and SHP-KO alcohol-treated mice. Notably, tumor necrosis factor-α mRNA expression in the liver of SHP-KO mice was significantly increased following alcohol administration, compared with WT mice. Furthermore, the mRNA expression levels of C-C motif chemokine ligand 2, C-X-C motif chemokine ligand 2 and interleukin-4, which are all potent chemoattractants of NKT cells, as well as neutrophil expression levels, were significantly increased in the livers of SHP-KO mice compared with WT mice following alcohol administration, as determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry. Enhanced infiltration of NKT cells, determined by flow cytometry, was also demonstrated in the livers of SHP-KO mice following alcohol administration, compared with WT mice. The results of the present study indicate that SHP may be involved in liver-associated protective mechanisms, with regards to the attenuation of damage caused by acute binge drinking, via regulation of NKT cell and neutrophil migration to the liver. The modulation of SHP may be a novel therapeutic strategy for the treatment of acute binge drinking-induced liver injury.

Impaired learning and memory in rats induced by a high-fat diet: Involvement with the imbalance of nesfatin-1 abundance and copine 6 expression.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, resulting not only in liver dysfunction, glucose and lipid metabolism disorder, but also in neuropsychiatric damage. In the present study, a NAFLD rat model was established via feeding of a high-fat diet, and behaviour was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST) and the Morris water maze (MWM). The plasma concentrations of alanine aminotransferase (ALT), glucose, free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin and insulin were measured via enzyme-linked immunosorbent assay, and the protein expressions of p-glycogen synthase kinase-3β (GSK-3β), GSK-3β, p-β-catenin, β-catenin, cyclinD and copine 6 in the hippocampus and prefrontal cortex (PFC) were detected using western blotting. After 4 consecutive weeks of feeding with a high-fat diet, the rats showed obesity; increased plasma concentrations of ALT, glucose, FFA, TC, TG, HDL-C and LDL-C; decreased plasma levels of leptin and insulin; and inflammation and mild hepatocyte steatosis in the liver. Although there was no significant difference between groups with regard to performance in the OFT, EPM or FST, the NAFLD rats showed a decreased sucrose preference index in the SPT and impaired learning and memory in the MWM task. Moreover, the present study provides the first evidence of an increased plasma nesfatin-1 concentration in NAFLD rats, which was significantly correlated with plasma lipid concentrations and behavioural performance. Furthermore, copine 6 and p-β-catenin protein expression decreased and p-GSK-3β increased in the hippocampus and PFC of NAFLD rats. These results suggest that consuming of a high-fat diet for 4 consecutive weeks could successfully induce a NAFLD rat model. More importantly, these results provide the first evidence that impaired learning and memory in NAFLD rats was, at least partly, associated with increased plasma nesfatin-1 concentration and decreased copine 6 expression in the hippocampus and PFC.

Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis. Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP. Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis. These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.

Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats.

To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects. The conjugate halved the α-2-M liver mRNA (3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein (201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver mRNA or serum levels of α-2-M. Also, the conjugate reduced TNF-α (7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6 (15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight (421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group. Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.

Feeding a high-grain diet reduces the percentage of LPS clearance and enhances immune gene expression in goat liver.

BackgroundThe effects of feeding a high-grain (HG) diet on lipopolysaccharide (LPS) clearance and innate immune defence responses in the liver remain unclear. Therefore, we conducted the present study in which twelve female goats were randomly assigned to either a treatment group fed a HG diet (60% grain, n = 6) or a control group fed a low grain diet (LG; 40% grain, n = 6) for 6 weeks. Catheters were installed in the mesenteric, portal and hepatic veins, as well as one femoral artery of the goats, for determining blood flow and net clearance rate of LPS in the liver. Plasma and tissue samples were collected in the week 6 for analyzing pro-inflammatory cytokines, acute phase protein and biochemical parameters, as well as expression of genes involved in immune response.ResultHG diet feeding increased blood flow and LPS concentration in the portal vein, hepatic vein and artery. Hepatic net LPS clearance showed that HG diet feeding elevated the rate of hepatic LPS clearance, but decreased the percentage of removed LPS accounting for the total entry of LPS into the liver. Our results demonstrated that the feeding of HG diet increased plasma concentrations of pro-inflammatory cytokines and acute phase proteins and triggered a systemic inflammatory response. In addition, peripheral blood plasma concentrations of alanine aminotransferase, alkaline phosphatase and total bilirubin were increased in the HG group compared to the LG group. This indicated that the impairment of hepatocytes occurred after 6 weeks of HG diet feeding. The expression of genes involved in immune response and Toll-like receptor (TLR)4 protein in the liver was up-regulated in the HG group compared to the LG group, indicating that increased entry of LPS enhanced hepatic immune defence responses and contributed to hepatic inflammatory responses.ConclusionThese results provide insight into the capacity of the liver to clear LPS. The increased entry of LPS into liver enhanced hepatic immune defence responses, thereby elevated the rate of LPS clearance. However, the reduction of the percentage of hepatic LPS clearance could be due to the formation of hepatocyte lesion during HG diet feeding.

Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.

Prevalence and associated metabolic factors of fatty liver disease in the elderly

ObjectiveThe aim of this study was to investigate the metabolic risk factors for fatty liver disease in the elderly, and determine the prevalence of fatty liver disease in the elderly in Wuhan, central China. MethodsThe study was a case–control study based on all 4226 adults above 60years of age from a cohort investigated in 2010–11 at the medical examination center of Zhongnan hospital, using 3145 randomly selected adults under 60years of age from the same cohort as controls. Fatty liver disease (FLD) was identified with ultrasound imaging. The risk factors measured were body mass index (BMI), and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) and serum uric acid (SUA). The probability of steatohepatitis with advanced fibrosis was predicted using a score based on BMI, age, ALT, and TG (BAAT),and using AST/ALT ratio (AAR). ResultsFLD was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, p>0.05). BMI, TC, TG, LDL, SUA, AST and ALT were all significantly higher in FLD, whereas the level of HDL was markedly lower. Multiple regression analyses showed that obesity, high TC, TG, SUA, low HDL, and elevated ALT, AAR<1 were closely related to the elderly FLD, while male sex, obesity, high TC, TG, low HDL, elevated ALT, AST and AAR<1 were closely related to the non-elderly FLD. The prevalence of steatohepatitis with advanced fibrosis estimated as BAAT index≥3 was 2.4% in all subjects, and was higher in the elderly FLD patients than in the non-elderly FLD patients. ConclusionThe prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the non-elderly FLD controls.

Inhalation of hydrogen gas reduces liver injury during major hepatotectomy in swine.

To study the effect of H2 gas on liver injury in massive hepatectomy using the intermittent Pringle maneuver in swine. Male Bama pigs (n = 14) treated with ketamine hydrochloride and Sumianxin II as induction drugs followed by inhalation anesthesia with 2% isoflurane, underwent 70% hepatotectomy with loss of bleeding less than 50 mL, and with hepatic pedicle occlusion for 20 min, were divided into two groups: Hydrogen-group (n = 7), the pigs with inhalation of 2% hydrogen by the tracheal intubation during major hepatotectomy; contrast-group (n = 7), underwent 70% hepatotectomy without inhalation of hydrogen. Hemodynamic changes and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA) in liver tissue were measured at pre-operation, post-hepatotectomy (PH) 1 h and 3 h. The apoptosis and proliferating cell nuclear antigen (PCNA) expression in liver remnant were evaluated at PH 3 h. Then we compared the two groups by these marks to evaluate the effect of the hydrogen in the liver injury during major hepatotectomy with the Pringle Maneuver in the swine. There were no significant differences in body weight, blood loss and removal liver weight between the two groups. There was no significant difference in changes of portal vein pressure between two groups at pre-operation, PH 30 min, but in hydrogen gas treated-group it slightly decrease and lower than its in contrast-group at PH 3 h, although there were no significant difference (P = 0.655). ALT and AST in Hydrogen-group was significantly lower comparing to contrast-group (P = 0.036, P = 0.011, vs. P = 0.032, P = 0.013) at PH 1 h and 3 h, although the two groups all increased. The MDA level increased between the two group at PH 1 h and 3 h. In the hydrogen gas treated-group, the MDA level was not significantly significant at pre-operation and significantly low at PH 1 h and 3 h comparing to Contrast-group (P = 0.0005, P = 0.0004). In Hydrogen-group, the HA level was also significantly low to contrast-group (P = 0.0005, P = 0.0005) although the two groups all increased at PH 1 h and 3 h. The expression of cluster of differentiation molecule 31 molecules Hydrogen-group was low to Contrast-group. However, PCNA index (%) was not statistically significant between the two groups (P = 0.802). Microphotometric evaluation of apoptotic index (AI) in terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-stained tissue after hepatotectomy for 3h, the AI% level in the hydrogen was significantly low to contrast-group (P = 0.012). There were no significant difference between Hydrogen-group and contrast-group at pre-operation (P = 0.653, P = 0.423), but after massive hepatotectomy, the TNF-α and IL-6 levels increase, and its in Hydrogen-group was significantly low compared with contrast-group (P = 0.022, P = 0.013, vs. P = 0.016, P = 0.012), respectively. Hydrogen-gas inhalation reduce levels of these markers and relieved morphological liver injury and apoptosis. H2 gas attenuates markedly ischemia and portal hyperperfusion injury in pigs with massive hepatotectomy, possibly by the reduction of inflammation and oxidative stress, maybe a potential agent for treatment in clinic.

Prevalence of abnormal plasma liver enzymes in older people with Type 2 diabetes

To determine the prevalence and distribution of abnormal plasma liver enzymes in a representative sample of older adults with Type 2 diabetes. Plasma concentrations of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase were measured in a randomly selected, population-based cohort of 1066 men and women aged 60-75 years with Type 2 diabetes (the Edinburgh Type 2 Diabetes Study). Overall, 29.1% (95% CI 26.1-31.8) of patients had one or more plasma liver enzymes above the upper limit of the normal reference range. Only 10.1% of these patients had a prior history of liver disease and a further 12.4% reported alcohol intake above recommended limits. Alanine aminotransferase was the most commonly raised liver enzyme (23.1% of patients). The prevalence of abnormal liver enzymes was significantly higher in men (odds ratio 1.40, 95% CI 1.07-1.83), in the youngest 5-year age band (odds ratio 2.02, 95% CI 1.44-2.84), in patients with diabetes duration < 5 years (odds ratio 1.38, 95% CI 1.01-1.90), plasma HbA(1c) ≥ 58 mmol/mol (7.5%) (odds ratio 1.43, 95% CI 1.09-1.88), obese BMI (odds ratio 2.84, 95% CI 1.59-3.06) and secondary care management for their diabetes (odds ratio 1.40, 95% CI 1.05-1.87). However, all these factors combined accounted for only 7.6% of the variation in liver enzyme abnormality. The prevalence of elevated liver enzymes in people with Type 2 diabetes is high, with only modest variation between clinically defined patient groups. Further research is required to determine the prognostic value of raised, routinely measured liver enzymes to inform decisions on appropriate follow-up investigations.

Vitamin A Deficiency Increases Protein Catabolism and Induces Urea Cycle Enzymes in Rats

Chronic vitamin A deficiency induces a substantial delay in the rates of weight and height gain in both humans and experimental animals. This effect has been associated with an impaired nutrient metabolism and loss of body protein. Therefore, we analyzed the effect of vitamin A deficiency on endogenous proteolysis and nitrogen metabolism and its reversibility with all-trans retinoic acid (RA). Male weanling rats, housed in pairs, were pair-fed a vitamin A-deficient (VAD) or control diet until they were 60 d old. A group of deficient rats were further treated with daily intraperitoneal injections of all-trans RA for 10 d. Final body and tissue (i.e. liver and heart) weights were significantly lower and tissue:body weight ratios were similar in VAD rats and in controls. Conversely, the epididymal white fat:body weight ratio and the plasma concentrations of alanine aminotransferase and adiponectin were significantly higher in VAD rats, which also had hepatic macrovesicular lipid accumulations. Plasma and gastrocnemius muscle 3-methylhistidine, urine nitrogen, and plasma and urine urea concentrations were all significantly higher in the VAD group. The expression of the genes encoding urea cycle enzymes and their activities increased in VAD livers. These changes were partially reverted by all-trans RA. We propose that fuel partitioning in vitamin A deficiency may shift from fatty acids to protein catabolism as an energy source. Our results emphasize the importance of vitamin A on the energy balance control system and they provide an explanation for the role of vitamin A in protein turnover, development, and growth.

Effect of Oral Treatment with Pyrazole Carbohydrazide Derivatives against Murine Infection by Leishmania amazonensis

Newly synthesized pyrazole carbohydrazide derivatives with substituents X = Br/Y = NO(2) and X = NO(2)/Y = Cl were independently investigated in the CBA mouse model of cutaneous leishmaniasis. Animals were infected with Leishmania amazonensis and treated two weeks after the parasitic infection with the pyrazole carbohydrazides for 45 days. Oral treatment with both compounds controlled evolution of footpad cutaneous lesions and dissemination of parasites to draining lymph nodes. Nitric oxide generation was observed in supernatants of lymph node cells from infected CBA mice that were treated with these compounds. The pyrazole carbohydrazide derivatives did not show any toxicity or cause alterations in body weight, plasma concentrations of alanine aminotransferase and aspartate aminotransferase, and urinary creatinine levels, but promoted a small decrease in blood neutrophils. These results provide new perspectives on the development of drugs with activities against leishmaniasis.

Serum adiponectin levels and enzyme markers of liver dysfunction in diabetic and non-diabetic Caribbean subjects

Low adiponectin levels are associated with elevated plasma alanine aminotransferase, a marker of reduced hepatic insulin sensitivity and a risk factor for type 2 diabetes. This study aims to determine the relationship between serum adiponectin level and alanine aminotransferase in diabetic and non-diabetic subjects. Fifty-six type 2 diabetic patients and 33 non-diabetic subjects participate in the study. Baseline plasma concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glucose are measured on a chemistry analyser. Insulin and adiponectin are measured using enzyme-linked immunoassay techniques and insulin resistance is determined using the homeostatic model assessment method. Diabetic patients showed significantly lower levels of serum adiponectin than did the non-diabetic subjects, whereas levels of alanine aminotransferase and alkaline phosphatase were similar in both groups. While female non-diabetic subjects showed higher serum adiponectin levels than did female diabetic patients, alanine aminotransferase level did not differ (P>0.05). No significant relationship was seen between adiponectin and alanine aminotransferase in diabetic and non-diabetic subjects (P>0.05). Serum adiponectin levels were higher in non-diabetic subjects but there was no significant correlation between adiponectin and alanine aminotransferase in both groups of subjects. The data suggest that low serum adiponectin level may not be a suitable marker for impaired liver function in diabetic patients.

Nonspecific Phosphodiesterase Inhibition Attenuates Liver Injury in Acute Endotoxemia

Endotoxemia is accompanied by pro-inflammatory cytokine production, generation of reactive oxygen species, and end-organ injury. Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, is known for its anti-inflammatory properties, including down-regulation of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha synthesis. Its effects on liver function and hepatic histology following acute endotoxemia have not been investigated fully. We hypothesized that PTX would preserve liver architecture and function after intravenous lipopolysaccharide (LPS) injection. Anesthetized Sprague-Dawley rats received an i.v. bolus injection of LPS (5 mg/kg), LPS + PTX (25 mg/kg), or saline (sham). Plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-alpha, IL-6, and nitrite were measured at different time points after LPS injection. Liver injury was graded according to a scoring system in a blinded fashion from 0 (normal) to 4 (severe) for hepatocellular necrosis, hemorrhage, and parenchymal and sinusoidal inflammatory infiltrates. Neutrophil infiltration was measured by counting myeloperoxidase (MPO)-positive stained cells. Nuclear factor (NF)-kappaB p-65 was measured by counting positive stained nuclei of hepatocytes and Kupffer cells (KC). Inducible nitric oxide synthase (iNOS) was evaluated by positively stained KC. Data are presented as mean +/- SEM. Analysis of variance with p < 0.05 was considered statistically significant. Animals treated with PTX showed a significant reduction in liver injury score and neutrophil infiltration. Treatment with PTX significantly decreased TNF-alpha, IL-6, and the concentrations of AST and ALT when compared to LPS alone. In addition, a significant decrease in NF-kappaB-positive staining in hepatocytes and KC, as well as in KC iNOS immunostaining was observed in PTX-treated animals compared to the LPS group. Pentoxifylline downregulates the inflammatory response significantly and decreases liver injury in acute endotoxemia.

Ethyl pyruvate reduces liver injury in a murine model of extrahepatic cholestasis.

Ethyl pyruvate has been shown to ameliorate liver injury and decrease expression of several proinflammatory cytokines when used to treat mice with hemorrhagic shock or alcoholic hepatitis. Herein we sought to determine whether delayed treatment with ethyl pyruvate dissolved in a Ringer's-type balanced salt solution--Ringer's ethyl pyruvate solution (REPS)--would be beneficial in a murine model of common bile duct ligation (CBDL)-induced liver injury. Male C57BL/6 mice were subjected to a sham (n = 6) procedure or CBDL (n = 27). Twenty-four hours after operation, mice subjected to CBDL were randomized to receive treatment with either REPS (40 mg/kg of ethyl pyruvate per dose) or Ringer's lactate solution (RLS) every 8 h over a 72 h period. Compared with sham-treated controls, CBDL in RLS-treated mice was associated with histological evidence of hepatocellular necrosis as well as significant increases in the plasma concentrations of alanine aminotransferase and total bilirubin. Relative to sham-treated controls, CBDL in RLS-treated mice also was associated with increased hepatic lipid peroxidation and increased hepatic expression of transcripts for TNF, IL-6, and iNOS. All of these changes were significantly attenuated by delayed treatment with REPS after CBDL. In the RLS-treated group, CBDL was associated with increased NF-kappaB DNA binding in nuclear extracts prepared from liver tissue. Treatment with REPS increased NF-kappaB DNA binding still further. CBDL was associated with increased hepatocellular apoptosis in both the RLS- and REPS-treated groups. These data support the view that ethyl pyruvate ameliorates hepatic inflammation, lipid peroxidation, and necrosis in mice subjected to CBDL. Ethyl pyruvate warrants further evaluation as an adjunctive treatment to ameliorate liver injury from extrahepatic biliary obstruction.

Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice

Ethyl pyruvate dissolved in a calcium-containing balanced salt solution—Ringer's ethyl pyruvate solution (REPS)—ameliorates ileal mucosal hyperpermeability and decreases the expression of several proinflammatory genes when it is used instead of Ringer's lactate solution (RLS) to resuscitate mice from hemorrhagic shock. Herein, we sought to determine whether delayed treatment with REPS would be beneficial in a murine model of acute alcoholic liver injury associated with binge drinking. Mice were gavaged with 3 doses of ethanol (5 g/kg each dose) over a 12-hour period and then randomized to treatment with 3 intraperitoneal doses of REPS or RLS over 12 hours. Compared with sham-treated controls not subjected to alcohol intoxication, RLS-treated mice demonstrated histologic evidence of fatty change and piecemeal necrosis of hepatocytes in the liver, as well as a significant increase in the plasma concentration of alanine aminotransferase. Biochemical changes induced by alcohol administration included increased hepatic lipid peroxidation, nuclear factor-κB activation, and tumor necrosis factor-α messenger RNA expression. All of these alcohol-induced effects were ameliorated by treatment with REPS instead of RLS. These data support the view that treatment with REPS ameliorates the hepatic inflammatory response and decreases hepatocellular injury in mice subjected to acute alcohol intoxication.

IgA against gut-derived endotoxins: does it contribute to suppression of hepatic inflammation in alcohol-induced liver disease?

Endotoxins of intestinal origin are supposed to play an important role in the development of alcoholic hepatitis in man. To estimate the role of immunoglobulin response to gut-derived endotoxin in the development of alcohol-induced liver disease, serum levels of IgA and IgG against fecal endotoxin, endotoxin, and acute-phase proteins were measured in patients with different stages of alcoholic liver disease and in healthy controls. Antibodies of type IgA, but not IgG, against fecal endotoxins were significantly increased in patients with alcohol-induced liver disease. IgA antibodies against fecal endotoxin were found to be closely correlated with the plasma concentrations of alanine aminotransferase, gamma-glutamyl transferase, and C-reactive protein in patients with alcoholic liver disease. In conclusion, as IgA located in body tissue was shown to suppress the inflammatory process, enhanced production of IgA against endotoxin of intestinal origin may contribute to inactivation of this compound, thereby reducing its damaging effect on the liver.