Plasma Levels Of Liver Enzymes Research Articles

Citri Reticulatae Pericarpium (Chenpi) Protects against Endothelial Dysfunction and Vascular Inflammation in Diabetic Rats.

Dried tangerine peel (Citri reticulatae Pericarpium, CRP; Chenpi in Chinese) possesses medicine and food homology with hypolipidemic, anti-inflammatory and antioxidant activities. This study aimed to explore the protective effect of CRP extract on endothelial function and inflammation in type 2 diabetic rats and the related mechanisms. Type 2 diabetes mellitus was induced by high-fat diet (HFD)/streptozotocin (STZ) in male Sprague Dawley rats, and CRP extract was orally administered at 400 mg/kg/day for 4 weeks. Rat and mouse aortas were treated with high glucose and CRP extract ex vivo. The data showed that the ethanolic extract of CRP normalized blood pressure and the plasma lipid profile as well as the plasma levels of liver enzymes in diabetic rats. Impaired endothelium-dependent relaxations in aortas, carotid arteries and renal arteries were improved. CRP extract suppressed vascular inflammatory markers and induced AMPK activation in aortas of diabetic rats. Exposure to high glucose impaired vasodilation in aortas of rats and mice, and this impairment was prevented by co-incubation with CRP extract. In conclusion, our findings suggest that CRP extract protects endothelial function by inhibiting the vascular inflammatory state on activation of AMPK in diabetic rats.

Chiliadenus iphionoides Reduces Body Weight and Improves Parameters Related to Hepatic Lipid and Glucose Metabolism in a High-Fat-Diet-Induced Mice Model of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become an epidemic with increasing prevalence. Limited treatment options and poor adherence emphasize the urgent need for novel therapies for the treatment and/or prevention of NAFLD. Bioactive natural compounds found in medicinal plants are promising as novel therapeutic agents for NAFLD. Chiliadenus iphionoides, a medicinal plant with several health-promoting properties, is an encouraging candidate. The current study aimed to elucidate the metabolic effects of C. iphionoides consumption in a high-fat-diet (HFD)-induced model of NAFLD. Male C57BL/6J mice (n = 40, 7-8-week-old) were fed a HFD (60% fat) with/without 0.5 or 2.5 gr C. iphionoides for fifteen weeks. Diet supplementation with C. iphionoides significantly ameliorated HFD-induced weight gain. Likewise, liver and adipose tissue weights were profoundly lower in the C. iphionoides-fed groups. Reduced liver steatosis in those groups was corroborated by histology, plasma liver enzyme levels, and lipid profile, indicating improved liver function and lipid metabolism in addition to enhanced insulin sensitivity. The addition of C. iphionoides to an obesogeneic diet can beneficially alleviate metabolic alterations and may be a practicable strategy for the management of NAFLD.

Effects of licorice root supplementation on liver enzymes, hepatic steatosis, metabolic and oxidative stress parameters in women with nonalcoholic fatty liver disease: A randomized double-blind clinical trial.

This study aimed to evaluate the effects of licorice root supplementation on liver enzymes, hepatic steatosis, metabolic and oxidative stress parameters in women with nonalcoholic fatty liver disease (NAFLD). In this randomized double-blind, placebo-controlled trial, 60 women with NAFLD were selected and randomly assigned into 2 groups to take 1,000 mg/day powder of licorice root extract or placebo for 12 weeks. In addition, all the patients were advised to follow a weight loss diet and healthy lifestyle. The plasma levels of liver enzymes, glycemic indices, lipid profile, oxidative stress parameters, as well as hepatic steatosis were measured at the beginning and end of the study. Through the 12-weeks period of supplementation, women who received powder of licorice root experienced a statistically significant improvement in alanine aminotransferase (p< .001), insulin (p= .002), insulin resistance (p= .003), malondialdehyde (p< .001) serum levels, and ultrasonographic findings of liver steatosis (p< .001), compared to the placebo group. In conclusion, licorice root supplementation in addition to gradual weight loss and lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD.

Impact of intravenous ferric carboxymaltose on heart failure with preserved and reduced ejection fraction.

AimsHeart failure (HF) is a proinflammatory disease often associated with the onset of iron deficiency (ID). ID alters mitochondrial function, reducing the generation of cellular energy in skeletal muscle and cardiomyocytes. This study aimed to analyse the response of patients with HF to intravenous iron administration according to the type of HF: preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF).Methods and resultsWe conducted a retrospective, single‐centre study of 565 consecutive outpatients diagnosed with HF, recruited over 5 years, who were given intravenous ferric carboxymaltose (FCM) for the treatment of ID [defined as ferritin < 100 μg/L or ferritin 100–300 μg/L with transferrin saturation (TSAT) < 20%]. Clinical, laboratory, and echocardiographic parameters were analysed before and after administration. After FCM administration, overall ferritin, TSAT, and haemoglobin levels increased up to 5‐fold, 1.6‐fold, and 1.1‐fold, respectively, relative to baseline values in HF patients with reduced and preserved ejection fraction (P < 0.0001), with a greater increase in ferritin and TSAT in HFpEF patients. The left ventricular ejection fraction of the overall series improved by 8 percentage points in both types of HF (from 40% to 48%, P < 0.0001). The percentage of patients with normalization of right ventricular function increased by 6.9 points (from 74.1% to 81%) in HFpEF patients and by 6.4 points (from 53% to 59.4%) in the HFrEF subgroup (P < 0.0001). New York Heart Association functional status slightly improved, from a median of 2.4 (interquartile range, IQR: 2–2.7) to 1.9 (IQR: 1.5–2.5; P < 0.0001) after FCM in both types of HF. No changes were noted in plasma levels of liver enzymes, creatinine, or natriuretic peptide (P > 0.05).ConclusionsIntravenous iron administration appeared to improve ejection fraction and cardiac functional status in outpatients with ID and HF with both preserved and reduced ejection fraction.

Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination - A Preclinical Study in Model Mice.

Amyloidogenic protein oligomers are thought to play an important role in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. Previously we demonstrated that oral or intranasal rifampicin improved the cognition of APP-, tau-, and α-synuclein-transgenic mice by reducing the amount of Aβ, tau, and α-synuclein oligomers in the brain. In the present study, to explore more effective and safer medications for dementia, we tested the drug combination of rifampicin and resveratrol, which is a multifunctional natural polyphenol with the potential to antagonize the adverse effects of rifampicin. The mixture was intranasally administered to APP-, tau-, and α-synuclein-transgenic mice, and their memory and oligomer-related pathologies were evaluated. Compared with rifampicin and resveratrol alone, the combinatorial medicine significantly improved mouse cognition, reduced amyloid oligomer accumulation, and recovered synaptophysin levels in the hippocampus. The plasma levels of liver enzymes, which reflect hepatic injury and normally increase by rifampicin treatment, remained normal by the combination treatment. Notably, resveratrol alone and the combinatorial medicine, but not rifampicin alone, enhanced the levels of brain-derived neurotrophic factor (BDNF) and its precursor, pro-BDNF, in the hippocampus. Furthermore, the combination showed a synergistic effect in ameliorating mouse cognition. These results show the advantages of this combinatorial medicine with regards to safety and effectiveness over single-drug rifampicin. Our findings may provide a feasible means for the prevention of neurodegenerative dementia that targets toxic oligomers.

Liver disease with unknown etiology - have you ruled out alpha-1 antitrypsin deficiency?

Although a less well-known consequence of alpha-1 antitrypsin deficiency (AATD) liver disease is the second leading cause of death among patients with the condition. The alpha-1 antitrypsin (AAT) protein is produced by hepatocytes within the liver, which retain pathological variants of AAT instead of secreting the proteinase inhibitor into the systemic circulation. This intracellular retention is caused by inefficient folding and polymerization of mutant AAT and the accumulation of these AAT aggregates leads to diverse manifestations of liver disease, which can present differently in both children and adults. The progression from hepatocyte apoptosis to liver inflammation, fibrosis and cirrhosis, and liver failure is still not fully understood, but in older patients, liver disease can surpass lung disease as the principal cause of death. Liver function tests (LFTs) can measure plasma levels of liver enzymes to assess liver function but require careful interpretation. Non-invasive tests are being developed that can detect early liver disease, but liver biopsy is still the gold standard for assessing liver fibrosis once abnormal LFTs have been detected in a patient. Currently, there is no licensed treatment for AATD-related liver disease (intravenous AAT therapy is not indicated for this purpose), but liver transplantation is associated with positive outcomes and may even slow emphysema progression. Therefore, new strategies are being developed to address treatment of AATD-related liver disease, such as accelerating degradation of mutant AAT and assisting hepatocytes in the folding and secretion of mutant AAT, but these approaches remain at early stages of development.

845-P: Changes in Plasma Levels of Liver Enzymes in Response to Dapagliflozin, Metformin, or Exercise in People with Prediabetes: The PRE-D Trial

Background: Plasma levels of liver enzymes are elevated in prediabetes but may improve in response to weight loss and glucose-lowering interventions. We examined the effects of dapagliflozin, metformin, or exercise on plasma levels of alanine transferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in people with prediabetes. Methods: 120 adults with prediabetes (30-70 years, BMI≥25 kg/m2, HbA1c 5.7-6.4%) were randomized to 13 weeks of dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 min, 5 days/week) or control (habitual living). Fasting plasma levels of ALT, AST, and GGT were measured at baseline and after 6 and 13 weeks of intervention and after 26 weeks of follow-up. Linear mixed-effects models were performed. Results: At baseline, median (Q1;Q3) HbA1c was 5.9% (5.7; 6.1). 17% had elevated ALT levels, 3% elevated AST levels, and 6% elevated GGT levels. ALT and AST levels did not change in response to the interventions (Table 1). Small within-group changes in GGT were observed in the active groups after 6, 13 or 26 weeks, but they did not differ from the control group (P≥0.09 for all comparisons). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in liver function markers compared with habitual living in people with prediabetes. Disclosure M.B. Blond: None. K.K. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H. Amadid: None. L.B. Nielsen: None. M. Ried-Larsen: None. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Faerch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Oil and extract of safflower seed improve fructose induced metabolic syndrome through modulating the homeostasis of trace elements, TNF-α and fatty acids metabolism

Ethnopharmacological relevanceSafflower (Carthamus tinctorius) has many applications in folk medicine. Its oil is used traditionally to treat obesity and other metabolic disorders. The anti-hypercholesterolemic and antioxidant effects of this plant have been well documented, but the anti-inflammatory effects and its role on fatty acid oxidation and homeostasis of trace elements are not fully understood. ObjectiveThe aim of this study was to evaluate the protective effects of different doses of oil and extract of safflower seed against fructose induced metabolic syndrome by investigating the homeostasis of trace elements, TNF-α, and fatty acids metabolism. MethodsEighty adult male Sprague-Dawley rats were randomly divided into ten groups and treated daily for 16 weeks. At the end of the study, plasma levels of liver enzymes, lipid profiles, blood glucose, insulin and TNF-α were measured. The levels of antioxidant enzymes and lipid peroxidation were also measured along with the expression of CD36, fatty acyl-CoA synthetase (FAS), and Carnitine palmitoyl transferase I (CPT-1) beta genes in the liver. ResultsThe antioxidant enzymes activity significantly decreased and lipid peroxidation, lipid profiles, liver enzymes, and TNF-α significantly increased in fructose-induced metabolic syndrome compared to the control groups, as well as the level of some trace elements significantly changed (p < 0.05). Treatment with oil and safflower seed extract in a dose dependent manner could improve biochemical parameters in groups of metabolic syndrome treated with oil and extract compared to metabolic syndrome (p < 0.05). The results also showed that the expression of above mentioned genes significantly increased in groups of metabolic syndrome treated with oil and extract compared to control and metabolic syndrome groups (p < 0.05). ConclusionIt can be concluded that safflower seed extract and its oil can improve fructose-induced metabolic syndrome through antioxidant and anti-inflammatory effects, adjustment of homeostasis of trace elements, and enhancing the beta-oxidation capacity of the liver by increasing the expression of CD36, FAS, and CPT-1beta genes.

Abuse of androgenic anabolic drugs with “Cycling” induces hepatic steatosis in adult male mice

BackgroundThe importance of the present study comes from the lack of sufficient information about the reversibility of the potential hepatic histopathological alterations which may result from anabolic androgenic drugs abuse by “Cycling” protocol. So, the aim of this study is to explore the negative effects of Deca-Durabolin abuse in hepatic function and structure during an administration cycle. MethodsFor our purpose, study was performed on 40 male adult mices. Animals were divided into five groups of 8 animals each treated weekly by Deca-Durabolin (nandrolone decanoate) at 30 g/kg of BW during one month (GI); during two months (GII); during three months (GIII); during three months followed by six weeks of treatment discontinuation (GIV) and Control (C). Plasma assay of liver enzymes (ALT and AST) and cytohistological examination to determine the histopathological damage properties of the liver were performed. ResultsOur results showed that the animals supported very well the administrated substance. Our study showed an increase in plasma levels of liver enzymes (ALT and AST) with the duration of treatment accompanied by important degenerative changes in hepatic tissue with peliosis evolution after two months of treatment. These damages worsen again 6 weeks after stopping treatment and ended by the development of hepatic steatosis with increases hepatic distress. ConclusionThese results ported that the use of AAS with “Cycling” may lead to the development of hepatic steatosis before progressing to more serious pathological liver situations in AAS abusers.

The association of plasma levels of liver enzymes and risk of gestational diabetes mellitus: a systematic review and dose-response meta-analysis of observational studies.

Relationship between liver enzymes such as gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase and risk of gestational diabetes mellitus (GDM) is a controversial issue. The aim of this systematic review and dose-response meta-analysis was to investigate the association between liver enzymes and risk of GDM in observational studies. A comprehensive systematic literature search was conducted in MEDLINE/PubMed, SCOPUS and Web of Science databases up to September 2019. Combined odds ratios (ORs) with 95% confidence intervals (CIs) were evaluated by DerSimonian and Laird random-effects models. Dose-response analyses of these relationships were also carried out. Eight studies with 25,451 participants containing 2549 cases were included in this study. Pooled results showed a significant association between GGT levels and risk of GDM (OR 2.10, 95% CI 1.14-3.86, I2 84%). In addition, random-effects model indicated a dramatic and direct significant association between GGT and risk of GDM in nonlinear (p < 0.001) and linear (p < 0.001) dose-response analysis. Associations between ALT and AST with risk of GDM were found to be non-significant (OR 1.32, 95% CI 0.91-1.90, I2 65% and OR 0.76, 95% CI 0.52-1.10, I2 16%, respectively). This systematic review and dose-response meta-analysis highlights GGT as a significant and robust predictor of the incidence of GDM in pregnant women.

The impact of Crocus sativus stigma against methotrexate-induced liver toxicity in rats.

Background The adverse effects of methotrexate (MTX) mainly hepatotoxicity restrict its clinical use. This study was designed to investigate the protective effects of saffron (Crocus sativus) (CS) extract on MTX-induced hepatotoxicity. Methods Twenty-eight male Wistar rats randomly divided into four equal groups. Except for control, all groups received a single intraperitoneal (i.p.) injection of MTX on the 3rd day of study. The CS extract was given (80 mg/kg i.p.) to rats 3days before MTX and continued for the next 7days (Pre&Post-CS group) or administrated after MTX injection and lasted for 7days (Post-CS group). On the 11th day, all rats were sacrificed and their plasma levels of liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were determined. Also, liver histopathology and hepatic levels of malondialdehyde (MDA), nitric oxide (NO) and super oxidase dismutase (SOD) were evaluated. Results The results showed that MTX significantly incremented plasma levels of AST, ALT, ALP and LDH (all p<0.001) and hepatic MDA and NO levels; whereas, decreased SOD activity. Histological alterations such as early fatty changes were evident in the MTX group. Administration of CS extract at both methods could ameliorate liver enzyme elevation, oxidative/nitrosative stresses and morphological alterations of the liver. Pre-and-post treatment with CS extract showed better protective effects than only post-treatment. Conclusion The present findings provide showing CS could effectively alleviate MTX-induced hepatotoxicity in rats. Further investigations are recommended to determine the exact mechanisms underlying the hepatoprotective potential of saffron.

Impaired metabolic and hepatic functions following subcutaneous lipectomy in adult obese rats.

What is the central question of this study? What is the impact and drawbacks of subcutaneous lipectomy on body metabolism? What is the main finding and its importance? Subcutaneous lipectomy resulted in deterioration of hepatic functions, atherosclerotic lipid profile and disturbed redox state. While the results support lipectomy as an effective treatment for obesity, lipectomy induces unfavourable changes in health. The number of obese older adults is on the rise, but data about proper treatment of obesity in the elderly is controversial. The present study was designed to investigate the effectiveness and consequences of partial subcutaneous lipectomy, as a rapid medical intervention against increased accumulation of body fat, in adult obese rats. The study was conducted on adult (9-12months) female rats, in which obesity was induced by bilateral surgical ovariectomy. They were randomized into two main groups: short term (5weeks) and long term (10weeks). Both groups were subdivided into control, ovariectomized (OVX) and ovariectomized lipectomized groups. Body weight (BW) was measured and body mass index (BMI) calculated. Fasting blood glucose, lipid profile and plasma levels of total proteins, albumin, liver enzymes, malondialdehyde (MDA), leptin and adiponectin were determined. The content of both blood and hepatic tissue of reduced glutathione was estimated. In addition, histological study of the liver, aorta and peri-renal fat was performed. Compared to controls, OVX rats showed significant increase in BW, BMI and plasma levels of liver enzymes, MDA and leptin. Histological study revealed vacuolated ballooned hepatocytes and enlarged irregular visceral adipocytes with atherosclerotic changes in the wall of aorta. Following subcutaneous lipectomy, rats exhibited significant fasting hyperglycaemia, dyslipidaemia, lowered plasma albumin and disturbed redox state with aggravation of the histological changes. The findings indicate that although subcutaneous lipectomy appears to be effective in combating obesity in older females, it has unfavourable effects on both metabolic and hepatic functions.

Effect of canagliflozin on the overall clinical state including insulin resistance in Japanese patients with type 2 diabetes mellitus

AimsInformation on the clinical efficacy of SGLT2 inhibitors in the Japanese population is limited. The aim of this single-arm, single-center, open-label study was to confirm the body weight- and fat mass-lowering effects of canagliflozin (CANA) and the accompanying improvement in insulin resistance in Japanese patients with Type 2 diabetes mellitus (T2DM). MethodsThirty-eight patients were enrolled and administered 100 mg CANA once daily for 24 weeks. Blood and anthropometric parameters were examined before and after treatment. In a subset of patients, insulin sensitivity was assessed based on the glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp test. ResultsCANA treatment significantly decreased hemoglobin A1c, fasting plasma glucose, and plasma liver enzyme levels, and increased plasma adiponectin levels. In addition, a significant reduction in body weight, visceral and subcutaneous fat area, fat and lean mass, and liver steatosis was also observed. The change in plasma adiponectin levels significantly correlated with the changes in both body fat mass and visceral fat area. GIR increased from 3.25 ± 1.53 to 4.11 ± 1.30 mg/kg/min (P < 0.05). ConclusionsCANA improved insulin resistance and decreased visceral fat mass in Japanese patients with T2DM.

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.

Blueberry, blackberry, and blackcurrant differentially affect plasma lipids and pro-inflammatory markers in diet-induced obesity mice.

BACKGROUND/OBJECTIVESEvidence indicates that berry anthocyanins are anti-atherogenic, antioxidant, and anti-inflammatory. However, berries differ vastly in their anthocyanin composition and thus potentially in their biological and metabolic effects. The present study compared hypolipidemic, antioxidant, and anti-inflammatory properties of blueberry (BB), blackberry (BK), and blackcurrant (BC) in a diet-induced obesity (DIO) mouse model.MATERIALS/METHODSMale C57BL/6J mice were fed a high fat (HF; 35% fat, w/w) control diet or a HF diet supplemented with freeze-dried 5% BB, 6.3% BK or 5.7% BC for 12 weeks (10 mice/group) to achieve the same total anthocyanin content in each diet. Plasma lipids, antioxidant status and pro-inflammatory cytokines were measured. The expression of genes involved in antioxidant defense, inflammation, and lipid metabolism was determined in the liver, epididymal adipose tissue, proximal intestine, and skeletal muscle. Histological analysis was performed to identify crown-like structure (CLS) in epididymal fat pads to determine macrophage infiltration.RESULTSNo differences were noted between the control and any berry-fed groups in plasma levels of liver enzymes, insulin, glucose, ferric reducing antioxidant power, superoxide dismutase, and tumor necrosis factor α. However, BK significantly lowered plasma triglyceride compared with the HF control and other berries, whereas BC significantly reduced F4/80 mRNA and the number of CLS in the epididymal fat pad, indicative of less macrophage infiltration.CONCLUSIONSThe present study provides evidence that BB, BK and BC with varying anthocyanin composition differentially affect plasma lipids and adipose macrophage infiltration in DIO mice, but with no differences in their antioxidant capacity and anti-inflammatory potential.

Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T-cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. A mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA-induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin-eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis-associated genes and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA-induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon-γ, tumor necrosis factor-α, interleukin (IL)-4 and IL-2, were detected in ConA-treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand and caspase-3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA-induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.

The Swedish α1-Antitrypsin Screening Study: Health Status and Lung and Liver Function at Age 34.

All Swedish newborn infants were screened for α1-antitrypsin (AAT) deficiency between 1972 and 1974. The cohort of 127 individuals with severe AAT deficiency (PiZZ) and 54 with moderate AAT deficiency (PiSZ) has been followed up regularly. To compare smoking habits, quality of life, respiratory symptoms, and lung and liver function at the age of 34 years in this cohort and among 300 age-matched control subjects randomly selected from the Swedish population registry. The study participants answered a questionnaire on smoking habits and symptoms; underwent spirometry, including FEV1 and FVC; and provided blood samples. Health-related quality of life was assessed by using the St. George's Respiratory Questionnaire (SGRQ). One hundred sixteen PiZZ, 48 PiSZ, and 229 control subjects (normal AAT level [PiMM]) answered the questionnaire. Eighty-eight PiZZ (76%), 36 PiSZ (75%), and 144 PiMM (63%) subjects had never smoked (P = 0.02). No significant differences were found in lung function parameters between the protease inhibitor (Pi) subgroups, nor were any discovered between the smoking subgroups. In all Pi subgroups, the symptom score on the SGRQ was significantly lower in ever-smokers than in never-smokers (P = 0.01 for PiZZ, P = 0.009 for PiSZ, and P = 0.01 for PiMM). The mean plasma levels of liver enzymes and albumin were within normal range in all Pi subgroups. However, the mean γ-glutamyl transpeptidase and albumin levels were significantly higher in the PiZZ than in the PiMM subjects (P < 0.05). In this population-based study, no differences in lung function or symptoms were found between subjects with AAT deficiency and control subjects, but smoking frequency was significantly lower among the subjects with AAT deficiency than in the controls at age 34 years.

Acute Effect of High‐dose Isoflavones from Pueraria lobata (Willd.) Ohwi on Lipid and Bone Metabolism in Ovariectomized Mice

We investigated the acute metabolic effects of isoflavones from Pueraria lobata (Willd.) Ohwi (IPL) in ovariectomized (OVX) mice. After 4 weeks of IPL feeding at 500 mg/day/kg body weight (OVX500), plasma 17β-estradiol concentrations were significantly higher (+25%, p < 0.05), whereas plasma triglyceride levels were significantly lower in OVX mice (-15%, p < 0.05) compared with controls. Abdominal adipose tissue weight was marginally reduced in IPL-fed groups compared with OVX controls and the plasma levels of liver enzymes were unchanged. In addition, IPL significantly inhibited the reduction of bone mineral density in the femurs of OVX mice (OVX200, +22%; OVX500, +26%; p < 0.05) compared with controls after 4 weeks of IPL feeding. In quantitative polymerase chain reaction analysis the expression of aromatase was significantly suppressed and SULT1E1 was increased by IPL feeding, showing that IPL feeding may not alter the risk for breast cancer in mice. Our results suggest that IPL could ameliorate menopausal symptoms in mice. Further studies will confirm the effects of IPL in humans.

Liver Enzymes and Trace Elements in the Acute Phase of Sickle Cell Anaemia

Trace elements are required for the performance of numerous functions of immune cells. It is not clear whether levels of trace elements are elevated and whether there is a relationship between the levels of liver enzymes and trace elements in patients with sickle cell anaemia in crisis. To compare the plasma levels of liver enzymes and trace elements in non sickle cell anaemia (NSCA), sickle cell anaemia subjects in the steady state (SCASS) and sickle cell anaemia patients in crisis (SCAC). Haematological parameters, liver enzymes and trace elements were determined in 20 NSCA subjects, 20 SCASS subjects and 18 SCAC subjects. Variables studied included aspartate aminotransferase (AST) , alanine aminotransaminase (ALT), alkaline phosphatase (ALP), and the trace elements copper, zinc, and manganese. Levels of liver enzymes were higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Plasma Cu++, Zn++ and Mn++ were also higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Correlationships were high and strong between AST and ALT (r=+0.7; p=0.03), AST and ALP (r=+0.9; p=0.001), Zn++ and Fe++ (r=+0.9; p=0.001) in SCAC. During crisis in sickle cell anaemia, liver enzymes, as well as the trace elements of Cu++, Zn++ and Mn++ are increased; levels of aspartate aminotransaminase are strongly correlated with those of ALT and ALP. Levels of liver enzymes do not appear to be related to those of the trace elements in painful sickle cell crisis.

Subchronic toxicity studies with ginsenoside compound K delivered to dogs via intravenous administration

Compound K, i.e., 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol, is the main metabolite of the protopanaxadiol type of ginseng saponin produced by intestinal bacteria after oral administration of ginseng extract. In the present study, the toxicity of compound K was evaluated in male and female dogs after 90days continuous intravenous infusion. Beagle dogs were treated with compound K at doses of 6.7, 20 and 60mg/kg/day, and observed for 90days followed by recovery periods. Measurements included clinical observations, body weight, food consumption, temperature, electrocardiogram (ECG), hematology, blood chemistry, urinalysis, gross necropsy, organ weight and histopathology. Under the conditions, the clinical condition of the animals, body weights, body weight gains and food consumption were unaffected by compound K administration relative to the control group. Hematology, ECG data and urinalysis parameters were also unaffected. However, the hepatotoxicity was evident from the observation of multiple parameters, including histopathological evaluation of liver tissue upon necropsy as well as large increases in plasma levels of liver enzymes (alanine aminotransferase, ALT, Gamma-glutamyltranspeptidase, γ-GT, alkaline phosphatase,ALP) in groups receiving compound K (20 or 60mg/kg/day), and this hepatoxicity might be reversible. In addition, the NOAEL of compound K is 6.7mg/kg/day in this 90days toxicity study.