Liver Dysfunction Biomarkers Research Articles

Early detection of liver injuries by the Serum enhanced binding test sensitive to albumin post-transcriptional modifications

Early and sensitive biomarkers of liver dysfunction and drug-induced liver injury (DILI) are still needed, both for patient care and drug development. We developed the Serum Enhanced Binding (SEB) test to reveal post-transcriptional modifications (PTMs) of human serum albumin resulting from hepatocyte dysfunctions and further evaluated its performance in an animal model. The SEB test consists in spiking serum ex-vivo with ligands having specific binding sites related to the most relevant albumin PTMs and measuring their unbound fraction. To explore the hypothesis that albumin PTMs occur early during liver injury and can also be detected by the SEB test, we induced hepatotoxicity in male albino Wistar rats by administering high daily doses of ethanol and CCl4 over several days. Blood was collected for characterization and quantification of albumin isoforms by high-resolution mass spectrometry, for classical biochemical analyses as well as to apply the SEB test. In the exposed rats, the appearance of albumin isoforms paralleled the positivity of the SEB test ligands and histological injuries. These were observed as early as D3 in the Ethanol and CCl4 groups, whereas the classical liver tests (ALT, AST, PAL) significantly increased only at D7. The behavior of several ligands was supported by structural and molecular simulation analysis. The SEB test and albumin isoforms revealed hepatocyte damage early, before the current biochemical biomarkers. The SEB test should be easier to implement in the clinics than albumin isoform profiling.

Evaluating variations in metabolic profiles during the dry period related to the time of hyperketonemia onset in dairy cows.

Hyperketonemia (HYK) in early lactation can have a different impact on health and productivity depending on the timing of HYK onset. While specific metabolites measured during the dry period may serve as biomarkers of HYK, the correlations between metabolites represent a challenge for the use of metabolic profiles dataset, and little has been explored on HYK. This exploratory cohort study aimed a) to characterize the correlations among metabolites measured during the late dry period in dairy cows, and b) to identify biomarkers in the late dry period associated with the onset of HYK at the first (wk1) and second (wk2) week of lactation. Individual blood samples from 440 Holstein dairy cows were collected at 21 ± 3 days before expected parturition. From each sample, 36 different metabolites were measured in serum and plasma. Hyperketonemia was diagnosed in wk1 and wk2 of lactation based on the blood concentration of beta-hydroxybutyrate (BHB > 1.2 mmol/L). Principal component analysis (PCA) was performed to reduce metabolites to a smaller number of uncorrelated components. Multivariable logistic regression models were applied to assess the associations between principal components (PC) and HYK at wk1 only (HYK+ wk1), wk2 only (HYK+ wk2), or both weeks (HYK+ wk1-2). The incidence of HYK was 16.2% in the first week, 13.0% in the second week, and 21.2% within the first two weeks of lactation. The results of PCA highlighted 10 PCs from which two were associated with HYK+ wk1 as compared with cows without HYK during the first two weeks of lactation (non-HYK); the PC a2 led by bilirubin and non-esterified fatty acids (OR = 1.29; 95%CI: 1.02-1.68), and the PC a5 led by alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) (OR = 2.77; 95%CI: 1.61-4.97). There was no evidence of an association between any PC and HYK+ wk2 (vs. non-HYK cows). Cows with elevated PC a5 (led by ALP and GGT) in the dry period were 3.18 times more likely to be HYK+ wk1 than HYK+ wk2 (OR: 3.18, 95%CI: 1.34-8.73; P = 0.013). Overall, the main hypothesis generated by our exploratory study suggests that cows with biomarkers of liver dysfunction (ALP, GGT, bilirubin) assessed by PCA at 3 weeks before calving are more likely to develop HYK during the first week of lactation compared to the second week. In addition, results suggest that cows with HYK in both of the first two weeks of lactation had an overall metabolic disbalance during the onset of the late dry period, which based on PCs, encompass biomarkers related to glucogenic and ketogenic metabolic pathways as well as liver dysfunction and fatty liver. Further research is needed to determine the underlying mechanisms associated with the different adaptations between cows that develop HYK during the first and second week of lactation.

Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1\u03b2 and IL-4/MCP-1 signaling pathways

The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.

Heavy metals exposure is associated with early liver dysfunction among rural residents aged 40-75 years in southwest China.

Heavy metals exposure has been associated with liver dysfunction in recent reports, while the hepatoxicity of lead (Pb) and cadmium (Cd) has been well established. However, the combined effects of multi-metal in real-world scenario on liver dysfunction are still unclear. This cross-sectional study examined associations between 10 biomarkers of early liver injury and multiple heavy metals levels. The levels of heavy metals/metalloid (magnesium [Mg], calcium [Ca], iron [Fe], zinc [Zn], arsenic [As], Cd, copper [Cu], and Pb) were measured in blood and urinary sample collected from 725 participants in a Cd-polluted area and an unpolluted area in southwest China. The early liver dysfunction biomarkers included the liver enzymes (ALT, ALP, AST, and GGT), proteins (TP, ALB, and GLO), and bilirubin (TBIL, DBIL, and IBIL). Confounder-adjusted beta coefficients were determined using multiple linear regression model analysis for the group-classified and gender-classified samples. Our results showed that blood Fe, Cd, and Cu levels were found to be positively related to elevated ALT levels and blood Cu was positively associated with AST levels in the Cd-polluted area, while the highest blood Zn quartile in the polluted area and blood Mg quartile in the unpolluted area were associated with lower ALT levels. Our finding implies that industrial pollution results in heavy metals of Cd and Pb exposure and effects of Fe, Cd, Cu, and Pb in the Cd-polluted area may be the main contributors to increase the risk of liver dysfunction while Zn in the Cd-polluted area and Mg in the unpolluted area may be the protective factors.

Bilirubin nanoparticles activate PPARalpha to remodel the hepatic lipidome and produce hepatic ketones in obese mice, improving liver function

Global obesity has nearly tripled over the last five decades, leading to comorbidities such as non-alcoholic fatty liver disease (NAFLD), insulin-resistant diabetes, and cardiovascular disease. Pharmaceutical interventions remain limited, and many anti-obesity therapeutics such as sibutramine may be associated with deleterious cardiovascular outcomes. There is an urgent need for new, effective, and safe therapeutic strategies for obesity and comorbidities such as NAFLD. Our previous work has shown that bilirubin functions as a hormone by binding directly to the PPARalpha nuclear receptor to reduce adiposity and NAFLD, which suggests that it might have a potential therapeutic use. However, bilirubin is very hydrophobic, which lowers its translation potential. Bilirubin nanoparticles, a soluble form of bilirubin made by PEGylating bilirubin (PEG-BR), can be dissolved in saline. We treated diet-induced obese mice with NAFLD by IP injection with the bilirubin nanoparticles (30 mg/kg every 48 hours) or vehicle for four weeks. We found that bilirubin nanoparticle treatment improved hepatic function in obese mice with NAFLD by lowering AST and ALT, biomarkers of liver dysfunction. Lipidomic analysis of the livers using mass spectrometry showed remodeling of the hepatic lipid profile and significantly reduced (p<0.05) ceramide and dihydroceramide lipid species in obese mice treated with bilirubin nanoparticles. We found that bilirubin nanoparticles activated PPARalpha and ACOX1 to induce fatty acid β-oxidation. Further analysis of the metabolome using a Bruker In Vitro Diagnostic Research platform with nuclear magnetic resonance spectroscopy showed significantly increased (p<0.05) plasma ketone β-hydroxybutyrate concentrations in subjects treated with bilirubin nanoparticles. These data suggest that bilirubin nanoparticles activate the PPARalpha-induced transcriptome to remodel the hepatic lipid profile, increase fatty acid β-oxidation, and use of these metabolites for the generation of ketones. These data indicate that bilirubin nanoparticles may be used as a potential therapeutic for NAFLD.

Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19).

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory disease, which can evolve into multi-organ failure (MOF), leading to death. Several biochemical alterations have been described in COVID-19 patients. To date, many biomarkers reflecting the main pathophysiological characteristics of the disease have been identified and associated with the risk of developing severe disease. Lymphopenia represents the hallmark of the disease, and it can be detected since the early stage of infection. Increased levels of several inflammatory biomarkers, including c-reactive protein, have been found in COVID-19 patients and associated with an increased risk of severe disease, which is characterised by the so-called "cytokine storm". Also, the increase of cardiac and liver dysfunction biomarkers has been associated with poor outcome. In this review, we provide an overview of the main biochemical characteristics of COVID-19 and the associated biomarkers alterations.

Biomarkers of liver dysfunction correlate with a prothrombotic and not with a prohaemorrhagic profile in patients with cirrhosis

Background & AimsDifferent liver dysfunction biomarkers are used to assess the bleeding risk of patients with cirrhosis, either as such or included in bleeding risk assessment scores. Since the current model of coagulation in patients with cirrhosis describes a procoagulant tendency with increasing severity according to Child-Pugh stage, we decided to investigate the relation between liver dysfunction biomarkers and thrombin generation. Our aim was to verify their adequacy for bleeding risk assessment.MethodsWe performed a prospective single-centre study including 260 patients with liver cirrhosis. Thrombin generation was measured using ST Genesia® Thrombin Generation System without and with thrombomodulin in order to assess the role of proteins C and S. Relations between thrombin generation and Child-Pugh/model for end-stage liver disease (MELD) scores, prothrombin time (PT)/international normalised ratio (INR), activated partial thromboplastin time (aPTT), factor V activity, albumin, and total bilirubin were assessed.ResultsThrombomodulin-mediated inhibition of thrombin generation was significantly decreased in patients with liver cirrhosis compared with healthy donors (p <0.0001) and in Child-Pugh B and C compared with A (p <0.0001 [A–B], 0.4515 [B–C], <0.0001 [A–C]). Thrombomodulin-mediated inhibition significantly decreased with increasing PT/INR, aPTT, and total bilirubin levels and with decreasing factor V activity and albumin levels.ConclusionsWorsening liver dysfunction biomarkers reflect an increasing prothrombotic profile in patients with liver cirrhosis. In particular, prolonged PT/INR and aPTT as well as decreasing factor V activity are related to an increasing thrombotic risk and not to an increasing bleeding risk. These parameters should not be used to assess bleeding risk due to haemostatic anomalies in patients with liver cirrhosis. Alternative biomarkers for bleeding risk assessment in patients with liver cirrhosis need to be developed.Lay summaryWe demonstrate that the laboratory parameters used to assess bleeding risk of patients with liver disease, e.g. prothrombin time/international normalised ratio (PT/INR) and activated partial thromboplastin time (aPTT), are inadequate for this purpose because they are correlated with a prothrombotic coagulation profile. In this article, we highlight the need for alternative parameters to assess bleeding risk in patients with liver disease.

Similar Weight Loss Induces Greater Improvements in Insulin Sensitivity and Liver Function among Individuals with NAFLD Compared to Individuals without NAFLD.

Background: Preliminary evidence suggests that weight loss among obese has differential metabolic effects depending on the presence of non-alcoholic fatty liver disease (NAFLD). We assessed whether NAFLD predisposes to differential changes in liver fat content, liver function, and metabolic parameters upon diet-induced weight loss in a 50-week intervention trial. Methods: 143 overweight and obese non-smokers underwent a 12-week dietary intervention and a 38-week follow-up. Diet-induced changes in anthropometric measures, circulating biomarkers, and magnetic resonance (MR)-derived liver fat content and adipose tissue volumes were evaluated by mixed linear models stratifying by NAFLD at baseline. Results: The prevalence of NAFLD at baseline was 52%. Diet-induced weight loss after 12 (NAFLD: 4.8 ± 0.5%, No NAFLD: 5.1 ± 0.5%) and 50 weeks (NAFLD: 3.5 ± 0.7%, No NAFLD: 3.5 ± 0.9%) was similar in both groups, while the decrease in liver fat was significantly greater in the NAFLD group (week 12: 32.9 ± 9.5% vs. 6.3 ± 4.0%; week 50: 23.3 ± 4.4% vs. 5.0 ± 4.2%). Decreases in biomarkers of liver dysfunction (GGT, ALT, AST) and HOMA IR were also significantly greater in the NAFLD group. Other metabolic parameters showed no significant differences. Conclusion: Our data suggest that individuals with NAFLD show greater improvements of liver function and insulin sensitivity after moderate diet-induced weight loss than individuals without NAFLD.

A conceptually-derived, normally-distributed overall liver dysfunction index (OLDI) predicts short- and long-term outcomes after hepatectomy for hepatocellular carcinoma: Single-institution validation in 844 HCC patients

Introduction: We developed the OLDI index: a non-empirically-derived and normally-distributed statistic which summarizes measures of liver synthetic function and hepatocyte death using the concept of geometric averages. The geometric average is superior to the arithmetic or harmonic average for representing central tendencies as it is unit-agnostic i.e. preserves the underlying statistical distribution during scale conversion (e.g. U/L to mmol/L). Method: Most prognostic scores that have been proposed are empirically-calibrated using regression techniques (i.e. have coefficient terms), and are therefore sensitive to the sample size and representativeness of the derivation set, and often fail to be reproduced in external validation sets. We showed that the geometric average of commonly-reported liver dysfunction biomarkers (“OLDI”) can be mathematically-rearranged as: (Albumin (g/L))/((Prothrombin time (s)×Bilirubin (μmol/L)×(AST [U/L]×ALT [U/L])1/2)1/3). The OLDI index was validated in the Singapore General Hospital cohort of 844 HCC patients who underwent hepatectomy between 2001 and 2016. Result: OLDI was found to be normally-distributed in the overall cohort (mean[SD]=2.104 [0.671], median[range]=2.105[0.205-4.485]), and in clinically-partitioned subsets of our cohort. In univariable analyses, OLDI predicted Clavien-Dindo grade≥2 complications (OR=0.686, 95% CI: 0.543-0.866, P=0.0016), post-hepatectomy liver failure using the ISGLS Grade B/C criteria (OR=0.631, 95% CI: 0.444-0.897, P=0.0103) or 50-50 criteria (OR=0.520, 95% CI: 0.290-0.933, P=0.0283), length of hospital stay (beta=-1.29 days; 95% CI: -2.04 to -0.54, P=0.0008 for every additional 1-point increase in OLDI), recurrence-free survival (HR=0.700, 95% CI: 0.605-0.811, P<0.0001), and overall survival (HR=0.655, 95% CI: 0.551-0.780, P<0.0001). The OLDI score remained an independent predictor of all outcomes in multivariable models adjusted for clinically-relevant confounders. Crucially, OLDI was found to outperform popular risk-stratification systems including Child-Pugh points, MELD score, TNM staging, and albumin-bilirubin score for all outcomes examined. Conclusion: OLDI outperformed many widely-used risk-stratification systems for predicting a multitude of short-term and long-term outcomes after hepatectomy for HCC, and is also easily-interpretable because of its normal distribution.

Association of peripheral blood cell count-derived ratios, biomarkers of inflammatory response and tumor growth with outcome in previously treated metastatic colorectal carcinoma patients receiving cetuximab

Abstract The aim of the present study was to investigate the association of peripheral-blood cell count (PBC)-derived ratios, other biomarkers of inflammation and biomarkers of tumor growth with outcome in a cohort of patients presenting for the next line of therapy after the failure of prior systemic treatment. The data of 51 patients with advanced/metastatic colorectal carcinoma treated with cetuximab in the second or higher line of therapy were retrospectively analyzed. The median duration of cetuximab therapy and the median survival were 5.1 and 12.1 months, respectively. C-reactive protein (CRP), but not urinary neopterin correlated significantly with PBC-derived ratios. Both CRP and urinary neopterin correlated positively with carcinoembryonic antigen (CEA) concentrations and biomarkers of liver dysfunction. Although a number of parameters predicted overall survival in univariate analysis, only hemoglobin, CEA change and serum bilirubin were independent predictors of survival. In conclusion, in patients with metastatic colorectal carcinoma and predominantly liver metastases, the outcome of therapy in the advanced line setting was associated with initial hemoglobin level, a decrease of CEA concentration and initial presence of liver dysfunction. Urinary neopterin did not correlate with PBC-derived ratios, in contrast to CRP, but both urinary neopterin and serum CRP concentrations correlated with laboratory parameters of liver dysfunction.

Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes

Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity.

The potential role of p53 and MAPK pathways in the hepatotoxicity of deep‐fried oil and in resistant starch‐induced protection

In this study, rats with a fresh oil diet, a deep‐fried oil diet, and a deep‐fried oil and resistant starch (RS) diet were investigated for revealing the effects of deep‐fried oil to the metabolic system and if RS could effectively attenuate metabolic dysfunction caused by deep‐fried oil. The results showed that DO feeding led to significant increases of liver biomarkers of alanine aminotransferase (ALT) and aspartate transaminase (AST), accompanied by consistent reduction of total antioxidation (T‐AOC) and glutathione peroxidase (GSH‐Px) activity compared to the rats feeding with unheated canola oil (FO group) (p &lt; 0.05). Liver histology of rats in DO group exhibited membrane blebbing and boundary ambiguity, indicating DO might exert significant hepatotoxic effects. However, RS intervention (DO‐RS group) significantly reversed these changes. Furthermore, the results in this study revealed that p53 and MAPK signaling pathways presented in the significantly enriched KEGG pathways list in FO versus DO group, but not in FO versus DO‐RS group, suggesting RS intervention modulated these two signaling pathways. This is the first study to investigate RS intervention on the attenuation of hepatotoxicity induced by DO intake in the dietary.Practical applications: This study investigates the toxic effects of deep‐fried oil consumption on health, in particular on hepatic immune system and the related mechanisms involved in this process. The main target of this research work is to contribute with useful information of deep‐fried oil intake to the food industry and to find out effective ways to ameliorate the risk of deep‐fried oil diet.A deep‐fried oil diet can cause hepatotoxicity; in contrast, rats fed a deep‐fried oil and RS diet are protected. The modulation of p53 and MAPK pathways might be one of the key regulations for RS intervention to attenuate liver dysfunction biomarkers (ALT and AST).

Acute toxicity of the aqueous-methanolic Moringa oleifera (Lam) leaf extract on female Wistar albino rats

Background: Herbal preparations are widely assumed to be safe on oral administration and therefore the documentation of the toxic potential of some herbal concoctions used as medicine and nutrients is limited. Moringa oleifera ( MO ) is a plant that is gaining tremendous popularity in rural communities in Kenya as a means of offsetting nutritional and medicinal needs. However, very little is known about the safety of the plant on oral administration. Thus, the aim of the current study was to assess the biochemical and histological changes in the liver following the administration of an aqueous-methanolic (AQ-ME) MO leaf extract in female Wistar albino rats. Methods: Acute oral toxicity study on the AQ-ME MO leaf extract was conducted by the use of the limit test dose of the up and down procedure (OECD guideline number 425) with slight modifications. Briefly, ten (10) healthy, nulliparous, non-pregnant female Wistar strain albino rats aged 8-12 weeks and weighing 180±20 grams were used for the study. These animals were randomly selected into two groups; control and treatment group each having five (5) animals. They were then labelled to enable identification and control group animals were orally administered with physiological buffer saline once daily over a 48-hour period. The five (5) rats in the treatment group were dosed orally one at a time and once daily with a 2000 mg/kg dose of the AQ-ME MO leaf extract to determine the median lethal dose over a 48 hour period. Blood was then collected and used to prepare serum for biochemical analysis of aspartate amino transferase (AST), alanine amino transferase (ALT) and total bilirubin (TB) which are important biomarkers of liver dysfunction. Biochemical assays of these enzymes were performed using the method of the International Federation of Clinical Chemists (IFCC). Death was used as an endpoint, livers harvested and used to prepare transverse sections for histopathological examination. These sections were stained using the haematoxylin and eosin (H&E) method and observed for pathological changes using an optical microscope. Results: A 2000 mg/kg oral dose of AQ-ME MO leaf extract caused a significant (p 0.05) increase in the mean levels of total bilirubin in the treatment group relative to the control group. On the other hand, the extract caused a non-significant (p>0.05) decrease in the mean levels of ALT in the treatment group relative to the control. The post mortem analysis of the hepatic index (liver to body weight ratio) revealed that there was a non-significant increase (p>0.05) in the hepatic index of the treatment group relative to the control. However, the transverse liver sections of treatment group animals showed mild distortions in the architecture of liver cells. Conclusions: Based on these results, the LD 50 of the AQ-ME MO leaf extract was found to be >2000 mg/kg in female wistar albino rats.

Hypolipidemic, Hepatoprotective and Renoprotective Effects of Cydonia Oblonga Mill. Fruit in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus is associated with complications in several different systems of the body, and the incidence of diabetes is rapidly increasing worldwide. The objective of the present study was to evaluate the effect of aqueous extract of Cydonia oblonga Mill. Fruit on lipid profile and some biochemical parameters in streptozotocin-induced diabetic rats. The extract showed anti hyper lipidemic activity as evidenced by significant decreases in serum triglyceride, total cholesterol, and low density lipoprotein cholesterol (LDL-C) levels along with the elevation of high density lipoprotein cholesterol (HDL-C) in the diabetic rats. The biochemical liver functional tests were also analyzed and it was shown that serum biomarkers of liver dysfunction, including alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were significantly reduced in aqueous extract of Cydonia oblonga Mill. treated diabetic rats. In addition, our results showed that the oral administration of the extract prevented diabetes-induced increase in serum urea and creatinine levels as the markers of renal dysfunction. In conclusion, the present study indicates that aqueous extract of Cydonia oblonga Mill. Is able to improve some of the symptoms associated with diabetes and possesses hypolipidemic, hepatoprotective, and renoprotective effects in streptozotocin-induced diabetic rats.

Evaluation of Mango Byproduct Extracts as Antioxidant against Pb-acetate induced Oxidative Stress and Genotoxicity in Mice

The antioxidant and antiproliferative properties of mango by-products were investigated. This study was carried out to evaluate the protective role of mango peel or kernel defatted extracts against Pb-acetate adverse effects on oxidant/antioxidant status, liver dysfunction biomarkers, histopathological changes and genotoxicity in male mice. Total phenolic content and antioxidant activity of both extracts were evaluated. Two doses of both extracts (50 and 100 mg/kg) were used to evaluate their role against the toxicity of Pb-acetate (500 ppm). Mice given mango extracts with Pb-acetate had signifi cantly lower plasma MDA, AST and ALT and higher glutathione than mice given Pb-acetate alone. Mango extracts prevented the histopathological changes in liver induced by Pb-acetate and decreased the cytotoxicity of lead by increasing the ratio of PCE/NCE. Mango extract treatment reduced the DNA damage induced by Pb-acetate in liver as demonstrated by a reduction in micronuclei and decrease in tail length, tail DNA% and Olive tail moment. It can be concluded that mango by-product extracts have potential to protect from oxidative stress and genotoxicity of lead.

Multilevel evaluations of potential liver injury of bifenthrin

The widespread use of pesticides, such as pyrethroids, increases health risks to non-target organisms. The potential toxicity of pyrethroids to the liver remains unclear and could be easily overlooked if only the common clinical indicators of liver disease are examined. In the present study, BALB/c mice were given intraperitoneal injections of 0, 2, 4, or 8 mg/kg bifenthrin (BF) for 7 days. The potential liver injury of BF and its underlying mechanism were then investigated through multilevel evaluations. Histological analyses and serum enzyme activities showed no obvious clinical evidence of liver damage. Oxidative stress was induced and caspases were activated in response to increased BF concentrations. Exposure to BF also significantly altered the expression levels of mitochondrial apoptosis-related genes in dose-dependent relationships. The microarray results showed that BF could disturb the metabolic profile and extensively induce genes related to oxidative stress, including the cytochrome P450 family, glutathione peroxidases, glutathione s-transferases and kinases. In the in vivo model, BF induced liver injury through caspase-mediated mitochondrial-dependent cell death, a process that is closely related to oxidative stress, even in the absence of classical clinical biomarkers of liver dysfunction. The results of this study suggest that classical evaluations are not adequate for liver toxicity of pyrethroids, and highlight the need for more comprehensive assessment of health risks of these widely used pesticides.

Serum soluble CD40 is associated with liver injury in patients with chronic hepatitis B.

Soluble cluster of differentiation 40 (sCD40) is proteolytically cleaved from membrane-bound CD40 and binds to CD154, thereby inhibiting CD40-CD154-mediated immune responses. The aim of the present study was to clarify the role of sCD40 in chronic hepatitis B (CHB). The sCD40 levels in sera from 132 patients with CHB and 33 healthy individuals were retrospectively measured. sCD40 concentrations in patients with CHB were higher than those in healthy controls, and sCD40 levels correlated positively with serum levels of the liver dysfunction biomarkers alanine transaminase (ALT) and aspartate transaminase (AST). sCD40 concentrations increased with a rise in the severity of liver necroinflammation and fibrosis. Patients with >75% liver tissue staining positive for hepatitis B virus (HBV) antigen expression showed significantly lower sCD40 levels than those who stained negative for the HBV antigen. The area under the receiver operating characteristic curve of sCD40 was greater than that of ALT and AST; thus, sCD40 levels have a high diagnostic accuracy for detecting severe liver inflammation in patients with CHB, and could serve as an immunological marker of hepatic tissue injury.

Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample of men and women

Background and objectivePersistent organic pollutants (POPs) are stable organic compounds generated through different industrial activities. Liver is involved in the metabolism of POPs, and hence exposure to POPs may interfere with liver function. Although a few studies have shown adverse effects of POPs on liver function, large-scale studies involving humans are lacking. We performed this large population-based cross-sectional study to assess the associations between different POPs and liver dysfunction biomarkers. MethodsA total of 992 individuals (all aged 70 years, 50% males) were recruited as part of Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The total toxic equivalency (TEQ) value was calculated for seven mono-ortho and two non-ortho substituted polychlorinated biphenyls (PCBs) and octachloro-p-dibenzodioxin (OCDD) to assess their toxicological effects. The association of TEQ values, summary measures of 16 PCBs (sum of PCBs) and three organochlorine pesticides (sum of OC pesticides) with liver dysfunction biomarkers (bilirubin; alkaline phosphatase, ALP; alanine aminotransferase, ALT; and gamma-glutamyltransferase, GGT) was analyzed utilizing linear regression analysis. ResultsThe mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=0.71, P=0.008), while sum of OC pesticide concentrations was negatively associated with ALP (β=−0.02, P=0.002) after adjusting for various potential confounders. When analyzed individually, a number of different POPs were associated with ALP, ALT and bilirubin. No such association with GGT was observed. ConclusionVarious POPs including PCBs, OCDD and pesticides were associated with the liver dysfunction biomarkers bilirubin, ALT and ALP, suggesting adverse effects on liver function from these environmental pollutants.

Kolaviron, a Garcinia biflavonoid complex ameliorates hyperglycemia-mediated hepatic injury in rats via suppression of inflammatory responses

BackgroundChronic inflammation plays a crucial role in hyperglycemia-induced liver injury. Kolaviron (KV), a natural biflavonoid from Garcinia kola seeds have been shown to possess anti- inflammatory properties which has not been explored in diabetes. To our knowledge, this is the first study to investigate the effect of KV on pro-inflammatory proteins in the liver of diabetic rats.MethodsDiabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) in male Wistar rats. Kolaviron (100 mg/kg) was administered orally five times a week for six weeks. The concentrations of cytokines and chemokine were measured using Bio-plex Pro™ magnetic bead-based assays (Bio-Rad Laboratories, Hercules, USA). Plasma glucose and serum biomarkers of liver dysfunction were analyzed with diagnostic kits in an automated clinical chemistry analyzer. Insulin concentration was estimated by radioimmunoassay (RIA).ResultKolaviron (100mg/kg) treatment significantly ameliorated hyperglycemia and liver dysfunction. Serum levels of hepatic marker enzymes were significantly reduced in kolaviron treated diabetic rats. Kolaviron prevented diabetes induced increase in the hepatic levels of proinflammatory cytokines; interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF-α) and monocyte chemotactic protein (MCP-1).ConclusionThe results of this study demonstrate that the hepatoprotective effects of kolaviron in diabetic rats may be partly associated with its modulating effect on inflammatory responses.

Amelioration of Prallethrin-Induced Oxidative Stress and Hepatotoxicity in Rat by the Administration ofOriganum majoranaEssential Oil

This study was carried out to evaluate the adverse effects of exposure to prallethrin on oxidant/antioxidant status and liver dysfunction biomarkers and the protective role of Origanum majorana essential oil (EO) in rat. Male rats were divided into 4 groups: (i) received only olive oil (ii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) in olive oil via oral route daily for 28 days, (iii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) and EO (160 μL/kg b.wt.) in olive oil and (iv) received EO (160 μL/kg b.wt.) in olive oil via oral route twice daily for 28 days. Prallethrin treatment caused decrease in body weight gain and increase in relative liver weight. There was a significant increase in the activity of serum marker enzymes, aspartate transaminase, alanine transaminase, and alkaline phosphatase. It caused increase in thiobarbituric acid reactive substances and reduction in the activities of superoxide dismutase, catalase, and glutathione-S-transferase in liver. Consistent histological changes were found in the liver of prallethrin treatment. EO showed significant protection with the depletion of serum marker enzymes and replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of EO. We can conclude that prallethrin caused oxidative damage and liver injury in male rat and co-administration of EO attenuated the toxic effect of prallethrin. These results demonstrate that administration of EO may be useful, easy, and economical to protect human against pyrethroids toxic effects.