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Liver damage and metabolic dysfunctions, the defining features of non‐alcoholic fatty liver disease (NAFLD), are marked by inflammation, oxidative stress, and excessive hepatic fat accumulation. The current therapeutic approaches for NAFLD are limited, necessitating exploring novel treatment strategies. Dioxopiperidinamide derivatives, particularly DOPA‐33, have shown effective anti‐inflammatory and antioxidant properties, potentially offering therapeutic benefits against NAFLD. This study investigated the combined potential of vitamin D3 (Vit D3) and DOPA‐33 in treating NAFLD. The network pharmacology analysis identified key NAFLD targets modulated by Vit D3 and DOPA‐33, emphasizing their potential mechanisms of action. In NAFLD‐induced zebrafish models, Vit D3 and DOPA‐33 significantly reduced hepatic lipid accumulation, oxidative stress, and apoptosis, demonstrating superior efficacy over individual treatments. The treatment also lowered reactive oxygen species (ROS) levels, decreased liver damage, and enhanced antioxidant defense mechanisms. Moreover, behavioral analyses showed improved locomotion and reduced weight gain in treated zebrafish. Biochemical analyses revealed lower triglycerides (TG) and glucose levels with improved oxidative markers. Furthermore, histological analyses indicated reduced hepatic steatosis and inflammation, with decreased expression of lipogenesis‐related genes and inflammatory mediators. Finally, high‐performance liquid chromatography (HPLC) confirmed a significant reduction in hepatic cholesterol levels, indicating the effectiveness of the combination therapy in addressing key NAFLD‐related dyslipidemias. These findings suggest that Vit D3 + DOPA‐33 targets pathways involved in lipid metabolism, inflammation, and oxidative stress by offering a promising therapeutic approach for NAFLD. [ABSTRACT FROM AUTHOR]

This study investigated the protective effects of chlorogenic acid (CGA) on production performance and liver function of rabbits under heat stress (HS) condition. A total of 120 healthy New Zealand weaned rabbits with similar initial body weight, were randomly divided into 3 treatments with 20 replicates per treatment and 2 weaned rabbits per replicate: control (CON) group (rabbits were housed at 25 ± 1°C and fed a basal diet), HS group (rabbits were housed at 35 ± 1°C and fed a basal diet), and HS + CGA group (rabbits were housed at 35 ± 1°C and fed a basal diet supplemented with 800 mg/kg CGA). The trial lasted for 28 days. The results showed that HS challenge decreased (p < 0.05) growth performance, induced oxidative stress and hepatic apoptosis, and caused liver damage in rabbits. However, dietary CGA supplementation increased (p < 0.05) body weight gain and feed efficiency, and enhanced (p < 0.05) antioxidative capacity in serum and liver in HS‐challenged rabbits; attenuated HS‐induced increases in urea nitrogen (p = 0.03), alanine aminotransferase (p = 0.03), aspartate aminotransferase (p = 0.01), caspase‐8 (p = 0.02), and caspase‐3 (p = 0.04) as well as decrease albumin (p = 0.04). Moreover, supplementation with CGA upregulated Nrf2/HO‐1 pathway‐related genes expressions, including Nrf2 (p = 0.009), HO‐1 (p = 0.03) and SOD1 (p = 0.04) in HS‐challenged rabbits. Our findings demonstrated that dietary CGA supplementation could alleviate HS‐induced decline in growth performance, and protect against HS‐induced liver damage partially through enhancing antioxidant capacity via acting Nrf2/HO‐1 pathway and inhibiting hepatic apoptosis in rabbits. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) remains a public health concern. Blood donors screened for HBV surface antigen (HBsAg) along with aspartate transaminase (AST)/alanine aminotransferase (ALT) could play a key in providing safe blood products. We investigated the features related to HBV infection among rejected blood donors in Luanda, Angola. Methods: This was a cross‐sectional study conducted with 164 rejected donors. Donors were screened for HBsAg from March to May 2022. Overall, 63.4% tested positive for HBV. Results: The mean age of the HBV‐positive (29.2 ± 8.02) was lower than the HBV‐negative (33.9 ± 10.0) (p < 0.001). Donors between 20 and 40 years (odds ratio [OR]: 2.34, p = 0.045), females (OR: 1.40, p = 0.516), residents in urbanized areas (OR: 1.23, p = 0.530), low educational (OR: 1.54, p = 0.458), unemployed (OR: 1.65, p = 0.271), and unmarried (OR:1.41, p = 0.616) might be likely to contract HBV. AST/ALT ratio was higher in HBV‐infected (2.07 ± 1.42) than in HBV‐uninfected (1.90 ± 1.14). About 20% of HBV‐positive were classified as having acute liver disease, while 80% with chronic liver disease, based on AST/ALT ratio. Age ranged from 20 to 40 years (OR: 1.97, p = 0.305), females (OR: 1.61, p = 0.557), donors from non‐urbanized (OR: 1.69, p = 0.557), a low educational (OR: 1.64, p = 0.571), and unemployed donors (OR: 1.81, p = 0.289) were likely to develop chronic liver disease. Conclusions: Our findings indicated the failure of viral hepatitis control measures. Authorities should consider including HBV nucleic acid testing to ensure early identification of HBV in Angola. [ABSTRACT FROM AUTHOR]

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro‐fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro‐inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4‐treated ΔEGFR mice when compared with CCl4‐treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro‐fibrotic and pro‐inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase‐dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Arsenic (As) is a highly toxic metalloid that can be found in insufficiently purified drinking water and exerts adverse effects on the physiology of living organisms that can negatively affect human health after subchronic exposure, causing several diseases, such as liver damage. A high‐fat diet, which is increasing in frequency worldwide, can aggravate hepatic pathology. However, the mechanisms behind liver injury caused by the combinatory effects of As exposure and a high‐fat diet remain unclear. In this study, we investigated such underlying mechanisms by focusing on three different aspects: As biotransformation, pathological liver damage, and differential expression of signaling pathway components. We employed mice that were fed a regular diet or a high‐fat diet and exposed them to a range of arsenite concentrations (As(III), 0.05–50 mg/L) for 12 weeks. Our results showed that a high‐fat diet increased the absorption of As into the liver and enhanced liver toxicity, which became progressively more severe as the As concentration increased. Co‐exposure to a high‐fat diet and As(III) activated PI3K/AKT and PPAR signaling as well as fatty acid metabolism pathways. In addition, the expression of proteins related to lipid cell function, lipid metabolism, and the regulation of body weight was also affected. Our study provides insights into the mechanisms that contribute to liver injury from subchronic combinatory exposure to As and a high‐fat diet and showcases the importance of a healthy lifestyle, which may be of particular benefit to people living in areas with high As(III) concentrations, as a means to reduce or prevent aggravated liver damage. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP‐4 inhibitor known for its safe profile, has exhibited noteworthy anti‐inflammatory and anti‐oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10‐week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti‐inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage. [ABSTRACT FROM AUTHOR]

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme‐mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD‐promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Neurotensin (NT), an intestinal peptide able to promote fat absorption, is implicated in the pathogenesis of obesity. Increased levels of proneurotensin (pro‐NT), a stable NT precursor fragment, have been found in subjects with nonalcoholic fatty liver disease (NAFLD); however, whether higher pro‐NT levels are associated with an increased NAFLD risk independently of other metabolic risk factors is unsettled. Methods: Ultrasound‐defined presence of NAFLD was assessed on 303 subjects stratified into tertiles according to fasting pro‐NT levels. The longitudinal association between pro‐NT levels and NAFLD was explored on the study participants without NAFLD at baseline reexamined after 5 years of follow‐up (n = 124). Results: Individuals with higher pro‐NT levels exhibited increased adiposity, a worse lipid profile, and insulin sensitivity as compared to the lowest tertile of pro‐NT. Prevalence of NAFLD was progressively increased in the intermediate and highest pro‐NT tertile as compared to the lowest tertile. In a logistic regression analysis adjusted for several confounders, individuals with higher pro‐NT levels displayed a raised risk of having NAFLD (OR = 3.43, 95%CI = 1.48–7.97, p = 0.004) than those in the lowest pro‐NT tertile. Within the study cohort without NAFLD at baseline, subjects with newly diagnosed NAFLD at follow‐up exhibited higher baseline pro‐NT levels than those without incident NAFLD. In a cox hazard regression analysis model adjusted for anthropometric and metabolic parameters collected at baseline and follow‐up visit, higher baseline pro‐NT levels were associated with an increased risk of incident NAFLD (HR = 1.52, 95%CI = 1.017–2.282, p = 0.04). Conclusion: Higher pro‐NT levels are a predictor of NAFLD independent of other metabolic risk factors. [ABSTRACT FROM AUTHOR]

Background & Aims: Various intracellular pathways regulate inflammation in NASH. Cyclic GMP‐AMP synthase (cGAS) is a DNA sensor that activates STING and plays a role in inflammatory diseases. Here, we explored the role of cGAS in hepatic damage, steatosis, inflammation, and liver fibrosis in mouse models of NASH. Methods: cGAS deficient (cGAS‐KO) and STING deficient (STING‐KO) mice received high fat‐high cholesterol‐high sugar diet (HF‐HC‐HSD) or relevant control diets. Livers were evaluated after 16 or 30 weeks. Results: HF‐HC‐HSD diet, both at 16 and 30 weeks, resulted in increased cGAS protein expression as well as in increased ALT, IL‐1β, TNF‐α and MCP‐1 in wild‐type (WT) mice compared to controls. Surprisingly, liver injury, triglyceride accumulation, and inflammasome activation were greater in HF‐HC‐HSD cGAS‐KO compared to WT mice at 16 and to a lesser extent at 30 weeks. STING, a downstream target of cGAS was significantly increased in WT mice after HF‐HC‐HSD. In STING‐KO mice after HF‐HC‐HSD feeding, we found increased ALT and attenuated MCP1 and IL‐1β expression compared to WT mice. Markers of liver fibrosis were increased in cGAS‐ and STING‐KO mice compared to WT on HF‐HC‐HSD. We discovered that cGAS‐KO mice had a significant increase in circulating endotoxin levels on HF‐HC‐HSD that correlated with changes in intestinal morphology which was exacerbated by HF‐HC‐HSD compared to WT mice. Conclusion: Our findings indicate that cGAS or STING deficiency exacerbate liver damage, steatosis, and inflammation in HF‐HC‐HSD diet‐induced NASH, which might be linked to the disruption of the gut barrier. [ABSTRACT FROM AUTHOR]

The hepatoprotective effects of methanol extract of Mimusops elengi Linn. (M. elengi L.) leaves and isolated pure myricitrin (3‐, 4‐, 5‐, 5, 7‐five hydroxyflavone‐3‐O‐α‐l‐rhamnoside) (Myr) were evaluated in male rats exposed to γ‐irradiation. The extraction of M. elengi L. leaves was performed using ethyl acetate (EtOAC). Seven groups of rats were used: control group, irradiated (IRR) group (6 Gy of γ‐rays in a single dose), vehicle group (oral administration of 0.5% carboxymethyl cellulose for 10 days), EtOAC extract group (100 mg/kg body weight of extract, orally for 10 days), EtOAC + IRR group (administration of extract and exposure to γ‐rays on Day 7), Myr group (50 mg/kg body weight Myr, orally for 10 days), and Myr + IRR group (administration of Myr and exposure to γ‐rays on Day 7). High‐performance liquid chromatography and 1H‐nuclear magnetic resonance were used to isolate and characterize the compounds from M. elengi L. leaves. Enzyme‐linked immunosorbent assay was used for biochemical analyses. Identified compounds were Myr, myricetin 3‐O‐galactoside, myricetin 3‐O‐rahmnopyranoside (1 → 6) glucopyranoside, quercetin, quercitol, gallic acid, α‐,β‐amyrin, ursolic acid, and lupeol. Serum aspartate transaminase and alanine transaminase activities were significantly increased, while serum protein and albumin levels were significantly decreased after irradiation. Hepatic levels of tumor necrosis factor‐α, prostaglandin 2, inducible nitric oxide synthase, interleukin‐6 (IL‐6), and IL‐12 were increased following irradiation. Improvements were observed in most serological parameters after treatment with extract or pure Myr, with histological analyses confirming decreased liver injury in treated rats. Our study demonstrates that pure Myr has a greater hepatoprotective effect than M. elengi leaf extracts against irradiation‐induced hepatic inflammation. Significance statement: The present study is interested in using a natural compound to eliminate the side effects of γ‐irradiation during radiotherapy. [ABSTRACT FROM AUTHOR]

Tamoxifen‐induced hepatotoxicity is an inevitable side effect during breast cancer treatment. Low‐dose gamma irradiation (IRR) shows many beneficial effects by stimulating various biological processes. This study evaluates the possible effect of sildenafil and low‐dose gamma radiation on liver damages as new treatment strategies. Group I (control), group II: (tamoxifen), group III: (tamoxifen + Sildenafil), group IV: (tamoxifen+ irradiation) and group V: (tamoxifen +Sildenafil + irradiation). Rats were sacrificed after 5 h from tamoxifen injection. Results showed that tamoxifen caused elevation in serum AST, ALT and ALP as well hepatic ROS, iNOS, MDA, Keap‐1 and NF‐Kb, in addition to diminution in hepatic Nrf2 and HO‐1. Exposure to low‐dose gamma radiation and sildenafil amended the alterations in the measured parameters in serum and tissue. Moreover, all results were confirmed by histopathological examination. In conclusion, sildenafil and low‐dose gamma radiation can mitigate the toxicity induced by tamoxifen in liver tissues. Hence, this treatment could be further evaluated as a new approach for alleviating various liver disorders. [ABSTRACT FROM AUTHOR]

In this study, the effects of curcumin, glutathione (GSH), malondialdehyde (MDA) levels, advanced protein oxidation products (AOPP), superoxide dismutase (SOD), and catalase (CAT) activities in experimental liver damage with diethylnitrosamine (DEN) in Swiss albino mice were investigated. The subjects (n = 9) used in the study were divided into 5 groups as tumor control 1, tumor control 2, curcumin protective, curcumin treatment and healthy control groups Curcumin oral gavage (in 150 mg/kg of ethylalcohol) was given to the protecting group for 19 days, 5 days before the administration of DEN, and 24 h after the administration of DEN. Hundred microliters of ethylalcohol oral gavage was given to the healthy group for 19 days. While MDA levels decreased significantly in the curcumin preservative group (p < 0.05), (p = 0.002), the decrease was not significant in the treatment groups (p > 0.05), (p = 0.128). AOPP levels decreased significantly in the curcumin protective group (p < 0.05), (p = 0.009) but the decrease in the treatment group was not found significant (p > 0.05), (p = 0.073). SOD activities increased significantly in both groups. It was found as (p < 0.05), (p = 0.001) and (p < 0.05), (p = 0.002), respectively. GSH levels decreased but these reductions were not found statistically significant. CAT activities increased significantly in both groups. It was determined as (p < 0.05), (p = 0.001) for both groups. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to investigate the incidence of and risk factors for liver damage in patients with human immunodeficiency virus type‐1 (HIV‐1) mono‐infection receiving antiretroviral therapy (ART). Methods: We retrospectively analyzed the clinical data of patients who were diagnosed with HIV‐1 infection and initiated ART from January to December 2017. Among them, 382 patients with HIV‐1 mono‐infection and normal baseline liver function were included in the analysis. The incidence of liver damage at each follow‐up point, and possible risk factors for liver damage were evaluated via COX regression survival analyses. Results: The overall incidence of liver damage (grade I–IV) was 27.23% (interquartile range [IQR]: 26.38%–28.72%). Grade I liver damage was most common and accounted for 22.13% of cases (IQR: 21.06%–24.04%), while grade II liver damage accounted for 3.40% of cases (IQR: 3.19%–4.26%). COX regression and survival analyses revealed that baseline body mass index (BMI), alanine aminotransferase (ALT) level, CD4+ T cell count, HIV‐1 viral load, and the antiretroviral regimen were significantly correlated with the occurrence of liver damage. Moreover, baseline ALT levels and HIV‐1 viral load were identified as independent risk factors for liver damage in patients with HIV‐1 mono‐infection. Conclusion: Liver damage is common in patients with HIV‐1 mono‐infection undergoing ART. Patients with risk factors for liver damage should be well‐informed before the initiation of ART, and liver function should be closely monitored during ART even in patients with normal liver function before ART. [ABSTRACT FROM AUTHOR]

This study reviewed a case series of 11 Holstein‐Friesian (HF) cows with postpartum hemoglobinuria (PPH) from one dairy herd. The first clinical signs of PPH appeared in the animals during the second or third lactation, between 21 and 30 days after calving. The clinical signs, including depression, diminished appetite, a dark red to brown color in the urine, pale mucous membranes, and a decrease in milk yields were observed in these 11 animals. Three of the cows developed jaundice of the mucous membranes and five had dry, parched feces. PPH was confirmed on laboratory test results of blood and urine samples. Anemia, serum hypophosphatemia (Pi = 0.79 mmoL/L), and increased liver function analytes (total bilirubin, total protein, and urea concentrations) were observed in all animals. Animals were treated with intravenous phosphorus supplementations for the first 2 days after clinical signs were noted, and then oral supplementations were administered. After the clinical signs resolved and the treatments were discontinued, the animals still had mild anemia; however, the phosphorus concentration increased to 1.40 mmoL/L. Gamma‐glutamyltransferase activity increased compared with activities measured before treatments and total bilirubin concentrations decreased slightly; however, the concentrations were still more than twice the upper limit of the normal RI. These animals were diagnosed with liver damage that had developed over the course of PPH, indicating the need for the further monitoring and treatment of cows during the postparturient period, even if clinical signs are no longer present. [ABSTRACT FROM AUTHOR]

Background & aims: High consumption of ultra‐processed food (UPF) is associated with mortality and chronic morbidity but has not been studied concerning to non‐alcoholic fatty liver disease (NAFLD). We aimed to test the association of UPF consumption with metabolic syndrome, NAFLD and related‐liver damage. Methods: A cross‐sectional study among volunteers who underwent abdominal ultrasound (AUS), anthropometrics, blood pressure measurements, and fasting blood tests including FibroMax for non‐invasive assessment of NASH and significant fibrosis. A food‐frequency questionnaire was used to evaluate UPF consumption using the NOVA classification. Results: A total of 789 subjects were included in the total sample (mean age 58.83 ± 6.58 years, 52.60% men), a reliable FibroMax test was obtained from 714 subjects, 305 subjects were diagnosed with NAFLD. High consumption of UPF was associated with higher odds for metabolic syndrome (OR = 1.88, 95% CI 1.31‐2.71, P =.001) and its components; hypertension, hypertriglyceridemia, and low HDL, among the entire sample (OR = 1.53, 1.07‐2.19, P =.026; OR = 1.51, 1.08‐2.11, P =.017; OR = 1.55, 1.05‐2.29, P =.028). In addition, it was associated with higher odds for NASH and hypertension (OR = 1.89, 1.07‐3.38, P =.030; OR = 2.26, 1.20‐4.26, P =.012 respectively) among subjects with NAFLD. Stratification by smoking status revealed an association between high UPF consumption and significant fibrosis among ever smokers in the entire sample and among subjects with NAFLD (OR = 1.89, 95% CI 1.03‐3.45, P =.039; OR = 2.85, 1.14‐7.14, P =.026 respectively). Conclusions: High UPF consumption is associated with metabolic syndrome in the general population, and among those with NAFLD it is associated with NASH marker. Ever‐smoking may act synergistically with UPF to amplify the risk for fibrosis. [ABSTRACT FROM AUTHOR]

Purpose: Hyperuricemia is a common disease that may lead to gout, renal damage, and cardiovascular events. Oral medication is the main treatment for hyperuricemia patients when lifestyle intervention fails. An evaluation of the safety of various urate‐lowering therapies (ULTs) is integral to clinical decision‐making. We constructed a network meta‐analysis (NMA) to evaluate the safety of oral ULTs. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched up to April 1, 2021, for randomized controlled trials that examined the safety of ULTs. The language restriction was English. The three outcomes used to assess the safety of uric acid lowering medications were treatment‐related adverse events, liver damage, and major adverse cardiovascular events (MACE). Results: Thirty‐two trials enrolling 23,868 individuals were included in the study. In terms of treatment‐related adverse events, there were no statistically significant differences between five uric acid lowering medications and placebo: allopurinol (risk ratio (RR): 1.08; 95% credible interval (CrI): 0.91, 1.29), febuxostat (RR: 1.05; 95% CrI: 0.89, 1.25), lesinurad (RR: 1.19; 95% CrI: 0.85, 1.67), lesinurad combined with xanthine oxidase inhibitor (XOI, RR: 1.05; 95% CrI: 0.83, 1.32), and topiroxostat (RR: 1.01; 95% CrI: 0.83, 1.23). Topiroxostat likely increases risk of liver damage (RR: 2.65; 95%CI: 1.24, 5.70; NNH: 33.40) as compared with placebo. With regard to MACE, there were no statistically significant differences between three uric acid lowering medications and placebo: allopurinol (RR: 0.63; 95% CrI: 0.36, 1.34), febuxostat (RR: 0.69; 95% CrI: 0.38, 1.66), and lesinurad combined with XOI (RR: 0.56; 95% CrI: 0.23, 1.85). The rankings of different interventions were depicted by cumulative ranking curve (SUCRA). Conclusions: Through NMA, we provide some evidence for the safety of ULTs. We found no statistically significant differences in their effects on treatment‐related adverse events and MACE. However, topiroxostat likely increases the risk of liver damage. [ABSTRACT FROM AUTHOR]

Background & Aims: The outbreak of coronavirus disease 2019 (COVID‐19) has been declared a pandemic. Although COVID‐19 is caused by infection in the respiratory tract, extrapulmonary manifestations including dysregulation of the immune system and hepatic injury have been observed. Given the high prevalence of hepatitis B virus (HBV) infection in China, we sought to study the impact of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and HBV coinfection in patients. Methods: Blood samples of 50 SARS‐CoV‐2 and HBV coinfected patients, 56 SARS‐CoV‐2 mono‐infected patients, 57 HBeAg‐negative chronic HBV patient controls and 57 healthy controls admitted to Renmin Hospital of Wuhan University were collected in this study. Complete blood count and serum biochemistry panels including markers indicative of liver functions were performed. Cytokines including IFN‐γ, TNF‐α, IL‐2, IL‐4, IL‐6 and IL‐10 were evaluated. T cell, B cell and NK cell counts were measured using flow cytometry. Results: SARS‐CoV‐2 and HBV coinfection did not significantly affect the outcome of the COVID‐19. However, at the onset of COVID‐19, SARS‐CoV‐2 and HBV coinfected patients showed more severe monocytopenia and thrombocytopenia as well as more disturbed hepatic function in albumin production and lipid metabolism. Most of the disarrangement could be reversed after recovery from COVID‐19. Conclusions: While chronic HBV infection did not predispose COVID‐19 patients to more severe outcomes, our data suggest SARS‐CoV‐2 and HBV coinfection poses a higher extent of dysregulation of host functions at the onset of COVID‐19. Thus, caution needs to be taken with the management of SARS‐CoV‐2 and HBV coinfected patients. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a newly emerging infectious disease. Our understanding of the clinical characteristics of liver damage and the relationship with disease severity in COVID‐19 is still limited. To investigate the serum hepatic enzyme activities in different phenotypes of COVID‐19 patients, evaluate their relationship with the illness severity and analyze the correlation of glycyrrhizin treatment and abnormal liver enzyme activities, one hundred and forty‐seven patients with COVID‐19 were enrolled in a retrospective study that investigated hepatic dysfunction. Liver alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), Y‐glutamyl transferase (GGT), superoxide dismutase (SOD), and alkaline phosphatase (ALP) were analyzed in these patients. Patients with diammonium glycyrrhizinate (DG) treatment were further investigated. Of the 147 patients, 56 (38.1%) had abnormal ALT activity and 80 (54.4%) had abnormal AST activity. The peak of abnormal hepatic enzyme activities occurred at 3 to 6 days after on admission. Serum AST and LDH levels were elevated, while the SOD level was decreased in severe and critical patients, compared with mild cases. DG treatment may alleviate the abnormal liver enzyme activities in non‐critical COVID‐19 patients. Abnormal liver functions may be observed in patients with COVID‐19, and were associated with SARS‐CoV‐2‐induced acute liver damage. Glycyrrhizin treatment may be an effective therapeutic approach for the outcome of abnormal hepatic enzyme activities in severe COVID‐19 cases. Serum hepatic enzyme tests may reflect the illness severity and should be monitored. [ABSTRACT FROM AUTHOR]

Quercetin is a plant flavonoid and has antioxidative properties. In this study, we evaluated the therapeutic effect of quercetin on thyroid dysfunction in L‐thyroxin (LT4)‐induced hyperthyroidism rats. LT4 was used to prepare the experimental hyperthyroidism model via the intraperitoneal injection. Quercetin was injected at a series doses (5, 50, and 100 mg/kg) to LT4‐induced hypothyroidism rats once a day for 14 days. The body weight and food intake were measured once a week. The levels of thyroid hormones, liver function, oxidative stress markers, and antioxidant markers were measured using commercial enzyme‐linked immunosorbent assay kits. Hematoxylin–eosin staining was used to observe the thyroid tissue histological changes. The levels of nuclear and total nuclear factor erythroid 2‐related factor 2 (Nrf2) were determined by western blot. The liver oxidative stress markers in LT4‐induced hyperthyroidism Nrf2 knockout rats were determined to evaluate the role of Nrf2 on quercetin induced protective effects. LT4 administration increased the levels of serum triiodothyronine and thyroxine, activity of oxidative stress markers with a parallel decrease in antioxidant markers and Nrf2. However, the simultaneous administration of quercetin, reversed all these effects indicating its potential in the regulation of hyperthyroidism. Furthermore, the loss function of Nrf2 diminished these effects resulting from the quercetin application, indicating the inhibitory effects caused by the quercetin may be involved in Nrf2 signaling pathway. These results indicate that quercetin could be used to protect against experimental hyperthyroidism‐induced liver damage via Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim‐3) and TLR4 receptors play important roles in CCl4‐induced acute liver injury. Tim‐3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim‐3 (anti‐Tim‐3 Ab), we studied the Tim‐3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti‐Tim‐3 Ab treatment increased interferon‐ɣ production by concanavalin A (ConA)‐stimulated spleen T cells, and we found that the expression level of interleukin (IL)‐6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin‐9 (Gal‐9, a Tim‐3 ligand) reduced the IL‐6 production. This indicates the importance of the Tim‐3/Gal‐9 signalling pathway in maintaining hepatic homeostasis. The Tim‐3 signalling pathway inhibits TLR4‐mediated NF‐κB activity, and an anti‐Tim‐3 Ab does not affect the liver injury in TLR4‐deficient mice. Regulation between Tim‐3 and TLR4 determines the severity of liver damage. The negative regulation of Tim‐3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5-27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC. [ABSTRACT FROM AUTHOR]

Summary: In Chronic hepatitis B (CHB) infection, virus and immune response interplay is thought to be responsible for pathogenesis. Yet, the impact of each immune cell population and viral protein expression in liver damage is still unknown. Our aim was to study the interplay between intrahepatic immune response and viral activity in relation to CHB liver damage. Immunostaining was performed in 29 liver biopsies from untreated CHB patients to characterize liver infiltrate [Th (CD4+), CTL (CD8+), Treg (FoxP3+), Th17 (IL‐17A+) and Th1 (T‐bet+)] and viral antigen expression (HBsAg and HBcAg). Inflammatory activity and fibrosis were assessed using the HAI and METAVIR scoring system. All studied populations were identified in the portal‐periportal (P‐P) areas with a CD4+ lymphocyte predominance, while only CD8+ and FoxP3+ cells were observed in the intralobular area. Both P‐P CD4+ and intralobular CD8+ cell frequencies were increased among severe hepatitis cases. Concerning HBsAg and HBcAg expression, a mutually exclusive pattern was observed. HBcAg was mainly detected among HBeAg‐positive patients and was associated with hepatitis severity and higher frequency of P‐P FoxP3+, intralobular CD8+ and FoxP3+ cells. HBsAg was identified among HBeAg‐negative cases with less severe hepatitis grade and lower frequency of P‐P CD4+ and intralobular FoxP3+ lymphocytes. In conclusion, the HBV antigen profile expression seen during CHB infection may be reflecting different stages of viral replication which impacts the host immune response and liver damage process. While HBcAg might be an inducer of a regulatory microenvironment, the intralobular CTL population seemed to have a key role in hepatitis severity. [ABSTRACT FROM AUTHOR]

Aim: Minimally invasive liver resection (MILR) is considered a safe and feasible treatment for malignant liver tumors. However, few studies have investigated the surgical outcomes of MILR in patients with impaired liver function. Liver damage is used for consideration of hepatectomy. The aim of this study is to clarify the efficacy of MILR for patients with impaired liver function by using propensity score matching. Methods: Ninety‐nine patients with liver damage B underwent hepatic resection were analyzed. The patients were divided into two groups, the MILR group (n = 24) and the open liver resection (OLR) group (n = 75). After matching of a propensity score, we compared clinicopathological features and surgical outcomes. Results: After matching, 36 patients (18 patients from each group) were selected and the patients’ characteristics and tumor characteristics were not significantly different between the two groups. Blood loss (P = 0.0163) and complication rate (P = 0.0162) were significantly decreased in the MILR group. Complications were observed in eight patients, comprising one patient in the MILR group and seven patients in the OLR group. The postoperative hospital stay was significantly shortened in the MILR group (P = 0.0118). Conclusion: Minimally invasive liver resection might be effective for patients with impaired liver function. It reduces surgical complications and consequently shortens hospitalization time. [ABSTRACT FROM AUTHOR]

Abstract: Imazalil (IMZ), which is a widely used fungicide, can accumulate in the body and threaten an animal's health. However, this fungicide has adverse effects on aquatic organisms and ultimately affects human health when it leaches into the environment. Our research tried to determine that if IMZ might cause liver damage and its potential to cause‐related diseases. In this study, male adult C57BL/6 mice were exposed to 0.1, 0.5, or 2.5 mg/kg body weight IMZ in drinking water for 15 weeks. Then, we evaluated the liver damage at the physiological, biochemical, and transcriptome levels in mice after chronic IMZ exposure. We observed serious ballooning degeneration of hepatocytes in the IMZ‐treated groups. And IMZ induced oxidative stress and caused the disorders of bile acid metabolism in mice. In addition, the transcriptome data showed that IMZ has substantial influence on several pathways, including metabolic pathways for drug metabolism, RNA transport, and bile secretion. We further confirmed that the mRNA expression of the key genes involved in oxidative stress and bile acid metabolism were changed of mice exposed to IMZ. Our data suggested that chronic IMZ exposure could induce hepatotoxicity in mice at the physiological, biochemical, and transcriptome levels. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy of the newly proposed albumin–bilirubin (ALBI) grade for therapy selection, clinical features of patients treated with radiofrequency ablation (RFA) were elucidated. Methods: From 2000 to 2015, 1101 patients with HCC (<3 cm, ≤3 tumors) treated with RFA were enrolled, with the following clinical features: 734 men and 367 women; 779 with hepatitis C virus, 153 with hepatitis B virus, 5 with hepatitis C and B, and 164 others; and Child–Pugh classification (CP) A : B ratio of 842:259. Liver damage classification (LD) using the indocyanine green retention rate at 15 min and ALBI‐grade were compared in regard to the prognoses of those patients. Results: Median tumor size was 1.7 cm (interquartile range, 1.4–2.2 cm) and single tumors were found in 802 cases (72.8%) (tumor–node–metastasis stage of the Liver Cancer Study Group of Japan I : II : III = 536:454:111). In the LD‐A group, the number of cases with ALBI‐grade 1, 2, and 3 were 294, 224, and 1, respectively, while those in the LD‐B group were 47, 490, and 12, respectively. In the LD‐C group, 19 and 14 patients were ALBI‐2 and ‐3, respectively. Akaike Information Criterion values for CP, LD‐grade, and ALBI‐grade were 6015.4, 5988.8, and 5990.7, respectively. However, there was no significant difference regarding prognosis between LD‐A/B (n = 228) and C (n = 31) (median survival time, 4.8 vs. 3.9 years, P = 0.0818) in CP‐B, whereas a significant difference was observed regarding prognosis for ALBI‐1/2 (n = 232) and ALBI‐3 (n = 27) (median survival time, 4.8 vs. 2.7 years, P = 0.0168). Conclusion: Albumin–bilirubin grade showed an assessment ability similar to that of LD‐grade. Furthermore, there was a small improvement in prognosis following RFA in patients with an ALBI‐grade of 3. Although only two serological parameters, albumin and total bilirubin, are used, assessment with ALBI‐grade may be more useful than with LD‐grade for avoiding a non‐beneficial RFA procedure. [ABSTRACT FROM AUTHOR]

Thioacetamide (TAA) is a hepatotoxin that rapidly triggers the necrotic process and oxidative stress in the liver. Nevertheless, organic selenium compounds, such as β-selenoamines, can be used as pharmacological agents to diminish the oxidative damage. Thus, the aim of this study was to investigate the protective effect of the antioxidant β-selenoamines on TAA-induced oxidative stress in mice. Here, we observed that a single intraperitoneal injection of TAA (200 mg/kg) dramatically elevated some parameters of oxidative stress, such as lipid peroxidation and reactive oxygen species (ROS) production, as well as depleted cellular antioxidant defenses. In addition, TAA-induced edema and morphological changes in the liver, which correlate with high serum aspartate and alanine aminotransferase enzyme activities, and a decrease in cell viability. Conversely, a significant reduction in liver lipid peroxidation, ROS production, and edema was observed in animals that received an intraperitoneal injection of β-selenoamines (15.6 mg/kg) 1 h after TAA administration. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the effect of selenium (Se) on chromium (VI) [Cr(VI)]-induced damage in chicken liver. A total of 105 chickens were randomly divided into seven groups of 15. Group I received deionized water; group II received Cr(VI) (7.83 mg/kg/d) alone; and other groups orally received both Cr(VI) (7.83 mg/kg/d) and Se of different doses (0.14, 0.29, 0.57, 1.14, and 2.28 mg/kg/d). The levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), Ca2+-ATPase, and mitochondrial membrane potential (MMP) were measured. Results showed that Cr(VI) increased MDA content and decreased GSH content, T-SOD activity, Ca2+-ATPase activity, and MMP level. Meanwhile, Se co-treatment (0.14, 0.29, and 0.57 mg/kg/d) increased the viability of the above indicators compared with Cr(VI)-treatment alone. In addition, histopathologic examination revealed that Cr(VI) can cause liver damage, whereas Se supplementation of moderate dose inhibited this damage. This study confirmed that Se exerted protective effect against Cr(VI)-induced liver damage. [ABSTRACT FROM AUTHOR]

SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT1 is regulated in vivo remain unclear. Here, we report that phosphorylation modification of T522 on SIRT1 is crucial for tissue-specific regulation of SIRT1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho-T522 level is reduced during adipogenesis. Knocking-in a constitutive T522 phosphorylation mimic activates the β-catenin/ GATA3 pathway, repressing PPARγ signaling, impairing differentiation of white adipocytes, and ameliorating high-fat diet-induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT1 in response to over-nutrition. Hepatic SIRT1 is hyperphosphorylated at T522 upon high-fat diet feeding. Knocking-in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high-fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT1 phosphorylation, and energy homeostasis and demonstrate that the phosphorylation of T522 is a critical element in tissue-specific regulation of SIRT1 activity in vivo. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) belongs to the group B trichothecenes, which are the most common mycotoxins in cereal commodities. It is very stable within the temperature range 170-350 °C, showing no reduction in its concentration after 30 min at 170 °C. This chemical property is a very dangerous factor for human and animal health. Liver is also responsible for the detoxification and formation of DON-glucuronide in both human and animals. Some studies already demonstrated that DON could induce liver damage remarkably through DON altering expressions of p53, caspase-3, caspase-7, caspase-8 and Bax in different cell lines. At the same time, other publications illustrated some opposite results. At present, a full and systematic discussion of the hepatic toxicity of DON is still lacking. Therefore, the aim of the present review is to summarize and update the prominent evidence, regarding DON effects on liver tissues and cell lines. Moreover, based on the current studies we outline some of the identified molecule targets or pathways involved in DON-induced hepatotoxicity, and put forward our opinions and suggest an hypothesis for future research. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32−/− mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32−/− mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32−/− mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

ABSTRACT The aim of this study was to explore the roles of cytochrome P450 2E1 (CYP2E1) in 1,2-dichloroethane (1,2-DCE)-induced liver damage. Two parts were included in this study: first, effect of 1,2-DCE on microsomal expression of CYP2E1, and second, potential of an inhibitor of CYP2E1 to reduce 1,2-DCE-induced liver damage. In part one, mice were exposed to 0, 0.225, 0.45, or 0.9 g/m3 1,2-DCE for 10 days, 3.5 h per day through static inhalation. In part two, mice were divided into blank control, solvent control, inhibitor control, 1,2-DCE-poisoned group, and low or high intervention group. In part one, compared to the control, serum alanine aminotransferase (ALT) activities and hepatic malondialdehyde (MDA) levels in 0.9 g/m3 1,2-DCE group, and microsomal CYP2E1 protein expression and activity in both 0.45 and 0.9 g/m3 1,2-DCE groups increased significantly; conversely, hepatic nonprotein sulfhydryl (NPSH) levels in both 0.45 and 0.9 g/m3 1,2-DCE groups and hepatic SOD activities in 0.9 g/m3 1,2-DCE group decreased significantly. In part two, microsomal CYP2E1 protein expression and activity decreased significantly in both low and high intervention groups compared to 1,2-DCE-poisoned group. Along with the changes of CYP2E1, hepatic MDA levels and serum ALT activities decreased; conversely, hepatic NPSH levels and SOD activities increased significantly in high intervention group. Taken together, our results suggested that 1,2-DCE could enhance CYP2E1 protein expression and enzymatic activity, which could cause oxidative damage in liver, serving as an important mechanism underlying 1,2-DCE-induced liver damage. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1430-1438, 2016. [ABSTRACT FROM AUTHOR]

Aim Besides the residual liver volume, damage of the microcirculation secondary to increased portal blood flow is a main determinant of postoperative liver failure (PLF). Endothelin-1 (ET-1), produced by sinusoidal endothelial cells, plays a key role in the regulation of hepatic microcirculation. The aim of this study was to determine whether ET-1 levels has any prognostic utility in predicting PLF. Methods Patients undergoing liver resection for primary or secondary liver tumors at San Raffaele Hospital, Milan, were prospectively enrolled in the study. Serial postoperative serum ET-1 levels in patients undergoing liver resections were correlated with indices of inflammatory response, liver failure and death. Results A total of 144 patients were included. ET-1 levels in patients who underwent major or extended liver resection were significantly higher than in patients who had a minor resection on postoperative day (POD) 1 ( P = 0.003), POD 2 ( P = 0.0001) and POD 5 ( P = 0.0001). Eight patients developed PLF and ET-1 was significantly higher compared with patients without PLF on POD 2 ( P = 0.002) and POD5 ( P = 0.006). Serum ET-1 concentration on POD 2 was an independent predictor of PLF in multivariate analysis. Conclusion ET-1 is as an early index of PLF and provides a rationale for therapeutic manipulation, with many potential clinical implications to prevent PLF onset and reduce its severity. [ABSTRACT FROM AUTHOR]

Recent studies have shown that metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1) was overexpressed in many human solid cancers, however, its roles in plasma of hepatocellular carcinoma ( HCC) patients were unclear. The aim of this study was to investigate the significance of plasma MALAT1 levels in HCC patients. Plasma samples were collected from pre-operative HCC, hepatic disease patients, and healthy controls, and tissue samples from HCC patients and colorectal cancer patients with liver metastasis. Plasma and tissue MALAT1 levels were measured. Plasma MALAT1 levels were progressively and significantly higher in HCC patients than hepatic disease patients, and higher in hepatic disease patients than healthy controls. The expression of MALAT1 in HCC tissue was slightly higher than that in paired non-cancerous liver tissue, but not significant. The expression of MALAT1 in the non-cancerous liver tissue of 20 HCC patients was significantly higher than that in normal liver tissue of 13 colorectal cancer patients. In contrast, plasma MALAT1 levels were significantly low in HCC patients with hepatitis B infection, and significantly high in patients with liver damage B or liver cirrhosis. In a receiver-operator curve analysis of HCC and hepatic disease patients, the cut-off value of plasma MALAT1 was 1.60 and the area under the curve was 0.66. Plasma MALAT1 levels were not correlated with α-fetoprotein or protein induced by vitamin K absence II, whereas sensitivity and specificity for the detection of HCC with the combination of MALAT1, α-fetoprotein, and protein induced by vitamin K absence II were 88.6% and 75%, respectively. In conclusion, the plasma MALAT1 level is associated with liver damage, and has clinical utility for predicting development of HCC. [ABSTRACT FROM AUTHOR]

Nobiletin and tangeretin are polymethoxy flavonoids (PMFs), found in rich quantities in the peel of citrus fruits. In the present study, we assessed the biological effect of the PMFs on liver damage using a mouse model of binge drinking. First, we extracted PMFs from the peels of Citrus aurantium to make Citrus aurantium extract (CAE). Male C57BL/6 mice were orally treated with silymarin and CAE (50, 100, and 200 mg/kg) for 3 days prior to ethanol (5 g/kg, total of 3 doses) oral gavage. Liver injury was observed in the ethanol alone group, as evidenced by increases in serum hepatic enzymes and histopathologic alteration, as well as by hepatic oxidative status disruption. CAE improved serum marker and hepatic structure and restored oxidative status by enhancing antioxidant enzyme levels and by reducing lipid peroxidation levels. In addition, CAE evidently suppressed inflammation and apoptosis in the livers of mice administered with ethanol, by 85% (tumor necrosis factor-α) and 44% compared to the control group, respectively. Furthermore, CAE activated lipid metabolism related signals and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and nuclear factor E2-related factor 2 (Nrf2) with several cytoprotective proteins including heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrated that, CAE possesses antioxidant, anti-inflammatory, and antiapoptotic activity against ethanol-induced liver injury. [ABSTRACT FROM AUTHOR]

The scarcity of donor livers and the impracticality of hepatocyte transplantation represent the biggest obstacles for the treatment of liver failure. Adipose-derived stem cells, with their ability to differentiate into the hepatic lineage, provide a reliable alternative cell source with clear ethical and practical advantages. Moreover, adipose-derived stem cells can effectively repair liver damage by the dominant indirect pattern and increase the number of hepatocytes by the secondary direct pattern. In recent years, the development of the indirect pattern, which mainly includes immunomodulatory and trophic effects, has become a hot topic in the field of cell engineering. Therefore, adipose-derived stem cells are considered to be ideal therapeutic stem cells for human liver regeneration. In this article, we reviewed the advantages of adipose-derived stem cells in liver regeneration, and explore their underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background & Aims Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. Methods Forty-six Sprague-Dawley rats with CCl4-induced cirrhosis were randomized into two groups: VSL#3 group ( n = 22) that received VSL#3 in drinking water, and water group ( n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. Results Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) ( P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group ( P = 0.03 vs. VSL#3 group) and 0/11 in the control group ( P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group ( P < 0.05). Conclusions VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis. [ABSTRACT FROM AUTHOR]

Twenty-eight rats were examined in a 5-week experiment to investigate the effect of curcumin on gene expression and activities of hepatic antioxidant enzymes in rats intoxicated with aflatoxin B1 (AFB1). The rats were divided into four groups. Rats in 1-4 groups served as control, oral curcumin treated (15 mg/kg body weight), single i.p. dose of AFB1 (3 mg/kg body weight) and combination of single i.p. dose of AFB1 with oral curcumin treated, respectively. AFB1 Liver damage and oxidative stress were evident in untreated AFB1-intoxicated rats as indicated by a significant elevation in hepatic transaminases, elevation in lipid peroxide biomarkers (thiobarbituric acid reactive substances; TBARS), reduction of reduced glutathione (GSH) concentration, reduction in the activities of antioxidant enzymes namely catalase (CAT), total superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione-S-transferase (GST) and down-regulation of gene expression of these antioxidant enzymes compared to control. Liver sections of rats intoxicated with AFB1 showed a disrupted lobular architecture, scattered necrotic cells and biliary proliferation. Administration of curcumin with AFB1 resulted in amelioration of AFB1-induced effects compared to untreated AFB1-intoxicated rats via an up-regulation of antioxidant enzyme gene expression, activation of the expressed genes and increase in the availability of GSH. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Interleukin-21 ( IL-21) participates in tissue damage in various immune-mediated diseases. Its role in the pathogenesis of chronic active hepatitis B ( CAHB) has not been clarified. The frequency of circulating IL-21+ T cells and the levels of serum and intrahepatic IL-21 have been characterized in 70 CAHB patients, 32 inactive carrier ( IC), 18 chronic hepatitis C ( CHC) and 20 healthy controls ( HC). Their potential association with liver injury was analysed. The percentages of IL-21+ CD3+ CD8− and IL-21+ CD3+ CD8+ T cells and the levels of serum IL-21 in CAHB patients were significantly higher than that in the IC, CHC patients and HC ( P < 0.001) and were correlated positively with the levels of serum alanine aminotransferase ( ALT, r = 0.424, P < 0.001; r = 0.392, P = 0.001) and aspartate aminotransferase ( AST, r = 0.388, P = 0.001; r = 0.329, P = 0.005) in CAHB patients, respectively. The levels of IL-21 expression in the liver tissues were associated significantly with increased degrees of inflammation and fibrosis in CAHB patients ( P < 0.01 or P < 0.05). Our findings suggest that aberrant IL-21 responses may be associated with the progression of CHB. [ABSTRACT FROM AUTHOR]

Aim: To compare the blood dynamics of anticancer drugs (cisplatin, mitomycin, epirubicin) and the negative effect on normal liver tissue among the following procedures: hepatic arterial infusion (HAI), HAI with lipiodol (Lp-HAI) and transcatheter arterial chemoembolization (TACE) with Lp plus particles (Lp-TACE). Methods: Nine swine were divided into three groups: (i) HAI group animals were infused with 5 mg/mL cisplatin, 1 mg/mL mitomycin and 4 mg/mL epirubicin in 0.1 mL/kg contrast medium; (ii) Lp-HAI group animals, with the same doses in 0.1 mL emulsified fluid (0.05 mL/kg, Lp); and (iii) Lp-TACE group animals, with the same doses in 0.1 mL emulsified fluid plus gelatin sponge particles. Outflow ratio (area under plasma concentration curve [AUC0-60] / total infused dose of anticancer drug) and necrosis volume ratio (necrosis volume / total slice volume × 100) were explored. Results: Outflow ratios (AUC0-60/mg) of cisplatin, mitomycin and epirubicin, and the necrosis volume ratio (%) of the livers, were 2.30, 6.91, 0.97 and 0, respectively, in the HAI group; 1.71, 5.43, 0.79 and 1.37, respectively, in the Lp-HAI group; and 1.23, 3.37, 0.47 and 20.88, respectively, in the Lp-TACE group. The significantly lowest outflow ratio for each anticancer drug ( P = 0.05/3) and the significantly highest necrosis volume ratio ( P = 0.05/3) were found in Lp-TACE, followed by Lp-HAI and HAI. Conclusion: Although the necrosis volume ratio of the liver was tolerable, Lp-TACE caused the greatest delay in outflow ratio for each cancer drug and the greatest negative effect to liver in a swine model. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose Acetaminophen is a commonly used analgesic; excessive doses can lead to liver damage. We sought to determine the proportion of acetaminophen users exceeding the recommended maximum daily dose of 4 g and identify correlates of such behavior. Methods U.S. adults were recruited from an internet panel in summer 2010, oversampling past 30-day acetaminophen users. Among 47 738 starting the study, 5649 completed all phases; individuals with low education were underrepresented. Subjects completed a 7-day daily diary online, reporting intake of acetaminophen products selected from a comprehensive list; total daily dose was computed from product names. An exit survey elicited: attitudes/knowledge related to product ingredients, label reading, dosing behavior; demographics, medical history, general physical, and mental health status. Unconditional logistic regression identified variables independently associated with use exceeding 4 g. Results Among 3618 acetaminophen users, 163 took >4 g on ≥1 day (4.5%); the median dose was 5.5 g; 26 took >8 g (0.7%). >4-g users were characterized by chronic pain, poor physical status, and heavy use of medical care. Knowledge of ingredients and recommended OTC doses for all products taken was inversely associated with >4-g use (multivariable odds ratios [ORs] = 0.5-0.6), as was the attitude to start with the lowest dose (OR = 0.6). The attitude that users could choose their own dose was positively associated (OR = 1.3). Conclusions The results estimate the proportion of acetaminophen users exceeding 4 g in a group of U.S. adults, identify potentially modifiable attitudes and knowledge associated with such use, and characterize subpopulations at higher risk. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

MicroRNAs are small non-coding RNA molecules that post-transcriptionally regulate gene expression. Liver-specific microRNA-122 (miR-122) has been shown to facilitate the replication of hepatitis C virus (HCV) in human hepatoma cells in vitro. However, the clinical significance of hepatic miR-122 on HCV in human body is unclear. Hepatic miR-122 expression was quantified using quantitative reverse-transcription polymerase chain reaction. We investigated the correlation between miR-122 expression and HCV load in liver samples from 185 patients seropositive for HCV antibody, including 151 patients seropositive for HCV RNA, and 31 patients seronegative for HCV RNA. Although hepatic miR-122 expression was weakly and positively correlated with the serum HCV load (ρ=0.19, P<0.05), it was not correlated with the hepatic HCV load (ρ=−0.14, P=0.08). The absence of a correlation between miR-122 expression and hepatic HCV load was also confirmed after stratification of histopathological liver damage (inflammatory activity grades and fibrosis stages). Furthermore, hepatic miR-122 expression in patients seronegative for HCV RNA was significantly higher than that in patients seropositive for HCV RNA ( P<0.0001). The level of hepatic miR-122 expression was inversely correlated with the severity of functional and histopathological liver damage ( P<0.0001), serum transaminase levels ( P<0.0005). Compared with in vitro findings, hepatic miR-122 expression is not correlated with HCV load in the human liver. Therefore, miR-122, by itself, is not a critical molecular target for HCV therapy. MiR-122 expression is inversely correlated with both functional and histopathological liver damage. [ABSTRACT FROM AUTHOR]

Since aflatoxin B (AFB)-mediated hepatic damage is related to the production of AFB-8,9-epoxide and reactive oxygen species, bioactive compounds having antioxidant potentials are suggested to be capable of reducing AFB-induced toxicity. We previously purified a mixture of flavonoids that we named RCMF ( Rhus verniciflua Stokes chloroform-methanol fraction), from a traditional Korean food additive and herbal medicine. RCMF exhibited various biological effects, including antioxidant and antitumor activities. In this study, we examined whether RCMF protects against AFB-induced liver injury using in vitro and in vivo systems. Pretreatment of HepG2 cells with RCMF significantly reduced AFB-stimulated production of ROS and malondialdehyde (MDA) to the control levels. RCMF also prevented the reduction in HepG2 cell viability caused by AFB. Oral administration of RCMF to mice significantly suppressed an AFB-induced increase in serum levels of alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase. It also prevented MDA formation and blocked decreases in glutathione levels and superoxide dismutase activities in the livers of AFB-treated mice. In addition, RCMF supplementation prevented an AFB-induced decrease in serum titers of IgA and IgG1. Collectively, these results suggest that RCMF attenuates AFB-mediated damage to the liver, and that this effect is at least partially related to the restoration of antioxidant defense systems and an increase in AFB-GSH conjugate formation. Copyright © 2010 John Wiley & Sons, Ltd. Since aflatoxin B (AFB)-mediated hepatic damage is related to the production of AFB-8,9-epoxide and reactive oxidants, bioactive compounds having antioxidant potentials are suggested to be capable of reducing AFB-induced toxicity. This study examined whether a mixture of flavonoids, named RCMF, protects against AFB1-induced liver injury. Herein we demonstrate that RCMF attenuates AFB-mediated damage to the liver, and that this effect is at least partially related to the restoration of antioxidant defense systems and an increase in AFB-GSH conjugate formation. [ABSTRACT FROM AUTHOR]

Since 1900 bc, several therapeutic activities have been attributed to the rhizomes of the plant Curcuma longa for a variety of diseases, including liver disorders. Curcumin, the main active compound obtained from this plant, was first isolated two centuries ago and its structure as diferuloylmethane was determined in 1910. Curcumin has shown anti-inflammatory, anti-oxidant, antifungal, antibacterial and anticancer activities. The pharmacological properties of curcumin were reviewed recently and focused mainly on its anticancer properties. However, its beneficial activity on liver diseases (known centuries ago, and demonstrated recently utilizing animal models) has not being reviewed in depth until now. The curcumin ability to inhibit several factors like nuclear factor-κB, which modulates several pro-inflammatory and profibrotic cytokines as well as its anti-oxidant properties, provide a rational molecular basis to use it in hepatic disorders. Curcumin attenuates liver injury induced by ethanol, thioacetamide, iron overdose, cholestasis and acute, subchronic and chronic carbon tetrachloride (CCl4) intoxication; moreover, it reverses CCl4 cirrhosis to some extent. Unfortunately, the number of studies of curcumin on liver diseases is still very low and investigations in this area must be encouraged because hepatic disorders constitute one of the main causes of worldwide mortality. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze drug-induced liver disease over an 8-year period from January 2000 to December 2007 in one gastroenterological department. METHODS: International consensus of standard definitions and criteria for assessing causality of adverse drug reactions were applied to all patients with abnormal hepatic test results. RESULTS: Drugs were implicated in hepatic injury in 30 patients (15 men and 15 women) in whom there was a causal or highly probable relationship between drug use and liver disease. The drugs responsible for liver damage were Chinese medicinal herbs ( n = 12), cyclosporin ( n = 2), fosfomycin, gentamicin, flutamide, acipimox and nimesulide ( n = 1 each). Of the 30 patients, 19 (63.3%) were classified as having hepatocellular or mixed hepatitis, eight (26.7%) as having cholestatic injury and the remaining three as having a severe hepatic drug reaction (prothrombin < 50%), including death. CONCLUSION: A thorough history of medication should be taken in all patients presenting with abnormal hepatic test results. Chinese medicinal herbs were the most frequent hepatotoxic factor in our patients, although the liver injury was not severe in most cases and was relieved after the prompt withdrawal of the suspected drug. [ABSTRACT FROM AUTHOR]

Genetic disorders of homocysteine (Hcy) or folate metabolism or high-methionine diets elevate plasma Hcy and its atherogenic metabolite Hcy-thiolactone. In humans, severe hyperhomocysteinemia due to genetic alterations in cystathionine β-synthase (Cbs) or methylenetetrahydrofolate reductase (Mthfr) results in neurological abnormalities and premature death from vascular complications. In mouse models, dietary or genetic hyperhomocysteinemia results in liver or brain pathological changes and accelerates atherosclerosis. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates modified proteins (N-Hcy-protein) with autoimmunogenic and prothrombotic properties. Our aim was to determine how N-Hcy-protein levels are affected by genetic or nutritional disorders in Hcy or folate metabolism in mice. We found that plasma N-Hcy-protein was elevated 10-fold in mice fed a high-methionine diet compared with the animals fed a normal commercial diet. We also found that inactivation of Cbs, Mthfr, or the proton-coupled folate transporter (Pcft) gene resulted in a 10- to 30-fold increase in plasma or serum N-Hcy-protein levels. Liver N-Hcy-protein was elevated 3.4-fold in severely and 11-fold in extremely hyperhomocysteinemic Cbs-deficient mice, 3.6-fold in severely hyperhomocysteinemic Pcft mice, but was not elevated in mildly hyperhomocysteinemic Mthfr-deficient animals, suggesting that mice have a capacity to prevent accumulation of N-Hcy-protein in their organs. These findings provide evidence that N-Hcy-protein is an important metabolite associated with Hcy pathophysiology in the mouse. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the link of nuclear factor-κB (NF-κB) in liver diseases. It states that there are five NF-κB transcription factors with significant roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. It notes that a link between inflammation and hepatocellular carcinoma through the NF-κB pathway has been observed for its tumor-promoting function, as well as a target for drug therapy. Results found that NF-κB has an inflammatory role in vivo setting.

Background and purpose:Reactive oxygen species (ROC) are the main causes of carbon tetrachloride (CCl4)-induced acute liver injury. Chondroitin-4-sulphate (C4S) is known to inhibit lipid peroxidation through antioxidant mechanisms. Activation of nuclear factor (NF)-κB and caspases may strongly intensify inflammation and cell damage, in addition to that directly exerted by ROS. We investigated whether treatment with C4S, besides exerting antioxidant activity, was able to modulate NF-κB and apoptosis activation in CCl4-induced liver injury in mice.Experimental approach:Acute hepatitis was induced in mice by an i.p. injection of CCl4. Varying doses of C4S were administered i.p. 1 h before, 6 and 12 h after CCl4 injection. 24 h after CCl4 injection, the mice were killed for biochemical and histological analysis.Key results:CCl4 injection produced: marked elevation of alanine aminotransferase and aspartate aminotransferase; hepatic membrane lipid peroxidation, assayed by 8-isoprostane levels; and depletion of reduced glutathione and superoxide dismutase. CCl4 also decreased NF-κB translocation and IkBα, and increased gene expression of mRNA and protein of metalloproteases (MMP)-2 and -9, and of pro- and cleaved forms of caspases-3 and -7. There was also increased liver polymorphonuclear infiltration, evaluated by elastase assay, and hepatic cell disruption.C4S treatment inhibited lipid peroxidation; blocked NF-κB activation and IkBα protein loss; decreased mRNA and proteins for MMPs and caspases; restored endogenous antioxidants; limited hepatic polymorphonuclear accumulation and tissue damage.Conclusions and implications:As antioxidants may inhibit NF-κB and caspase activation, we hypothesize that treatment with C4S was able to inhibit NF-κB and apoptosis activation in hepatic injury.British Journal of Pharmacology (2008) 155, 945–956; doi:10.1038/bjp.2008.338; published online 25 August 2008 [ABSTRACT FROM AUTHOR]

Background: The diverse incidence of alcoholic cirrhosis around the world and the fact that not all alcoholic drinkers develop liver disease indicates that genetic and environmental factors play an important role in the development of liver cirrhosis. Lipids participate in early stages of alcoholic cirrhosis. Therefore variations in the plasma lipid profile due to primary (genetic) or secondary (environmental) dyslipidemia could affect the development of liver disease. The aim of this study was to analyze the lipid profile and apolipoprotein E (APOE) polymorphism in patients with alcoholic liver cirrhosis (AC) and determine the risk associated with genotype polymorphism with the onset of alcoholic cirrhosis. Methods: In a case and control study, 86 patients with AC divided into hyperlipidemic (H) and non-hyperlipidemic (non-H) groups, and 133 healthy individuals (C) matched by age and sex were studied. Lipid profile and liver function tests were measured by enzymatic methods. The APOE genotypes were identified by PCR-RFLP′s. Results: A statistically significant increase of the APOE*2 allele and genotypes 2/2, 2/3, and 2/4 was present in AC patients compared to C group. A hyperlipidemic state characterized by increased levels of triglycerides and apolipoprotein B (APOB) and a decrease of high density lipoprotein-cholesterol (HDL-c) was detected in young-aged patients (31.2 ± 6.2 years old vs. 46.3 ± 12.5 years old). In this group, hypertriglyceridemia was closely associated to APOE*2 allele and to an early onset of liver cirrhosis. By contrast, APOE*4 allele was associated with a longer duration of alcohol intake (>20 years) in the non-H group. Conclusions: This study shows the association of hypertriglyceridemia and APOE allele with the early onset of alcoholic liver cirrhosis, and the interaction between environmental factors, such as duration of alcohol abuse and amount of alcohol intake, and genetic factors (APOE*2 allele) on the hypertriglyceridemic process. [ABSTRACT FROM AUTHOR]

This article presents a study regarding the significance of hydroxyl groups in the hepatoprotective and antioxidant properties of resveratrol. Resveratrol or trimethylated resveratrol were administered to male rats and liver damage was induced by acute administration of CCI4 where appropriate controls were performed. The results of the study suggests that hydroxyl groups are significant hepatoprotective and antioxidant properties of the molecule of resveratrol, which can be improved by replacing hydrogen by a methyl in these groups.

The article analyzes and reviews some of the most promising and studied drugs used for liver diseases including colchicine, corticosteroids, curcumin, glycyrrhizin, interferons, Liv 52, nitric oxide, resveratrol, sylimarin, sulfoadenosylmethionine, and thalidomide. The study of colchicine and corticosteroids in animals and humans inferred that the two are not useful in the treatment of liver diseases. The herbal medicine glycyrrhizin has hepatoprotective properties in patients with subacute failure but deserves more controlled trials just like the interferon with antifibrotic properties. On the other hand, curcumin, resveratrol and thalidomide are said to be protective and curative compounds on hepatic diseases as well as the sulfoadenosylmethionine and silymarin.