Hepatocellular Damage Research Articles

СУЧАСНІ КРИТЕРІЇ ВЕРІФІКАЦІЇ ТА ОСНОВНІ ПРИНЦИПИ ВЕДЕННЯ НЕАЛКОГОЛЬНОЇ ЖИРОВОЇ ХВОРОБИ ПЕЧІНКИ У ДІТЕЙ

The article summarizes the knowledge about epidemiological data, clinical features, criteria for verification of the diagnosis, modern principles of diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD) in children based on the analysis of literature sources using paper and electronic databases PubMed, CyberLeninka, Web of Science, MedLine, The Cochrane Library. A review of literary sources on the study of this pathology demonstrates that at the present stage NAFLD has become one of the most common causes of chronic liver disease in children and adolescents because of the growing worldwide epidemic of childhood obesity. The article presents the latest recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the American Association for the Study of Liver Diseases on the screening strategy and basic criteria for verification of the diagnosis, as well as the principles of treatment of this pathology in pediatric practice. Particular attention is paid to the description of the main imaging methods that play a key role in the diagnosis of NAFLD in children and adolescents. The role of lifestyle modification as the main method of NAFLD treatment according to current international recommendations is described in detail. The review also analyzes the main researches that have focused on alternative treatments targeting the basic pathogenic factors of pathology development. In conclusion, the author considered the problem of lack of accurate non-invasive markers of hepatocellular damage and fibrosis in the pediatric practice, as well as the lack of clinical trials to determine optimal approaches to the treatment of non-alcoholic fatty liver disease in children.

Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy.

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium‐binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.

COVID-19 and comorbidities of hepatic diseases in a global perspective.

The worldwide outbreak of coronavirus disease 2019 (COVID-19) has challenged the priorities of healthcare system in terms of different clinical management and infection transmission, particularly those related to hepatic-disease comorbidities. Epidemiological data evidenced that COVID-19 patients with altered liver function because of hepatitis infection and cholestasis have an adverse prognosis and experience worse health outcomes. COVID-19-associated liver injury is correlated with various liver diseases following a severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infection that can progress during the treatment of COVID-19 patients with or without pre-existing liver disease. SARS-CoV-2 can induce liver injury in a number of ways including direct cytopathic effect of the virus on cholangiocytes/hepatocytes, immune-mediated damage, hypoxia, and sepsis. Indeed, immediate cytopathogenic effects of SARS-CoV-2 via its potential target, the angiotensin-converting enzyme-2 receptor, which is highly expressed in hepatocytes and cholangiocytes, renders the liver as an extra-respiratory organ with increased susceptibility to pathological outcomes. But, underlying COVID-19-linked liver disease pathogenesis with abnormal liver function tests (LFTs) is incompletely understood. Hence, we collated COVID-19-associated liver injuries with increased LFTs at the nexus of pre-existing liver diseases and COVID-19, and defining a plausible pathophysiological triad of COVID-19, hepatocellular damage, and liver disease. This review summarizes recent findings of the exacerbating role of COVID-19 in pre-existing liver disease and vice versa as well as international guidelines of clinical care, management, and treatment recommendations for COVID-19 patients with liver disease.

Biliary atresia liver histopathological determinants of early post-Kasai outcome

BackgroundA retrospective chart review of liver histologies in Kasai biliary atresia BA patients operated 1/2017- 7/2019 at our institution was conducted to identify histologic prognostic factors for biliary outcome. MethodsPatients with wedge liver biopsies and portal plate biopsies (n = 85) were categorized into unfavorable and favorable outcome, based on a 3-month serum total bilirubin level of <34 μM or mortality. Hepatocellular histologies, presence of ductal plate malformation (DPM) and of large bile duct of ≥ 150 μm diameter size at the portal plate were evaluated. ResultsTotal Bilirubin levels> 34 μM correlates with worse 1-year survival. Age at surgery, histologic fibrosis or inflammation does not predict outcome. Potential adverse predictors are severe hepatocellular swelling, severe cholestasis, presence of DPM (n = 24), and portal plate bile duct size < 150 µm (n = 28). In multivariate analyses adjusting for age at Kasai and postop cholangitis, bile duct size and severe hepatocellular swelling remain independent histologic prognosticators (OR 3.25, p = 0.039 and OR 3.26, p = 0.006 respectively), but not DPM. ConclusionAdvanced histologic findings of portal plate bile duct size of <150 µm and severe hepatocellular damage predict poor post-Kasai jaundice clearance and short-term survival outcome, irrespective of Kasai timing.Level of Evidence: Level III

Carbon Tetrachloride-Induced Hepatocellular Damage in Balb C Mice and Pharmacological Intervention by Extract of Daucus Carota

Background: Present research was planned to examine the shielding effect of Daucus carota root extract pre-treatment on the carbon tetrachloride-induced hepatotoxicity in Balb C mice.&#x0D; Objective: To cover the assessment of the enzymatic activity such as Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) and biochemical constituents like cholesterol, protein, lipids, glucose and urea contents in both the blood and liver while RNA and DNA substances exclusively in the liver.&#x0D; Setting: The induction of carbon tetrachloride (CCl4)-induced hepatotoxicity caused a rise in ALT of plasma and a decline in LDH.&#x0D; Method: The mice were treated with CCl4 and Daucus carota extract to check their effect on the level of biochemical constituents.&#x0D; Main Outcome Measure: Daucus carota extract pre-treatment obliterated CCl4-induced variations in the actions of enzymes.&#x0D; Results: cholesterol content decreased while glucose level increased in the blood. Glucose, lipids, cholesterol and urea in the liver were reduced while total protein level rose. Daucus carota extract pre-treatment also prohibited CCl4-induced variations in total protein contents, urea, glucose and lipids in the liver. CCl4 action caused huge hepatic damage. This was averted by Daucus carota extract.&#x0D; Conclusion: These outcomes reveal that Daucus carota root extract pre-treatment inhibited hepatic damage induced by CCl4 in the mice model, which corroborates its defensive effects against hepatic damage produced by both non-oxidative and oxidative mechanisms.

Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and resultsTranscriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. ConclusionsOur study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.

Profile of Heavy Metals and Antioxidant Defense in the Muscle Tissues of Pigeons (Columba livia f. urbana) from Anthropogenically Transformed Areas in the Pomeranian Region (Northern Poland)

Pigeons can be successfully used as bioindicators of a contaminated environment. We studied the relationship between the functioning of the pro/antioxidant balance in muscle tissues (skeletal muscle and cardiac tissues) of pigeons (Columba livia f. urbana) living in areas with different levels of pollution (Pomeranian Voivodeship, Northern Poland). The current study demonstrated the impact of the environment with preferential high Pb contamination in soil and feathers of pigeons on the formation of adaptive redox mechanisms in muscle tissues. An increase in the intensity of lipid peroxidation (estimated by the TBARS level) accompanied by enhancement of the oxidative modification of proteins (aldehydic and ketonic derivatives) and an important decrease in the activity of antioxidant enzymes (SOD, CAT, and GR) in pigeon muscle tissue was observed. These changes in enzyme activities were dependent on the type of muscle tissue (skeletal muscle and cardiac tissues). Our results confirm the concept of the recalculation of the De Ritis ratio (AsAT/AlAT) in both types of muscles indicating the tendency to cardio- and hepatocellular damage and toxicity caused by heavy metals from the polluted environment.

ASSESSMENT OF HEPATOTOXICITY OF MULTIPLE ANTIVIRAL RIAMILOVIR PREPARATION ADMINISTRATION IN NON-LINEAR GUINEA PIGS MODEL

The aim of this study was to asses hepatoxicity of riamilovir with repeated administration on the animal model. Materials and methods. Twenty non-linear guinea pigs were randomized into 4 groups: control and three experimental, receiving 64 days of daily riamilovir orally in doses of 48, 96, 144 mg/kg. Biochemical profile: ALT, AST, GGT, total protein, total and direct bilirubins, albumin, cholesterol, triglycerides: on 0, 33 and 65 days from the start of the experiment. Results. A significant decrease of serum albumin and cholesterol levels was found only in group 2 and there were no statistically significant changes of other indicators. Conclusion. The data obtained indicate afunctional liver synthetic function changes without signs of hepatobiliary and hepatocellular damage.

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p= 0.0083) and in patients with underlying liver disease (p= 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.

Tripartite Motif-Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor β-Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation.

Background and AimsHepatic ischemia‐reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif‐containing (TRIM) 27 in hepatic I/R injury remains worthy of study.Approach and ResultsThis study systemically evaluated the putative role of TRIM27/transforming growth factor β–activated kinase 1 (TAK1)/JNK (c‐Jun N‐terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down‐regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27‐KO mice) and hepatocyte‐specific Trim27 transgenic mice (Trim27‐HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R‐induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling.ConclusionsTRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1‐JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R‐mediated hepatocellular damage in transplant recipients.

Green Tea (Camellia sinensis) Ameliorate Non-alcoholic Fatty Liver Disease Induced by Highly Active Antiretroviral Therapy

Background: Highly Active Antiretroviral Therapy (HAART) has significantly enhanced the life expectancy of HIV-infected patients. However, utilization of HAART has been identified with adverse events including nonalcoholic fatty liver disease (NAFLD). Objectives: The Objective of this experiment was to explore the conceivable protective effect of green tea (Camellia sinensis) hydro-methonolic extract (GTE) on highly active antiretroviral therapy-induced NAFLD in albino Wistar rats. Methods: Thirty adult rats of comparative weights were chosen and divided into 5 groups of six rats each. Group-1 was a control group, Group II was given HAART and served as negative control, Groups III, IV and V were given HAART and 100, 200 and 400 mg/kg of GTE, respectively for sixty days. At the end of experiment day, the rats were fasted overnight sacrificed by cervical dislocation and blood was taken via cardiac puncture. Serum was separated and liver function test was assessed. Liver were excised from the rats, histopathological studies and lipid profiles were also investigated. Results: Elevated levels of serum TGL, total cholesterol, ALT, AST and liver TGL, TBARS and decreased levels of TAC was seen in HARRT treated rats. The amelioration potential of GTE was observed in a dose-dependent manner, the highest dose 400mg/kg more potently ameliorated HAART affected parameters near to the normal control. Conclusion: This consequence of HAART induced NAFLD may be due to oxidative stress by mitochondrial ROS that leads to increased hepatocellular oxidative damage. This may progress to hepatic inflammation and the development of NAFLD. The effect of GTE against NAFLD and oxidative stress might be due to its antioxidant activity and scavenging of reactive oxygen species induced by HAART.

Ginsenoside Rg3 ameliorates acetaminophen-induced hepatotoxicity by suppressing inflammation and oxidative stress.

Improper usage of acetaminophen (APAP) leads to morbidity and also mortality secondary to liver damage. Ginseng could suppress APAP-induced hepatotoxicity and ginsenoside Rg3 is a kind of major component in ginseng against liver damage. Herein, we intended to estimate the beneficial function and molecular mechanism of Rg3 on APAP-caused hepatotoxicity and identified hepatoprotection. A total of 50 C57BL/6J mice were divided into five random groups, and each contains 10 mice as the control, acetaminophen (350 mg/kg) and Rg3 (5, 10 and 20 mg/kg) + acetaminophen (350 mg/kg) groups. These mice were intragastric administration a single dose of acetaminophen by oral treatment behind pre-administered with several doses of ginsenoside Rg3 for six hours. According to our data, the injection of APAP (350 mg/kg) enhanced the basal levels of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and lactic dehydrogenase. However, these abnormal added were alleviated by Rg3. Moreover, Rg3 treatment obviously relieved APAP-caused inflammation and oxidant in liver tissues. The depletion of glutathione, glutathione peroxidase, total antioxidant capacity and generation of malondialdehyde induced by APAP treatment were reduced by Rg3. By H&E staining, Rg3 effectively reduced APAP-caused apoptosis and inflammatory infiltration. Moreover, Rg3 attenuated APAP-caused hepatic damage in part by regulating the pro-inflammatory and anti-inflammatory cytokines. Moreover, we found that Rg3 could bind to NLRP3 suggesting the anti-inflammatory effects of Rg3 by molecular docking study. In summary, Rg3 showed hepatic protective function in APAP-induced hepatotoxicity as evidenced by a reduction of the oxidant and the inflammatory reply, relieve of hepatocellular damage, showing potential in Rg3 as a potential therapeutic medicine to prevent hepatic injury.

Inhibition of hyaluronan synthesis by 4-methylumbelliferone ameliorates non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-induced murine model.

Hyaluronan (HA) as a glycosaminoglycan can bind to cell-surface receptors, such as TLR4, to regulate inflammation, tissue injury, repair, and fibrosis. 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, is a drug used for the treatment of biliary spasms. Currently, therapeutic interventions are not available for non-alcoholic steatohepatitis (NASH). In this study, we investigated the effects of 4-MU on NASH using a choline-deficient amino acid (CDAA) diet model. CDAA diet-fed mice showed NASH characteristics, including hepatocyte injury, hepatic steatosis, inflammation, and fibrogenesis. 4-MU treatment significantly reduced hepatic lipid contents in CDAA diet-fed mice. 4-MU reversed CDAA diet-mediated inhibition of Ppara and induction of Srebf1 and Slc27a2. Analysis of serum ALT and AST levels revealed that 4-MU treatment protected against hepatocellular damage induced by CDAA diet feeding. TLR4 regulates low molecular weight-HA-induced chemokine expression in hepatocytes. In CDAA diet-fed, 4-MU-treated mice, the upregulated chemokine/cytokine expression, such as Cxcl1, Cxcl2, and Tnf was attenuated with the decrease of macrophage infiltration into the liver. Moreover, HA inhibition repressed CDAA diet-induced mRNA expression of fibrogenic genes, Notch1, and Hes1 in the liver. In conclusion, 4-MU treatment inhibited liver steatosis and steatohepatitis in a mouse model of NASH, implicating that 4-MU may have therapeutic potential for NASH.

ER stress preconditioning ameliorates liver damage after hemorrhagic shock and reperfusion.

The mismatch of oxygen supply and demand during hemorrhagic shock disturbs endoplasmic reticulum (ER) homeostasis. The resulting accumulation of unfolded proteins in the ER lumen, which is a condition that is defined as ER stress, triggers the unfolded protein response (UPR). Since the UPR influences the extent of organ damage following hemorrhagic shock/reperfusion (HS/R) and mediates the protective effects of stress preconditioning before ischemia-reperfusion injury, the current study investigated the mechanisms of ER stress preconditioning and its impact on post-hemorrhagic liver damage. Male C56BL/6-mice were injected intraperitoneally with the ER stress inductor tunicamycin (TM) or its drug vehicle 48 h prior to being subjected to a 90 min pressure-controlled hemorrhagic shock (30±5 mmHg). A period of 14 h after hemorrhagic shock induction, mice were sacrificed. Hepatocellular damage was quantified by analyzing hepatic transaminases and hematoxylin-eosin stained liver tissue sections. Additionally, the topographic expression patterns of the ER stress marker binding immunoglobulin protein (BiP), UPR signaling pathways, and the autophagy marker Beclin1 were evaluated. TM injection significantly increased BiP expression and modified the topographic expression patterns of the UPR signaling proteins. In addition, immunohistochemical analysis of Beclin1 revealed an increased pericentral staining intensity following TM pretreatment. The histologic analysis of hepatocellular damage demonstrated a significant reduction in cell death areas in HS/R+TM (P=0.024). ER stress preconditioning influences the UPR and alleviates post-hemorrhagic liver damage. The beneficial effects were, at least partially, mediated by the upregulation of BiP and autophagy induction. These results underscore the importance of the UPR in the context of HS/R and may help identify novel therapeutic targets.

Hepatocellular damage and inflammation in various forms of alcoholic liver disease

The aim of the study was to evaluate hepatocellular damage and immune inflammation in various forms of alcoholic liver disease (ALD). 104 patients with ALD were examined: 15 (14.4%) with liver steatosis (LS), 19 (18.3%) with steatohepatitis and 70 (67.3%) with liver cirrhosis (LC); men 50 (48.1%), women 54 (51.9%); age 45.78.4 years. Traditional clinical, laboratory, instrumental studies were performed, the levels of fragments of cytokeratin-18 (FCK-18), cytokines IL-1, TNF-, IL-4, IL-6, IL-8 were determined by ELISA. The control group consisted of 39 healthy individuals: men 20 (51.2%), women 19 (48.7%), age 48.58.3 years. In LS, an increase in the level of FCK-18 was noted with normal aminotransferase activity, the content of TNF-, IL-6, IL-1, IL-8 increased and the level of IL-4 decreased compared to those in healthy individuals. In steatohepatitis, a triple increase in aminotransferases and FCK-18 was observed compared with LS, as well as an increase in the level of inflammatory mediators, to a greater extent IL-6, to a lesser extent IL-8, TNF-, a decrease in IL-4, IL-1 remained at the same level. In LC, there was a further increase in FCK-18, significantly more pronounced than an increase in AST, and the increase in cytokines continued to the same extent, the levels of IL-6 and IL-8, to a lesser extent IL-1 and TNF-, and the level of IL-4. With the progression of ALD from LS to steatohepatitis, hepatic cell damage was carried out by equally pronounced processes of hepatocyte necrosis and apoptosis, with the development of cirrhosis of the liver, parenchyma damage occurred mainly due to hepatocyte apoptosis. The immuno-inflammatory process progressively increased from the stage of LS to LC with IL-6 and IL-8 undergoing the greatest dynamics. FCK-18 can serve as a non-invasive marker of hepatic cell damage, and IL-6 and IL-8 markers of immune inflammation in ALD.

The Role of Elevated Liver-Type Fatty Acid-Binding Proteins in Liver Diseases.

Liver-type fatty acid-binding protein (L-FABP) is mainly expressed in the liver as well as the proximal tubular epithelial cells in the kidney. In general, the proteins and enzymes existing within the hepatocytes have the potential to become biomarkers, for instance alanine aminotransferase, which reflects hepatocellular damage. However, due to reduced hepatocellular function in late stage of chronic liver diseases (e.g. cirrhosis), proteins and enzymes relating to hepatocellular damage are not always accurate measures of disease progression. Recently, several publications have demonstrated elevated serum L-FABP levels during the progression of human liver diseases, including hepatocellular carcinoma (HCC), and were a prognostic factor for survival in acute and chronic liver disease patients. However, the study regarding serum L-FABP levels and hepatic L-FABP expression in liver diseases is not sufficient to understand the molecular mechanism of L-FABP during the progression of these disease states. In this review, we focus on the use of serum and/or hepatic L-FABP expression as a biomarker in human liver diseases, including mechanistic potential in HCC.

Aliskiren and Fenofibrate Constrict Liver Fibrosis by means of Focusing on TGF-β1/Smad Signaling Pathway and Actuating HGF Expression

Purpose: Liver fibrosis stems from changes in fibrotic genes expression in response to tissue damage in various chronic liver diseases, with no effective therapeutic program at present. This study designed to explore the possible protective effects and the molecular targets of aliskiren (ALS) and fenofibrate (FENO) against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Methods: Wister albino rats had been injected with 0.4ml/kg 50% CCl4, three times/week for eight weeks, to establish liver fibrosis model. Concurrently, ALS (25mg/kg/day) and/or FENO (25mg/kg/day) were orally administrated for 8 weeks to rats CCl4 intoxicated. Results: Treatment with ALS and/or FENO ameliorated oxidative stress and hepatocellular damage in CCl4-intoxicated rats as indicated by the marked reduction in hepatic lipid peroxidation and serum transaminases with concomitant significant increase in hepatic superoxide dismutase (SOD) as well as glutathione (GSH) content. The magnitude of liver inflammation and fibrosis was also alleviated by both medications, as is evident from the substantial decrease in hepatic proinflammatory and profibrotic cytokines such as tumor necrosis factor a (TNF-a), interlukin-6, (IL6), C-reactive protein (CRP) and transforming growth factor-β1 (TGF-β1) with restrain in fibrous deposition alongside architecture alteration that was shown upon histopathological examination. Additionally, simultaneous administration of ALS with FENO downregulated hepatic p-Smad3 protein and increased hepatic growth factor (HGF) expression in CCl4-intoxicated rats. Conclusion: Conclusively, this study highlights the hepatoprotective effect of ALS and FENO and imply that their anti-fibrotic mechanism involves blockade of TGF-β1/Smad signaling pathway, induction of HGF expression, besides modulation of inflammation as well as oxidative stress.

Toxicity Evaluation of Pharmaceutical Wastewater to the Nile Tilapia (&amp;lt;i&amp;gt;Oreochromis niloticus&amp;lt;/i&amp;gt;)

This study assessed the levels of oxidative stress biomarkers in gills and liver, as well as the activities of transaminases in the liver of Nile tilapia (Oreochromis niloticus), exposed to pharmaceutical effluents. The pharmaceutical effluents were collected from two pharmaceutical industries in Lagos, Nigeria. The assessment of physicochemical characteristics of the effluents indicated that some parameters were not in accordance with NESREA limits. The acute toxicity studies showed that 96hrLC50 values of “effluent A” and “effluent B” were 27.0 ml/L and 18.0 ml/L respectively. The juveniles of O. niloticus were exposed to 1/100th and 1/10th LC50s of the two effluents for a period of 14 and 28 days. These concentrations significantly increased the level of the lipid peroxidation product, malondialdehyde. There was also inhibition of the activities of superoxide dismutase and catalase as well as significantly lower levels of reduced glutathione after 28 days. The levels of the transaminases (aspartate aminotransferase and alanine transaminase) were elevated in the liver of the fish after the exposure to the effluents. The present findings showed that the wastewater caused oxidative stress and hepatocellular damage in the fish suggesting potential ecotoxicological risks of the wastewater to aquatic organisms.

Branched-chain amino acids and l-carnitine attenuate lipotoxic hepatocellular damage in rat cirrhotic liver

Branched-chain amino acids (BCAA) reverse malnutrition and l-carnitine leads to the reduction of hyperammonemia and muscle cramps in cirrhotic patients. BCAA and l-carnitine are involved in glucose and fatty acid metabolism, however their mechanistic activity in cirrhotic liver is not fully understood. We aim to define the molecular mechanism(s) and combined effects of BCAA and l-carnitine using a cirrhotic rat model. Rats were administered carbon tetrachloride for 10 weeks to induce cirrhosis. During the last 6 weeks of administration, cirrhotic rats received BCAA, l-carnitine or a combination of BCAA and l-carnitine daily via gavage. We found that BCAA and l-carnitine treatments significantly improved hepatocellular function associated with reduced triglyceride level, lipid deposition and adipophilin expression, in cirrhotic liver. Lipidomic analysis revealed dynamic changes in hepatic lipid composition by BCAA and l-carnitine administrations. BCAA and l-carnitine globally increased molecular species of phosphatidylcholine. Liver triacylglycerol and phosphatidylcholine hydroperoxides were significantly decreased by BCAA and l-carnitine. Furthermore, serum and liver ATP levels were significantly increased in all treatments, which were attributed to the elevation of mature cardiolipins and mitochondrial component gene expressions. Finally, BCAA and l-carnitine dramatically reduced hepatocellular death. In conclusion, BCAA and l-carnitine treatments attenuate hepatocellular damage through the reduction of lipid peroxides and the overall maintenance of mitochondrial integrity within the cirrhotic liver. These effectiveness of BCAA and l-carnitine support the therapeutic strategies in human chronic liver diseases.

Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review.

Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.