WorldWideScience

Sample records for 2e1-induced liver injury

  1. Hepatoprotective effects of S-adenosyl-L-methionine against alcohol-and cytochrome P450 2E1-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Arthur; I; Cederbaum

    2010-01-01

    S-adenosyl-L-methionine (SAM) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione. SAM is also a key metabolite that regulates hepatocyte growth, differentiation and death. Hepatic SAM levels are decreased in animal models of alcohol liver injury and in patients with alcohol liver disease or viral cirrhosis. This review describes the protection by SAM against alcohol and cytochrome P450 2E1-dependent cytotoxicity both in vitro and in vivo and evaluates mechanism...

  2. Naproxen-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sharif Ali; Jason D Pimentel; Chan Ma

    2011-01-01

    BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. METHODS: We treated a 30-year-old woman with jaundice and intractablepruritusthatdevelopedshortlyaftertakingnaproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. RESULTS: The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. CONCLUSIONS:  Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.

  3. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted...... and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline...

  4. Effect of matrine hydrochloride on liver injury

    Institute of Scientific and Technical Information of China (English)

    CHEN Li-bo; XU Feng; MA Wen-hui

    2008-01-01

    Objective Searching the function that the Injection of the matrine hydrochloride prevents and cures acute chemical liver injury of mice、 immunity liver injury of mice and chronic liver injury of rats. Methods Acute hepatic injury models of mice induced by Chemical poison carbon tetrachloride (CCl4), thioacetamide(TAA), D-galactosamine(D-GalN), immunity hepatic injury model of mice induced by BCG and fat polysaccharide (LPS), chronic liver injury model of rats induced by CCI, were introduced in the experiment. The serum ALT and AST were measured in acute hepatic injury experiments. Serum ALT, AST, AKP, ALB, TP, BiL-T, ereatinine, triglyceride, sialie acid, larninin, hyaluronic acid, type Ⅲ proeollagen and type Ⅳ collagen, hepatic hydroxyproline (HyP) of rats in chronic liver injury animals were determined after Injection of the matrine hydrochloride. Results The Injection of the matrine hydrochloride reduced serum ALT and AST level of acute chemical liver injury of mice induced by CCl4, TAA and D-GaIN. The index of the liver and the spleen of immunity liver injury of mice induced by BCG and LPS were decreased after the injection of matrine hydrochloride treatment. Compared with the model group, the injection may obviously inhibited serum ALT, AST, TP, AKP, TRI, BiL-T, creatinine, triglyceride, sialic acid, laminin , hyaluronic acid , type Ⅲ procollagen and type Ⅳ collagen activity of chronic liver injury of rats induced by CCl4, elevated ALB、A/G, reduced the liver HyP, decreased the index of the liver and the spleen. The liver visual observation, the pathology inspection and the HAI grading result showed the injection may reduce the inflammatory activity in liver tissue, restrain the liver cell damage, reduce the pseudolobuli formation. Conclusions The Injection of matrine hydrochloride had the protective function to acute chemical hepatic injury of mice induced by CCl4、TAA、D-GalN、immunity hepatic injury of mice induced by the BCG and LPS and

  5. Autophagy and Liver Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Raffaele Cursio

    2015-01-01

    Full Text Available Liver ischemia-reperfusion (I-R injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS, leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R.

  6. Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons.

    Science.gov (United States)

    Ijiri, Yoshio; Kato, Ryuji; Sadamatsu, Maiko; Takano, Mina; Yasuda, Yuki; Tanaka, Fumiaki; Oishi, Chiyo; Imano, Hideki; Okada, Yoshikatsu; Tanaka, Kazuhiko; Hayashi, Tetsuya

    2017-01-12

    1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.

  7. Sleep apnea hypopnea syndrome and liver injury

    Institute of Scientific and Technical Information of China (English)

    TIAN Jian-li; ZHANG Yun; CHEN Bao-yuan

    2010-01-01

    Objective A general review was made of studies involving: (1) the relationship between sleep apnea hypopneasyndrome/sleep apnea style intermittent hypoxia and liver injury and (2) the mechanism that causes the liver injury.Data sources The data used in this review were mainly from Medline and PubMed published in English from 1993 toFebruary 2009. The search term was "sleep apnea hypopnea syndrome".Study selection (1) Clinical and laboratory evidence that sleep apnea hypopnea syndrome and sleep apnea styleintermittent hypoxia leads to liver injury; (2) the mechanism that causes the liver injury.Results The effect of sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia on the liver functionis characterized by serum aminotransferase elevation. The liver histological injury includes hepatic steatosis, hepatocyteballooning, lobular inflammation, lobular necrosis, and liver fibrosis. Sleep apnea hypopnea syndrome and sleep apneastyle intermittent hypoxia can cause insulin resistance and oxidative stress.Conclusions Sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia can lead to chronic liverinjury, which, in most cases, is shown as nonalcoholic fatty liver disease. Insulin resistance and oxidative stress causedby sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia play an important role in the mechanismof chronic liver disease development.

  8. Protective effect of glycine on liver injury during liver transplantation

    Institute of Scientific and Technical Information of China (English)

    WANG Yao-sheng; YAN Ye-hong; ZOU Xun-feng

    2010-01-01

    @@ Multiple procedures of liver transplantation bring conditions producing cold ischemia-reperfusion (I/R) injury. During cold storage, the graft organ is subjected to cold ischemia, also known as hypoxia injury. After reperfusion, although hypoxic condition has been ameliorated, reoxygenation of the graft liver can produce not only reperfusion injury including generation of oxygen free radical, lipoperoxidation and calcium overload, but also aggravate the hypoxia damage, involving endothelial cell (EC) damage, Kupffer cell (KC) activation, and adherence of neutrophils and platelets to Ecs. Clinically, I/R injury is one of the major problems complicating liver transplantation, and can ultimately result in serious complications such as primary nonfunction and delayed graft function, which may lead to the need of urgent retransplantation. Therefore, the therapeutic strategies of attenuating graft I/R injury are clinically significant and might improve overall graft function and survival.

  9. Liver injury from herbal and dietary supplements.

    Science.gov (United States)

    Navarro, Victor J; Khan, Ikhlas; Björnsson, Einar; Seeff, Leonard B; Serrano, Jose; Hoofnagle, Jay H

    2017-01-01

    Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

  10. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Science.gov (United States)

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  11. Drug-induced liver injuries

    African Journals Online (AJOL)

    most clinicians and is synonymous with drug-induced hepatotoxicity. A succinct ... or herbal medicine resulting in liver test abnormalities or liver dysfunction with a ... and exclusion of other common aetiological factors, e.g. viral hepatitis. .... chronic alcohol use and hepatitis B or C infection. As a combination of drugs is used.

  12. Aspirin-Induced Acute Liver Injury

    Science.gov (United States)

    Satoskar, Rohit

    2014-01-01

    Aspirin is thought to be a relatively safe drug in adults. The association of aspirin and Reye syndrome in children is well documented. We report a 41-year-old female with pericarditis who was treated with high-dose aspirin and developed subsequent acute liver injury. After discontinuation of aspirin, liver enzyme elevation and right upper quadrant pain both resolved. We conclude that high-dose aspirin should be considered as a potentially hepatotoxic agent. PMID:26157904

  13. Prevention of grafted liver from reperfusive injury

    Institute of Scientific and Technical Information of China (English)

    Kai Ma; Yang yu; Xian-Min Bu; Yan-Jun Li; Xian-Wei Dai; Liang Wang; Yang Dai; Hai-Ying Zhao; Xiang-Hong Yang

    2001-01-01

    @@ INTRODUCTIONThe incidence of primary non-function(PNF)of grafted liver in the early postoperative stage is 2%-23%[1-4],its main cause is the ischemic-rechemic injure[5,6].In this experiment,anisodamine was added into the preserving fluid and the grafted liver was rewarmed at different temperatures to protect the cell membranc and prevent ischemic-reperfusive injury.

  14. Drug –induced liver injury:a review

    OpenAIRE

    Sreya Kosanam; Revathi Boyina; Lakshmi Prasanthi N

    2015-01-01

    The incidence of drug induced liver injury (DILI) is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized ...

  15. Translational biomarkers of acetaminophen-induced acute liver injury.

    Science.gov (United States)

    Beger, Richard D; Bhattacharyya, Sudeepa; Yang, Xi; Gill, Pritmohinder S; Schnackenberg, Laura K; Sun, Jinchun; James, Laura P

    2015-09-01

    Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

  16. Acute liver injury secondary to sertraline.

    Science.gov (United States)

    Suen, Christopher F D Li Wai; Boyapati, Ray; Simpson, Ian; Dev, Anouk

    2013-09-26

    Sertraline is widely prescribed to treat depression and anxiety disorders. However, hepatitis secondary to its use is a rare entity. We report the case of a 26-year-old woman in her 20th week of pregnancy presented with nausea, vomiting, malaise and dark urine. This occurred 6 months after sertraline 50 mg daily was started for the treatment of depression. Three weeks prior to her presentation, the dose of sertraline was increased to 100 mg daily. The patient's liver biochemical profile demonstrated increased transaminases. The biopsy of the liver showed lobular hepatitis, with a mild prominence of eosinophils, suggestive of a drug-induced or toxin-induced aetiology. Extensive biochemical work-up failed to show any other pathology to account for her hepatitis. Liver function tests normalised after cessation of sertraline, indicating a probable association between sertraline use and acute hepatocellular injury in our patient.

  17. Elemental characterization of injuries in fish liver

    Energy Technology Data Exchange (ETDEWEB)

    Stori, E.M., E-mail: elistori@gmail.com [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Post-Graduation Program on Science Materials – PGCIMAT, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, CEP 91501-970 Porto Alegre, RS (Brazil); Rocha, M.L.C.F.; Dias, J.F. [Oceanographic Institute, University of São Paulo, Praça do Oceanográfico, 191 Butantã, CEP 05508-120 São Paulo, SP (Brazil); Santos, C.E.I. dos [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Souza, C.T. de; Amaral, L; Dias, J.F. [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Post-Graduation Program on Science Materials – PGCIMAT, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, CEP 91501-970 Porto Alegre, RS (Brazil)

    2014-01-01

    Fish liver is the primary organ related to the biotransformation of organic contaminants and metals. This organ is very sensitive to organic and inorganic contaminants and can accumulate them in higher amounts relative to the environment itself and to other organs. One of the most common injuries is a histopathology called melanomacrophage centers, characterized as modifications of the cellular structure of the tissue and usually accompanied by pigmented cells. The aim of this study is to apply micro-PIXE in combination with conventional PIXE as a qualitative and quantitative analysis of elements to characterize histopathologies in the liver of fishes. Micro-PIXE results show that there is a higher concentration of Fe, P, K, Ti, Cr, Ni, Cu and Zn in melanomacrophage centers. On healthy tissue, the distribution of these elements is homogeneous. In cases where the histopathological study showed injuries without melanomacrophage centers, the micro-PIXE analysis showed much smaller clusters with higher concentrations of these elements, suggesting the presence of melanomacrophage centers which are too small to be detected by histopathological conventional methods. Broad PIXE results showed that the concentration of Si, Cl, K, Ti, Fe and Cu are directly related to the presence of melanomacrophage centers. Moreover, it could be observed that the concentration of Cr, Mn and Ni is directly related to the injuries but not to melanomacrophage centers.

  18. Autophagy and ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Terrence M Donohue Jr

    2009-01-01

    The majority of ethanol metabolism occurs in the liver. Consequently, this organ sustains the greatest damage from ethanol abuse. Ethanol consumption disturbs the delicate balance of protein homeostasis in the liver, causing intracellular protein accumulation due to a disruption of hepatic protein catabolism.Evidence indicates that ethanol or its metabolism impairs trafficking events in the liver, including the process of macroautophagy, which is the engulfment and degradation of cytoplasmic constituents by the lysosomal system. Autophagy is an essential, ongoing cellular process that is highly regulated by nutrients,endocrine factors and signaling pathways. A great number of the genes and gene products that govern the autophagic response have been characterized and the major metabolic and signaling pathways that activate or suppress autophagy have been identified. This review describes the process of autophagy, its regulation and the possible mechanisms by which ethanol disrupts the process of autophagic degradation. The implications of autophagic suppression are discussed in relation to the pathogenesis of alcohol-induced liver injury.

  19. Drug –induced liver injury:a review

    Directory of Open Access Journals (Sweden)

    Sreya Kosanam

    2015-03-01

    Full Text Available The incidence of drug induced liver injury (DILI is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized based on the pattern of liver enzyme alteration (hepatocellular, cholestatic or mixed pattern, the mechanism of hepatotoxicity (direct, immune mediated or idiosyncratic and histologic findings on liver biopsy (steatosis or sinusoidal obstruction syndrome. Treatment options for DILI include discontinuing the drug, conservative measurements and liver transplantation in the case of non-acetaminophen induced hepatotoxicity.

  20. Acute alcohol-induced liver injury

    Directory of Open Access Journals (Sweden)

    Gavin Edward Arteel

    2012-06-01

    Full Text Available Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, that also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

  1. Acute liver injury induced by weight-loss herbal supplements.

    Science.gov (United States)

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  2. Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Y. Maor

    2013-01-01

    Full Text Available Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies.

  3. A review of drug-induced liver injury databases.

    Science.gov (United States)

    Luo, Guangwen; Shen, Yiting; Yang, Lizhu; Lu, Aiping; Xiang, Zheng

    2017-07-17

    Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data.

  4. Alcoholic liver injury:Influence of gender and hormones

    Institute of Scientific and Technical Information of China (English)

    Patricia; K; Eagon

    2010-01-01

    This article discusses several subjects pertinent to a consideration of the role of gender and hormones in alcoholic liver injury (ALI). Beginning with an overview of factors involved in the pathogenesis of ALI, we review changes in sex hormone metabolism resulting from alcohol ingestion, summarize research that points to estrogen as a cofactor in ALI, consider evidence that gut injury is linked to liver injury in the setting of alcohol, and briefly review the limited evidence regarding sex hormones and gut...

  5. Review of liver injury associated with dietary supplements.

    Science.gov (United States)

    Stickel, Felix; Kessebohm, Kerstin; Weimann, Rosemarie; Seitz, Helmut K

    2011-05-01

    Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms 'dietary/nutritional supplements', 'adverse hepatic reactions', 'liver injury'; 'hepatitis', 'liver failure', 'vitamin A' and 'retinoids', and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.

  6. Platelet-activating factor in liver injury: A relational scope

    Institute of Scientific and Technical Information of China (English)

    Nikolaos P Karidis; Gregory Kouraklis; Stamatios E Theocharis

    2006-01-01

    The hepatocyte, the main cellular component of the liver, exhibits variable susceptibility to different types of injury induced by endogenous or exogenous factors.Hepatocellular dysfunction or death and regeneration are dependent upon the complicated interactions between numerous biologically active molecules. Plateletactivating factor (PAF) seems to play a pivotal role as the key mediator of liver injury in the clinical and experimental setting, as implied by the beneficial effects of its receptor antagonists. A comprehensive up-todate overview of the specific functional and regulatory properties of PAF in conditions associated with liver injury is attempted in this review.

  7. Severe liver injury induced by repeated use of hair dye

    Institute of Scientific and Technical Information of China (English)

    HOU Feng-qin; LIN Xiao-hong; YU Yan-yan; WANG Tai-ling; WANG Gui-qiang

    2009-01-01

    @@ Asignificant number of drugs has been proven,or at least suggested,to cause hepatotoxicity.1-3 Liver injury due to herbal medicines,chemicals or natural toxins also occur from household,occupational,or environmental exposure.4,5 However,liver toxicity due to hair dyes now is rarely recognized.Only in 2003,Tokumoto et al6 reported a case of hair dye-induced hepatitis,which presented a comparatively mild liver lesion.Here we described a case had more severe liver injury.

  8. PPAR and Liver Injury in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Maud Lemoine

    2009-01-01

    Full Text Available Due to the introduction of active HIV antiretroviral treatment, AIDS-related morbidity and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV-infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug-related toxicity, and NASH. HIV-infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1 the liver injuries in HIV-infected patients; (2 both the current experimental and human data regarding PPAR and liver diseases; (3 the interactions between HIV and PPAR; (4 the potential use of PPAR agonists for the management of HIV-related liver diseases.

  9. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury.

    Science.gov (United States)

    Kakuni, Masakazu; Morita, Mayu; Matsuo, Kentaro; Katoh, Yumiko; Nakajima, Miki; Tateno, Chise; Yokoi, Tsuyoshi

    2012-10-02

    Troglitazone (Tro) is a thiazolidinedione antidiabetic drug that was withdrawn from the market due to its association with idiosyncratic severe liver injury. Tro has never induced liver injury in experimental animals in vivo. It was assumed that the species differences between human and experimental animals in the pharmaco- or toxicokinetics of Tro might be associated with these observations. In this study, we investigated whether a chimeric mouse with a humanized liver that we previously established, whose replacement index with human hepatocytes is up to 92% can reproduce Tro-induced liver injury. When the chimeric mice were orally administered Tro for 14 or 23 days (1000mg/kg/day), serum alanine aminotransferase (ALT) was significantly increased by 2.1- and 3.6-fold, respectively. Co-administration of l-buthionine sulfoximine (10mM in drinking water), an inhibitor of glutathione (GSH) synthesis, unexpectedly prevented the Tro-dependent increase of ALT, which suggests that the GSH scavenging pathway will not be involved in Tro-induced liver injury. To elucidate the mechanism of the onset of liver injury, hepatic GSH content, the level of oxidative stress markers and phase I and phase II drug metabolizing enzymes were determined. However, these factors were not associated with Tro-induced liver injury. An immune-mediated reaction may be associated with Tro-induced liver toxicity in vivo, because the chimeric mouse is derived from an immunodeficient SCID mouse. In conclusion, we successfully reproduced Tro-induced liver injury using chimeric mice with a humanized liver, which provides a new animal model for studying idiosyncratic drug-induced liver injury. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. Role of IRAK-M in alcohol induced liver injury.

    Directory of Open Access Journals (Sweden)

    Yipeng Wang

    Full Text Available Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR signaling pathways and interleukin receptor-associated kinase-M (IRAK-M in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT, more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68(+ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.

  11. Acetaminophen-induced acute liver injury in HCV transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  12. Postoperative acute kidney injury in living donor liver transplantation recipients.

    Science.gov (United States)

    Atalan, Hakan K; Gucyetmez, Bulent; Aslan, Serdar; Yazar, Serafettin; Polat, Kamil Y

    2017-09-05

    There are many risk factors for postoperative acute kidney injury in liver transplantation. The aim of this study is to investigate the risk factors for postoperative acute kidney injury in living donor liver transplantation recipients. 220 living donor liver transplantation recipients were retrospectively evaluated in the study. According to the Kidney Disease Improving Global Outcomes Guidelines, acute kidney injury in postoperative day 7 was investigated for all patients. The patient's demographic data, preoperative and intraoperative parameters, and outcomes were recorded. Acute kidney injury was found in 27 (12.3%) recipients. In recipients with acute kidney injury, female population, model for end-stage liver disease score, norepinephrine requirement, duration of mean arterial pressure less than 60 mmHg, the usage of gelatin and erythrocyte suspension and blood loss were significantly higher than recipients with nonacute kidney injury (for all p5 mL kg-1 and duration of MAP less than 60 mmHg ≥5.5 minutes respectively (for all p<0.05). In living donor liver transplantation recipients, serum tacrolimus levels, intraoperative blood loss, hypotension period and the usage of gelatin may be risk factors for acute kidney injury in the early postoperative period.

  13. Role of stem cells during diabetic liver injury

    OpenAIRE

    Wan, Ying; Garner, Jessica; Wu, Nan; Phillip, Levine; Han, Yuyan; McDaniel, Kelly; Annable, Tami; Zhou, Tianhao; Francis, Heather; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco; Meng, Fanyin

    2015-01-01

    Abstract Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non‐alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic r...

  14. Pathomorphological changes after liver impact injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    麻晓林; 杨志焕; 王正国; 朱佩芳; 李晓炎; 王东

    2002-01-01

    Objective: To investigate the histopathological changes in the liver and other organs after impact injury. Methods: The rabbits were impacted with a BIM-IV biological impacting machine at the xiphoid process. The severity of liver injury was graded and scored through gross anatomy. At the same time, the pathological changes in the liver, heart, and lung were observed by light and electron microscopes. Results: Light microscopy showed that the pathological changes in the liver were: 1) loss of normal structure, hemorrhage and distortion of hepatic lobules; 2) cloudy swelling, degeneration, vacuolation and necrosis of liver cells; 3) infiltration of neutrophils. The lungs were injured and there were liver cell emboli in the small pulmonary arteries. Electron microscopy showed that the ultrastructure of the liver cells was severely damaged and the cells had significant features of necrosis. Conclusions: The major pathomorphological changes in the liver after impact injury are hemorrhage and necrosis. They may be complicated by exfoliation of liver cells to hepatic sinusoids. These cells circulate with the blood to form emboli in the pulmonary blood vessels.

  15. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  16. Liver transplantation in the mouse: Insights into liver immunobiology, tissue injury, and allograft tolerance.

    Science.gov (United States)

    Yokota, Shinichiro; Yoshida, Osamu; Ono, Yoshihiro; Geller, David A; Thomson, Angus W

    2016-04-01

    The surgically demanding mouse orthotopic liver transplant model was first described in 1991. It has proved to be a powerful research tool for the investigation of liver biology, tissue injury, the regulation of alloimmunity and tolerance induction, and the pathogenesis of specific liver diseases. Liver transplantation in mice has unique advantages over transplantation of the liver in larger species, such as the rat or pig, because the mouse genome is well characterized and there is much greater availability of both genetically modified animals and research reagents. Liver transplant experiments using various transgenic or gene knockout mice have provided valuable mechanistic insights into the immunobiology and pathobiology of the liver and the regulation of graft rejection and tolerance over the past 25 years. The molecular pathways identified in the regulation of tissue injury and promotion of liver transplant tolerance provide new potential targets for therapeutic intervention to control adverse inflammatory responses/immune-mediated events in the hepatic environment and systemically. In conclusion, orthotopic liver transplantation in the mouse is a valuable model for gaining improved insights into liver biology, immunopathology, and allograft tolerance that may result in therapeutic innovation in the liver and in the treatment of other diseases.

  17. Role of stem cells during diabetic liver injury.

    Science.gov (United States)

    Wan, Ying; Garner, Jessica; Wu, Nan; Phillip, Levine; Han, Yuyan; McDaniel, Kelly; Annable, Tami; Zhou, Tianhao; Francis, Heather; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco; Meng, Fanyin

    2016-02-01

    Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non-alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic reticulum stress. The realization that these factors are important in hepatocyte damage and lack of donor livers has led to studies concentrating on the role of stem cells (SCs) in the prevention and treatment of liver injury. Possible avenues that the application of SCs may improve liver injury include but are not limited to: the ability to differentiate into pancreatic β-cells (insulin producing cells), the contribution for hepatocyte regeneration, regulation of lipogenesis, glucogenesis and anti-inflammatory actions. Once further studies are performed to explore the underlying protective mechanisms of SCs and the advantages and disadvantages of its application, there will be a greater understand of the mechanism and therapeutic potential. In this review, we summarize the findings regarding the role of SCs in diabetic liver diseases.

  18. Isolated liver gunshot injuries: nonoperative management is feasible?

    Directory of Open Access Journals (Sweden)

    SIZENANDO VIEIRA STARLING

    2015-08-01

    Full Text Available ABSTRACTObjective:to evaluate the safety and effectiveness of non-operative management (NOM of liver injury, being the only abdominal injury, from gunshot wounds to the abdomen.Methods:patients who had liver damage diagnosed as single abdominal injury caused by PAF in the right thoracoabdominal region, hemodynamically stable were studied. All underwent examination with computed tomography. Were analyzed: age, gender, levels of trauma, hemodynamic condition and the abdominal examination on admission, the results of the CT scan, the extra-abdominal lesions found, the serum levels of hemoglobin, clinical course, complications, length of hospital stay, outpatient treatment and death.Results:during the study period 169 patients, treated non-operatively, presented liver gunshot wounds. Of these, only 28 patients (16.6% had liver injury as the only abdominal injury and consequently met the inclusion criteria for this study. The average age was 27.7 years and 25 patients (89.2% were male. The overall average of verified trauma scores were: RTS 7.45, ISS 10.9, and TRISS 98.7%. The most frequent injuries were grade II and grade III (85.7%. Complications occurred in only one patient who presented a progressive decline in hemoglobin. He underwent a CT scan which showed blush in the liver parenchyma. An arteriography was performed, which showed a successfully embolized arteriovenous fistula. There were no deaths in the patient sample. The average hospital stay was 5.3 days.Conclusion:isolated hepatic injury in gunshot abdominal trauma is uncommon. However, the NOM protocol for this type of injury is safe and has low morbidity. This approach should only be followed in institutions with adequate infrastructure, where an experienced and cohesive team is able to follow a specific protocol, with rigorous periodic evaluation of its results.

  19. Congenital biliary atresia: liver injury begins at birth

    DEFF Research Database (Denmark)

    Makin, Erica; Quaglia, Alberto; Kvist, Nina

    2009-01-01

    -note review for infants with definite BA who underwent laparotomy within first week of life. RESULTS: Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial. CONCLUSION: This suggests......BACKGROUND: The timing of onset of liver injury in biliary atresia (BA) is not known, although in approximately 10% of cases, biliary pathologic condition associated with the biliary atresia splenic malformation syndrome must begin well before birth. METHODS: The study involved retrospective case...... that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory...

  20. Liver injury suppressing compounds from avocado (Persea americana).

    Science.gov (United States)

    Kawagishi, H; Fukumoto, Y; Hatakeyama, M; He, P; Arimoto, H; Matsuzawa, T; Arimoto, Y; Suganuma, H; Inakuma, T; Sugiyama, K

    2001-05-01

    To evaluate the protective activity of fruits against liver injury, 22 different fruits were fed to rats with liver damage caused by D-galactosamine, a powerful liver toxin. As measured by changes in the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), avocado showed extraordinarily potent liver injury suppressing activity. Five active compounds were isolated and their structures determined. These were all fatty acid derivatives, of which three, namely, (2E,5E,12Z,15Z)-1-hydroxyheneicosa-2,5,12,15-tetraen-4-one, (2E,12Z,15Z)-1-hydroxyheneicosa-2,12,15-trien-4-one, and (5E,12Z)-2-hydroxy-4-oxoheneicosa-5,12-dien-1-yl acetate, were novel.

  1. Genetic tracing of hepatocytes in liver homeostasis, injury, and regeneration.

    Science.gov (United States)

    Wang, Yue; Huang, XiuZhen; He, Lingjuan; Pu, Wenjuan; Li, Yan; Liu, Qiaozhen; Li, Yi; Zhang, Libo; Yu, Wei; Zhao, Huan; Zhou, Yingqun; Zhou, Bin

    2017-05-26

    The liver possesses a remarkable capacity to regenerate after damage. There is a heated debate on the origin of new hepatocytes after injuries in adult liver. Hepatic stem/progenitor cells have been proposed to produce functional hepatocytes after injury. Recent studies have argued against this model and suggested that pre-existing hepatocytes, rather than stem cells, contribute new hepatocytes. This hepatocyte-to-hepatocyte model is mainly based on labeling of hepatocytes with Cre-recombinase delivered by the adeno-associated virus. However, the impact of virus infection on cell fate determination, consistency of infection efficiency, and duration of Cre-virus in hepatocytes remain confounding factors that interfere with the data interpretation. Here, we generated a new genetic tool Alb-DreER to label almost all hepatocytes (>99.5%) and track their contribution to different cell lineages in the liver. By "pulse-and-chase" strategy, we found that pre-existing hepatocytes labeled by Alb-DreER contribute to almost all hepatocytes during normal homeostasis and after liver injury. Virtually all hepatocytes in the injured liver are descendants of pre-existing hepatocytes through self-expansion. We concluded that stem cell differentiation is unlikely to be responsible for the generation of a substantial number of new hepatocytes in adult liver. Our study also provides a new mouse tool for more precise in vivo genetic study of hepatocytes in the field. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. The role of oxidative stress in alcoholic liver injury

    Directory of Open Access Journals (Sweden)

    Radosavljević Tatjana

    2009-01-01

    Full Text Available Introduction. Oxidative stress plays an important role in pathogenesis of alcoholic liver injury. The main source of free oxygen species is cytochrome P450-dependent monooxygenase, which can be induced by ethanol. Role of cytochrome P4502E1 in ethanol-induced oxidative stress. Reactive oxygen species produced by this enzyme are more important in intracellular oxidative damage compared to species derived from activated phagocytes. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in alcohol-induced oxidative stress. Production of mitochondrial reactive oxygen species is increased, and glutathione content is decreased in chronically ethanolfed animals. Oxidative stress in mitochondria leads to mitochondrial DNA damage and has a dual effect on apoptosis. Role of Kupffer cells in alcohol-induced liver injury. Chronic ethanol consumption is associated with increased release of endotoxin from gut lumen into portal circulation. Endotoxin activates Kupffer cells, which then release proinflammatory cytokines and oxidants. Role of neutrophils in alcohol-induced liver injury. Alcoholic liver injury leads to the accumulation of neutrophils, which release reactive oxygen species and lysosomal enzymes and contribute to hepatocyte damage and necrosis. Role of nitric oxide in alcohol-induced oxidative stress. High amounts of nitric oxide contribute to the oxidative damage, mainly by generating peroxynitrites. Role of antioxidants in ethanol-induced oxidative stress. Chronic ethanol consumption is associated with reduced liver glutathione and α-tocopherol level and with reduced superoxide dismutase, catalase and glutathione peroxidase activity. Conclusion. Oxidative stress in alcoholic liver disease is a consequence of increased production of oxidants and decreased antioxidant defense in the liver.

  3. Liver injury induced by herbal complementary and alternative medicine.

    Science.gov (United States)

    Navarro, Victor J; Seeff, Leonard B

    2013-11-01

    Herbal and dietary supplement use is common. Most marketed products consist of complex mixtures. Although they are perceived as safe, instances of hepatotoxicity attributable to these products underscore their potential for injury, but the exact component that is responsible for injury is difficult to discern. The lenient regulatory environment in the United States, which opens the possibility of adulteration and contamination, adds to the challenge of disease attribution. Although many different herbal and dietary supplements have been reported to cause liver injury, in the United States, products used for bodybuilding and weight loss are the most commonly implicated.

  4. Novel insight into mechanisms of cholestatic liver injury

    Institute of Scientific and Technical Information of China (English)

    Benjamin L Woolbright; Hartmut Jaeschke

    2012-01-01

    Cholestasis results in a buildup of bile acids in serum and in hepatocytes.Early studies into the mechanisms of cholestatic liver injury strongly implicated bile acidinduced apoptosis as the major cause of hepatocellular injury.Recent work has focused both on the role of bile acids in cell signaling as well as the role of sterile inflammation in the pathophysiology.Advances in modern analytical methodology have allowed for more accurate measuring of bile acid concentrations in serum,liver,and bile to very low levels of detection.Interestingly,toxic bile acid levels are seemingly far lower than previously hypothesized.The initial hypothesis has been based largely upon the exposure of μmol/L concentrations of toxic bile acids and bile salts to primary hepatocytes in cell culture,the possibility that in vivo bile acid concentrations may be far lower than the observed in vitro toxicity has far reaching implications in the mechanism of injury.This review will focus on both how different bile acids and different bile acid concentrations can affect hepatocytes during cholestasis,and additionally provide insight into how these data support recent hypotheses that cholestatic liver injury may not occur through direct bile acid-induced apoptosis,but may involve largely inflammatory cell-mediated liver cell necrosis.

  5. Effects ofSalmonella infection on hepatic damage following acute liver injury in rats

    Institute of Scientific and Technical Information of China (English)

    Yong-Tao Li; Cheng-Bo Yu; Dong Yan; Jian-Rong Huang; Lan-Juan Li

    2016-01-01

    BACKGROUND: Acute liver injury is a common clinical disor-der associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The pur-pose of this study was to address this unanswered question using a rat model. METHODS: Oral supplementation withSalmonella enterica serovar enteritidis (S. enteritidis) was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the con-centrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver injury. RESULTS: The levels of liver damage and endotoxin were sig-niifcantly increased in theSalmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury (P CONCLUSIONS: OralS. enteritidis administration exacer-bates acute liver injury, especially when injury was severe. Major factors of the exacerbation include inlfammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver.

  6. Hepatoprotective effect of kaempferol against alcoholic liver injury in mice.

    Science.gov (United States)

    Wang, Meng; Sun, Jianguo; Jiang, Zhihui; Xie, Wenyan; Zhang, Xiaoying

    2015-01-01

    Kaempferol is a biologically active component present in various plants. The hepatoprotective effect of kaempferol in drug-induced liver injury has been proven, while its effect against alcoholic liver injury (ALI) remains unclear. Hence, the present study aimed to evaluate the effect of kaempferol against ALI in mice. The experimental ALI mice model was developed and the mice were treated with different doses of kaempferol for 4 weeks. The liver functions were observed by monitoring the following parameters: Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) levels in serum; histopathological studies of liver tissue; oxidative stress by hydrogen peroxide (H2O2), superoxide dismutase (SOD) and glutathione (GSH); the lipid peroxidation status by malondialdehyde (MDA) and lipid accumulation by triglyceride (TG) level in serum; and the expression levels and activities of a key microsomal enzyme cytochrome 2E1 (CYP2E1), by both in vitro and in vivo methods. The ALI mice (untreated) showed clear symptoms of liver injury, such as significantly increased levels of oxidative stress, lipid peroxidation and excessive CYP2E1 expression and activity. The mice treated with different kaempferol dosages exhibited a significant decrease in the oxidative stress as well as lipid peroxidation, and increased anti-oxidative defense activity. The kaempferol treatment has significantly reduced the expression level and activity of hepatic CYP2E1, thus indicating that kaempferol could down regulate CYP2E1. These findings show the hepatoprotective properties of kaempferol against alcohol-induced liver injury by attenuating the activity and expression of CYP2E1 and by enhancing the protective role of anti-oxidative defense system.

  7. Intestinal microflora in rats with ischemia/reperfusion liver injury

    Institute of Scientific and Technical Information of China (English)

    XING Hui-chun; LI Lan-juan; XU Kai-jin; SHEN Tian; CHEN Yun-bo; SHENG Ji-fang; YU Yun-song; CHEN Ya-gang

    2005-01-01

    Objectives: To investigate the intestinal microflora status related to ischemia/reperfusion (I/R) liver injury and explore the possible mechanism. Methods: Specific pathogen free grade Sprague-Dawley rats were randomized into three groups: Control group (n=8), sham group (n=6) and I/R group (n=10). Rats in the control group did not receive any treatment, rats in the I/R group were subjected to 20 min of liver ischemia, and rats in the sham group were only subjected to sham operation. Twenty-two hours later, the rats were sacrificed and liver enzymes and malondialdehyde (MDA), superoxide dismutase (SOD), serum endotoxin,intestinal bacterial counts, intestinal mucosal histology, bacterial translocation to mesenteric lymph nodes, liver, spleen, and kidney were studied. Results: Ischemia/reperfusion increased liver enzymes, MDA, decreased SOD, and was associated with plasma endotoxin elevation in the I/R group campared to those in the sham group. Intestinal Bifidobacteria and Lactobacilli decreased and intestinal Enterobacterium and Enterococcus, bacterial translocation to kidney increased in the I/R group compared to the sham group. Intestinal microvilli were lost, disrupted and the interspace between cells became wider in the I/R group.Conclusion: I/R liver injury may lead to disturbance of intestinal microflora and impairment of intestinal mucosal barrier function,which contributes to endotoxemia and bacterial translocation to kidney.

  8. Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian

    For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

  9. Ginseng for Liver Injury: Friend or Foe?

    Directory of Open Access Journals (Sweden)

    Tae-Woo Kim

    2016-12-01

    Full Text Available Panax sp., including Panax ginseng Meyer, Panax quiquifolius L., or Panax notoginseng (Burk. FH Chen, have been used as functional foods or for traditional Chinese medicine for diabetes, inflammation, stress, aging, hepatic injury, and cancer. In recent decades, a number of both in vitro and in vivo experiments as well as human studies have been conducted to investigate the efficacy and safety of various types of ginseng samples and their components. Of these, the hepatoprotective and hepatotoxic effects of ginseng and their ginsenosides and polysaccharides are reviewed and summarized.

  10. Clozapine-induced liver injury and pleural effusion

    Directory of Open Access Journals (Sweden)

    Joseph P.M. Kane

    2014-09-01

    Full Text Available Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs.

  11. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography

    NARCIS (Netherlands)

    Stravitz, R. Todd; Lisman, Ton; Luketic, Velimir A.; Sterling, Richard K.; Puri, Puneet; Fuchs, Michael; Ibrahim, Ashraf; Lee, William M.; Sanyal, Arun J.

    2012-01-01

    Background & Aims: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. Methods: Fifty-one pa

  12. Normothermic acellular ex vivo liver perfusion reduces liver and bile duct injury of pig livers retrieved after cardiac death.

    Science.gov (United States)

    Boehnert, M U; Yeung, J C; Bazerbachi, F; Knaak, J M; Selzner, N; McGilvray, I D; Rotstein, O D; Adeyi, O A; Kandel, S M; Rogalla, P; Yip, P M; Levy, G A; Keshavjee, S; Grant, D R; Selzner, M

    2013-06-01

    We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

  13. Drug-induced liver injury: Is it somehow foreseeable?

    Institute of Scientific and Technical Information of China (English)

    Giovanni Tarantino; Matteo Nicola Dario Di Minno; Domenico Capone

    2009-01-01

    The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes -450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

  14. Ebselen prevents early alcohol-induced liver injury in rats.

    Science.gov (United States)

    Kono, H; Arteel, G E; Rusyn, I; Sies, H; Thurman, R G

    2001-02-15

    Oxidants have been shown to be involved in alcohol-induced liver injury. Moreover, 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), an organoselenium compound and glutathione peroxidase mimic, decreases oxidative stress and protects against stroke clinically. This study was designed to test the hypothesis that ebselen protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g/kg/d) continuously for up to 4 weeks using the intragastric enteral feeding protocol developed by Tsukamoto and French. Ebselen (50 mg/kg twice daily, intragastrically) or vehicle (1% tylose) was administered throughout the experiment. Mean urine ethanol concentrations were not significantly different between treatment groups, and ebselen did not affect body weight gains or cyclic patterns of ethanol concentrations in urine. After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (37 +/- 5 IU/l) by enteral ethanol (112 +/- 7 IU/l); ebselen blunted this increase significantly (61 +/- 8 IU/l). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver (pathology score: 4.3 +/- 0.3). In contrast, these pathological changes were blunted significantly by ebselen (pathology score: 2.5 +/- 0.4). While there were no significant effects of either ethanol or ebselen on glutathione peroxidase activity in serum or liver tissue, ebselen blocked the increase in serum nitrate/nitrite caused by ethanol. Furthermore, ethanol increased the activity of NF-kappaB over 5-fold, the number of infiltrating neutrophils 4-fold, and the accumulation of 4-hydroxynonenal over 5-fold. Ebselen blunted all of these effects significantly. These results indicate that ebselen prevents early alcohol-induced liver injury, most likely by preventing oxidative stress, which decreases inflammation.

  15. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  16. Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

    Science.gov (United States)

    Vliegenthart, Adb; Kimmitt, R A; Seymour, J H; Homer, N Z; Clarke, J I; Eddleston, M; Gray, A; Wood, D M; Dargan, P I; Cooper, J G; Antoine, D J; Webb, D J; Lewis, S C; Bateman, D N; Dear, J W

    2017-04-01

    Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  17. Acute kidney injury in acute liver failure: a review.

    Science.gov (United States)

    Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

    2013-11-01

    Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

  18. Hyperhomocysteinemia,endoplasmic reticulum stress,and alcoholic liver injury

    Institute of Scientific and Technical Information of China (English)

    Cheng Ji; Neil Kaplowitz

    2004-01-01

    Deficiencies in vitamins or other factors (B6, B12, folic acid,betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (Hhcy). Hhcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. Hhcy unleashes mediators of inflammation such as NFκB, IL-1β, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis,fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of Hhcy. ER stress may also be involved in other liver diseases such as α1-antitrypsin (α1-AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans,and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of Hhcy and liver disease.

  19. Macrophages and dendritic cells in the development of liver injury leading to liver failure.

    Science.gov (United States)

    Ananiev, J; Penkova, M; Tchernev, G; Chokoeva, A A; Philipov, S; Tana, C; Gulubova, M; Wollina, U

    2014-01-01

    Liver failure (LF) continues to be a serious problem due to different underlying disorders. Not only hepatocytes but Kupffer cells (KCs) and dendritic cells (DCs) are of importance in this instance. We wanted to investigate the possible role of KCs and liver DCs in the development of liver injury in patients with liver failure. Liver specimens from 23 patients who died after liver failure were examined for the presence and distribution of CD68-positive KCs and CD83-positive DCs by immunohistochemistry. The distribution of the CD83-positive DC in the sinusoidal and the periportal spaces was not even. While 39.1% of patients had a high sinusoidal density of CD83-positive cells, 60.9% demonstrated a high density of CD83-positive cells in the periportal tract. The number of CD83-positive DCs in periportal tracts in patients with advanced liver fibrosis (n=5) were high, while those with mild liver fibrosis (n=18) had low numbers of mature dendritic cells (χ2=4.107; p=0.043). In addition, all patients with intensive fibrosis had low counts of CD68-positive KC’s in portal tracts vs patients with mild fibrosis of which 67% had high counts (χ2=6.97; p=0.008). In seven of the patients with moderate steatosis (87.5%) low numbers of CD68-positive KCs were found in sinusoids, in contrast to those with severe steatosis, where 12 patients (80%) had high KC counts (χ2=13.4; p less than 0.001). The distribution and number of CD68-positive KC and CD83-positive DC reflect the progression of liver fibrosis leading to liver failure.

  20. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    Science.gov (United States)

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  1. Melatonin protects liver from intestine ischemia reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Jian-Yi Li; Hong-Zhuan Yin; Xi Gu; Yong Zhou; Wen-Hai Zhang; Yi-Min Qin

    2008-01-01

    AIM:To investigate the protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats.METHODS:One hundred and fifty male Wistar rats,weighing 190-210 g,aged 7 wk,were randomly divided into melatonin exposure group,alcohol solvent control group and normal saline control group.Rats in the melatonin exposure group received intraperitoneal (IP) melatonin (20 mg/kg) 30 min before intestinal ischemia-reperfusion (IR),rats in the alcohol solvent control group received the same concentration and volume of alcohol,and rats in the normal saline control group received the same volume of normal saline.Serum samples were collected from each group 0.5,1,6,12,and 24 h after intestinal IR.Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with an auto-biochemical analyzer.Serum TNF-a was tested by enzyme-linked immunosorbent assay (ELISA).Malondialdehyde (MDA) in liver was detected by colorimetric assay.Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope.RESULTS:The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups (P<0.05).The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels (%) 6,12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups (P<0.05).CONCLUSION:Exotic melatonin can inhibit the activity of ALT,AST and TNF-a decrease the accumulation of MDA,and depress the expression of ICAM-1 in liver after intestinal IR injury,thus improving the liver function.

  2. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  3. Acute liver failure and acute kidney injury: Definitions, prognosis, and outcome

    NARCIS (Netherlands)

    Włodzimirow, K.A.

    2013-01-01

    The objective of this thesis was to investigate definitions, prognostic indicators and their association with adverse events, mainly mortality for acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute kidney injury (AKI).

  4. Preventive effect of zinc on nickel-induced oxidative liver injury in rats

    African Journals Online (AJOL)

    MIDOU

    2013-12-18

    Dec 18, 2013 ... exposure of rats to nickel sulfate for 21 days resulted in a significant decrease in body weight gain and absolute liver weight ... Nickel treatment also produced oxidative liver injury ..... Biochemical toxicology of arsenic. Rev.

  5. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars;

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... endothelial activation. Here, we tested whether CD133 MP might be shed in a CD39-dependent manner in a model of liver injury and could potentially serve as biomarkers of liver failure in the clinic. METHODS: Wild-type and Cd39-null mice were subjected to acetaminophen-induced liver injury. Mice were...

  6. Sestrin2 protects against acetaminophen-induced liver injury.

    Science.gov (United States)

    Kim, Seung Jung; Kim, Kyu Min; Yang, Ji Hye; Cho, Sam Seok; Kim, Ji Young; Park, Su Jung; Lee, Sang Kyu; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2017-05-01

    Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.

    Science.gov (United States)

    Cotter, David G; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M; d'Avignon, D André; Graham, Mark J; Dietzen, Dennis J; Brunt, Elizabeth M; Patti, Gary J; Crawford, Peter A

    2014-12-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.

  8. Albendazole-induced liver injury: a case report

    Directory of Open Access Journals (Sweden)

    David Ríos

    2013-05-01

    Full Text Available We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a “likely” correlation between hepatocellular damage and drug toxicity etiology. 

  9. Albendazole-induced liver injury: a case report.

    Science.gov (United States)

    Ríos, David; Restrepo, Juan C

    2013-04-01

    We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a "likely" correlation between hepatocellular damage and drug toxicity etiology.

  10. Drug-induced liver injury and drug development: industry perspective.

    Science.gov (United States)

    Regev, Arie

    2014-05-01

    Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

  11. CXCL16 participates in pathogenesis of immunological liver injury by regulating T lymphocyte infiltration in liver tissue

    Institute of Scientific and Technical Information of China (English)

    Huan-Bin Xu; Yan-Ping Gong; Jin Cheng; Yi-Wei Chu; Si-Dong Xiong

    2005-01-01

    AIM: To investigate the role of CXCL16 in the pathogenesis of immunological liver injury and to explore the possible mechanism of T lymphocyte infiltration requlated by CXCL16.METHODS: Immunological liver injury in murine model was induced by Bacille Calmette-Guerin and lipopolysaccharide.Expression pattem and distribution of CXCL16 were examined by real-time quantitative RT-PCR and immunohistochemical analysis. Anti-CXCL16 antibody was administrated in vivo to investigate its effect on T-cell recruitment and acute hepatic necrosis. The survival of murine model was also evaluated.RESULTS: The murine immunological liver injury model was successfully established. CXCL16 expression increased and predominantly distributed in periportal areas and vascular endothelia in injured liver tissues. Administration of anti-CXCL16 Ab protected the mice from death and acute liver damage. Approximately 70% of the mice survived for 72 h in the anti-CXCL16 Ab treatment group, whereas 80% died within 72 h in control Ab group. The number of liver-infiltrating T lymphocytes was significantly reduced from 1.01×L07 to 3.52x 106/liver, compared with control Ab treatment.CONCLUSION: CXCL16 is involved in immunological liver injury by regulating T lymphocyte infiltration in liver tissue.

  12. Desferrioxamine attenuates minor lung injury following surgical acute liver failure.

    Science.gov (United States)

    Kostopanagiotou, G G; Kalimeris, K A; Arkadopoulos, N P; Pafiti, A; Panagopoulos, D; Smyrniotis, V; Vlahakos, D; Routsi, C; Lekka, M E; Nakos, G

    2009-06-01

    Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.

  13. Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Raffaele Cursio

    2012-01-01

    Full Text Available Ischemia-reperfusion (I-R injury after liver transplantation (LT induces intra- and/or extrahepatic nonanastomotic ischemic-type biliary lesions (ITBLs. Subsequent bile duct stricture is a significant cause of morbidity and even mortality in patients who underwent LT. Although the pathogenesis of ITBLs is multifactorial, there are three main interconnected mechanisms responsible for their formation: cold and warm I-R injury, injury induced by cytotoxic bile salts, and immunological-mediated injury. Cold and warm ischemic insult can induce direct injury to the cholangiocytes and/or damage to the arterioles of the peribiliary vascular plexus, which in turn leads to apoptosis and necrosis of the cholangiocytes. Liver grafts from suboptimal or extended-criteria donors are more susceptible to cold and warm I-R injury and develop more easily ITBLs than normal livers. This paper, focusing on liver I-R injury, reviews the risk factors and mechanisms leading to ITBLs following LT.

  14. [The Correlation Between MicroRNAs in Serum and the Extent of Liver Injury].

    Science.gov (United States)

    Zuo, Yi-Nan; He, Xue-Ling; Shi, Xue-Ni; Wei, Shi-Hang; Yin, Hai-Lin

    2017-05-01

    To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS). The acute liver injury model in rat by CCl4 (1.5 mL/kg), and the acute liver injury model in mice by APAP (160 mg/kg) were established. The serum at different time points on both models were collected respectively. The absolute quantification of microRNAs in serum were detected by using MiRbay(TM) SV miRNA Assay kit. Meanwhile, the pathological sections of liver tissue of the mice at each time point were collected to analyze the correlation between microRNAs and the degree of liver injury. In CCl4-induced rat acute liver injury model and APAP induced mouse acute liver injury, miR-122 and miR-192 appeared to be rising significantly, which remained the highest level at 24 h after treatment, and declined to the normal level after 72 h. In CCl4-induced rat acute liver injury model, the change of miR-92a was fluctuated and had no apparent rules, miR-451 declined gradually, but not obviously. In mice acute liver injury model induced by APAP, miR-92a and miR-451 in the progress of liver injury declined gradually, reached the lowest point at 48 h, and then recovered. The result of correlation analysis indicated that miR-122 and miR-192 presented a good positive correlation with the DILI-PSS ( r=0.741 3, Pcorrelation with DILI-PSS in APAP-induced liver injury models.

  15. Effect of leflunomide on immunological liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hong-Wei Yao; Jun Li; Yong Jin; Yun-Fang Zhang; Chang-Yu Li; Shu-Yun Xu

    2003-01-01

    AIM: To study the effect of leflunomide on immunologicalliver injury (ILI) in mice.METHODS: ILI was induced by tail vein injection of 2.5 mgBacilluS Calmette-Guerin (BCG), and 10 d later with :L0 μglipopolysaccharide (LPS) in 0.2 mL saline (BCG+LPS). Thealanine aminotransferase (ALT), aspartate aminotransferase(ASr), nitric oxide (NO) level in plasma and molondiadehyde(MDA), glutathione peroxidase (GSHpx) in liver homogenatewere assayed by spectroscopy. The serum content of tumornecrosis factors-α (TNF-α) was determined by ELISA.Interleukin-1 (IL-1), interleukin-2 (IL-2) and ConcanavalinA (ConA)-induced splenocyte proliferation response weredetermined by methods of 3H-infiltrated cell proliferation.RESULTS: Leflunomide (4, 12, 36 mg@kg-1) was found tosignificantly decrease the serum transaminase (ALT, AST)activity and MDA content in liver homogenate, and improvereduced GSHpx level of liver homogenate. Leflunomide (4,12, 36 mg@kg-1) significantly lowered TNF-α and NO level inserum, and IL-1 produced by intraperitoneal macrophagesinduced splenocyte proliferation response were furtherinhibited.CONCLUSION: These findings suggested that leflunomidehad significant protective action on ILI in mice.

  16. NRF2 Protection against Liver Injury Produced by Various Hepatotoxicants

    Directory of Open Access Journals (Sweden)

    Jie Liu

    2013-01-01

    Full Text Available To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd and Keap1-hepatocyte knockout (Keap1-HKO mice were used as a “graded Nrf2 activation” model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant. Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, bromobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1β, IL-6, and TNFα, oxidative stress genes (Ho-1, Egr1, ER stress genes (Gadd45 and Gadd153, and genes encoding cell death (Noxa, Bax, Bad, and caspase3. Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.

  17. Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.

    Science.gov (United States)

    Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

    2016-07-01

    Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD.

  18. Normothermic Machine Perfusion Reduces Bile Duct Injury and Improves Biliary Epithelial Function in Rat Donor Livers

    NARCIS (Netherlands)

    Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

    BACKGROUND: Bile duct injury may occur during liver procurement and transplantation, especially in livers donated after circulatory death (DCD). Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury, compared to static cold storage (SCS). However, it is unknown whether NMP

  19. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    Science.gov (United States)

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  20. Signaling mechanisms in alcoholic liver injury: Role of transcription factors,kinases and heat shock proteins

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Alcoholic liver injury comprises of interactions of various intracellular signaling events in the liver. Innate immune responses in the resident Kupffer cells of the liver, oxidative stress-induced activation of hepatocytes,fibrotic events in liver stellate cells and activation of liver sinusoidal endothelial cells all contribute to alcoholic liver injury. The signaling mechanisms associated with alcoholic liver injury vary based on the cell type involved and the extent of alcohol consumption. In this review we will elucidate the oxidative stress and signaling pathways affected by alcohol in hepatocytes and Kupffer cells in the liver by alcohol. The toll-like receptors and their down-stream signaling events that play an important role in alcohol-induced inflammation will be discussed. Alcohol-induced alterations of various intracellular transcription factors such as NFκB, PPARs and AP-1, as well as MAPK kinases in hepatocytes and macrophages leading to induction of target genes that contribute to liver injury will be reviewed. Finally, we will discuss the significance of heat shock proteins as chaperones and their functional regulation in the liver that could provide new mechanistic insights into the contributions of stress-induced signaling mechanisms in alcoholic liver injury.

  1. Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

    Science.gov (United States)

    Zhang, Jingyao; Zhang, Simin; Bi, Jianbin; Gu, Jingxian; Deng, Yan; Liu, Chang

    2017-04-01

    Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS

  2. Accuracy of the AAST organ injury scale for CT evaluation of traumatic liver and spleen injuries

    Directory of Open Access Journals (Sweden)

    Homann Georg

    2014-02-01

    Full Text Available 【Abstract】Objective: Detection of abdominal injury is a very important component in trauma management, so a precise assessment of liver and spleen injuries including their severity degree is necessary. There is a good case to believe that in emergency situations the radiologists’ performance may profit from a systematic approach using established scoring systems. Score systems as the organ injury scale (OIS drawn up by the American Association for the Surgery of Trauma are a valuable guidance for objective trauma assessment. Aim of this study was to evaluate retrospectively whether a structured approach using the OIS may help improve trauma assessment. Methods: Fifty-three patients, 38 male and 15 female who underwent CT and laparotomy after abdominal trauma were included in this study. The laparotomy was performed by experienced surgeons with a minimum experience of 6 years. While the original CT reports were written by different radiologists with a minimum experience of 3 years, and then a radiologist with experience of 4 years reviewed the same original CT pictures, resulting in the structured report. Both the original and structured CT results on liver and spleen injuries were transferred into OIS grades. Finally, the initial and structured CT results were compared with the intraoperative findings gathered from the surgery report. Results: Regarding the original CT report we found a mean divergence of 0.68±0.8 (r=0.45 to the OIS finding in the surgery report for liver injuries (0.69±1.17 for spleen injuries; r=0.69. In comparison with the structured approach, where we detected a divergence of 0.8±0.68; r=0.63 (0.47±0.77 for spleen injuries; r=0.91, there was no significant difference. However we detected a lower rate of over-diagnosis in structured approaches. Conclusion: Our study shows that a structured approach to triage abdominal trauma using an imaging check- list does not lead to a significantly higher detection rate, but a

  3. Apoptotic cell death as a target for the treatment of acute and chronic liver injury

    NARCIS (Netherlands)

    Schoemaker, Marieke Henriëtte

    2004-01-01

    Acute liver failure can develop as a consequence of viral hepatitis, drug- or toxin-induced toxicity or rejection after liver transplantation, whereas chronic liver injury can be due to long-term exposure to alcohol, chemicals, chronic viral hepatitis, metabolic or cholestatic disorders. During acut

  4. Revisiting acute liver injury associated with herbalife products.

    Science.gov (United States)

    Appelhans, Kristy; Smith, Casey; Bejar, Ezra; Henig, Y Steve

    2011-10-27

    In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.

  5. HIFU Hemostasis of Liver Injuries Enhanced by Ultrasound Contrast Agents

    Science.gov (United States)

    Zderic, Vesna; Vaezy, Shahram; Brayman, Andrew A.; Matula, Thomas J.; O'Keefe, Grant E.; Crum, Lawrence A.

    2005-03-01

    Our objective was to investigate whether High-Intensity Focused Ultrasound (HIFU) hemostasis can be achieved faster in the presence of ultrasound contrast agents (UCA). Incisions (3 cm long and 0.5 cm deep) were made in surgically exposed rabbit liver. Optison at a concentration of 0.18 ml/kg was injected into the mesenteric vein, immediately before the incision was made. The HIFU applicator (frequency of 5.5 MHz, and intensity of 3,700 W/cm2) was scanned manually over the incision (at an approximate rate of 1 mm/s) until hemostasis was achieved. The times to complete hemostasis were measured and normalized with the initial blood loss. The hemostasis times were 59±23 s in the presence of Optison and 70±23 s without Optison. The presence of Optison produced a 37% reduction in the normalized hemostasis times (phemostasis of internal organ injuries.

  6. Acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    Mossanen, J C; Tacke, F

    2015-04-01

    The induction of acute hepatic damage by acetaminophen (N-acetyl-p-aminophenol [APAP]), also termed paracetamol, is one of the most commonly used experimental models of acute liver injury in mice. The specific values of this model are the highly reproducible, dose-dependent hepatotoxicity of APAP and its outstanding translational importance, because acetaminophen overdose is one of the most frequent reasons for acute liver failure (ALF) in humans. However, preparation of concentrated APAP working solutions, application routes, fasting period and variability due to sex, genetic background or barrier environment represent important considerations to be taken into account before implementing this model. This standard operating procedure (SOP) provides a detailed protocol for APAP preparation and application in mice, aimed at facilitating comparability between research groups as well as minimizing animal numbers and distress. The mouse model of acetaminophen poisoning therefore helps to unravel the pathogenesis of APAP-induced toxicity or subsequent immune responses in order to explore new therapeutic interventions for improving the prognosis of ALF in patients.

  7. The Molecular Circadian Clock and Alcohol-Induced Liver Injury.

    Science.gov (United States)

    Udoh, Uduak S; Valcin, Jennifer A; Gamble, Karen L; Bailey, Shannon M

    2015-10-14

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  8. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  9. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  10. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Hadi, Mackenzie; Laarakkers, Coby M. M.; Masereeuw, Rosalinde; Groothuis, Geny M. M.; Russel, Frans G. M.

    2014-01-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker ide

  11. Hepatic pseudoaneurysm after traumatic liver injury; is CT follow-up warranted?

    DEFF Research Database (Denmark)

    Østerballe, Lene; Helgstrand, Frederik; Axelsen, Thomas

    2014-01-01

    INTRODUCTION: Hepatic pseudoaneurysm (HPA) is a rare complication after liver trauma, yet it is potentially fatal, as it can lead to sudden severe haemorrhage. The risk of developing posttraumatic HPA is one of the arguments for performing follow-up CT of patients with liver injuries. The aim...... no treatment failures. There was no correlation between the severity of the liver injury and development of HPA. 5 out of 7 patients were asymptomatic and would have been discharged without treatment if the protocol did not include a default follow-up CT. CONCLUSIONS: In conclusion, this study shows that HPA...... is not correlated to the severity of liver injury and it develops in 4% of patients after traumatic liver injury. In order to avoid potentially life-threatening haemorrhage from a post trauma hepatic pseudoaneurysm, it seems appropriate to do follow-up CT as part of the conservative management of blunt...

  12. Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Mei Liu

    2014-01-01

    Full Text Available Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by D-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.

  13. Role of transcription factor Egr-1 in liver injury following hemorrhagic shock and resuscitation

    Institute of Scientific and Technical Information of China (English)

    MEI Jian-min; Timothy R. Billiar; YU Cong-hui; David J. Gallo; YANG Rong-hua; LIU Sha-lei

    2005-01-01

    Objective: To investigate the role of transcription factor Egr-1 in liver injury following hemorrhagic shock (HS) /resuscitation (R). Methods: Both Egr-1 knockout (KO) and wild-type (WT) mice were subjected to HS and HSR injuries. The expressions of TNF-α, IL-6, G-CSF and ICAM-1 mRNAs in the liver were examined by RT-PCR, and their serum levels were measured by ELISA. The liver inflammatory infiltration and liver injury in both Egr-1 WT and KO mice following HS/R were evaluated by liver MPO content, serum ALT level and histological examination. Results: Egr-1 inhibition resulted in less mRNA expression of TNF-α, IL-6 , G-CSF and ICAM-1 in the liver, and lower serum levels of TNF-α, IL-6, G-CSF and ICAM-1 antigens in Egr-1 KO mice following HS/R. The liver inflammatory infiltration and liver injury were less severe in Egr-1 KO mice following HS/R, as evidenced by lower serum ALT level, lower hepatic MPO content and histological manifestations. Conclusion: Our data suggest that transcription factor Egr-1 is involved in regulating the expression of inflammatory response genes and plays a role in liver injury following HS/R.

  14. Characterization of chemically induced liver injuries using gene co-expression modules.

    Directory of Open Access Journals (Sweden)

    Gregory J Tawa

    Full Text Available Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20% genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.

  15. Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

    Science.gov (United States)

    Tawa, Gregory J.; AbdulHameed, Mohamed Diwan M.; Yu, Xueping; Kumar, Kamal; Ippolito, Danielle L.; Lewis, John A.; Stallings, Jonathan D.; Wallqvist, Anders

    2014-01-01

    Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules) specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1) known biochemical pathways associated with liver injuries and 2) clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20%) genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects. PMID:25226513

  16. Warm ischemic injury is reflected in the release of injury markers during cold preservation of the human liver.

    Directory of Open Access Journals (Sweden)

    Bote G Bruinsma

    Full Text Available Liver transplantation plays a pivotal role in the treatment of patients with end-stage liver disease. Despite excellent outcomes, the field is strained by a severe shortage of viable liver grafts. To meet high demands, attempts are made to increase the use of suboptimal livers by both pretransplant recovery and assessment of donor livers. Here we aim to assess hepatic injury in the measurement of routine markers in the post-ischemic flush effluent of discarded human liver with a wide warm ischemic range.Six human livers discarded for transplantation with variable warm and cold ischemia times were flushed at the end of preservation. The liver grafts were flushed with NaCl or Lactated Ringer's, 2 L through the portal vein and 1 L through the hepatic artery. The vena caval effluent was sampled and analyzed for biochemical markers of injury; lactate dehydrogenase (LDH, alanine transaminase (ALT, and alkaline phosphatase (ALP. Liver tissue biopsies were analyzed for ATP content and histologically (H&E examined.The duration of warm ischemia in the six livers correlated significantly to the concentration of LDH, ALT, and ALP in the effluent from the portal vein flush. No correlation was found with cold ischemia time. Tissue ATP content at the end of preservation correlated very strongly with the concentration of ALP in the arterial effluent (P<0.0007, R2 = 0.96.Biochemical injury markers released during the cold preservation period were reflective of the duration of warm ischemic injury sustained prior to release of the markers, as well as the hepatic energy status. As such, assessment of the flush effluent at the end of cold preservation may be a useful tool in evaluating suboptimal livers prior to transplantation, particularly in situations with undeterminable ischemic durations.

  17. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury.

    Science.gov (United States)

    Schaub, Johanna R; Malato, Yann; Gormond, Coralie; Willenbring, Holger

    2014-08-21

    Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  18. Evidence against a Stem Cell Origin of New Hepatocytes in a Common Mouse Model of Chronic Liver Injury

    Directory of Open Access Journals (Sweden)

    Johanna R. Schaub

    2014-08-01

    Full Text Available Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  19. Protective effect of salvianolate on lung injury induced by ischemia reperfusion injury of liver in mice

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

    Full Text Available Objective To evaluate the protective effect of salvianolate on lung injury induced by hepatic ischemia reperfusion(IR injury in mice and its underlying mechanisms.Methods A hepatic IR model of mice was reproduced,and 24 animals were assigned into 3 groups(8 each: sham operation(SO group,control group and salvianolate(SV group.Just before ischemia induction,animals in SV group received salvianolate injection at a dose of 60 mg/kg via tail vein,while in control group the mice received normal saline with an equal volume,and in SO group the mice received the same operation as in SV group but without producing liver ischemia.Four hours after reperfusion,the serum,liver and lung tissue were collected.The alanine aminotransferase(ALT and aspartate aminotransferase(AST levels in serum were detected and the histological changes in liver and lung were examined.The wet-to-dry weight ratio of pulmonary tissue was measured.The contents of tumor necrosis factor α(TNF-α,interleukin(IL-6,IL-1β and IL-10 in bronchoalveolar lavage fluid(BALF were detected by enzyme linked immunosorbent assay(ELISA,and the relative mRNA levels of TNF-α,IL-6,IL-1β and IL-10 in pulmonary tissue were analyzed by real-time reverse transcription PCR(RT-PCR.The activaty of transcription factor NF-κB was measured with Western blotting analysis.Results No significant pathologic change was found in mice of SO group.Compared with the mice in control group,those in SV group exhibited lower levels of ALT and AST(P < 0.01,lighter histological changes in liver and lung(P < 0.05,lower levels of wet-to-dry weight ratio of lung tissue(P < 0.05,lower expression levels of TNF-α,IL-6,IL-1β and IL-10 in BALF and lung tissue(P < 0.05 or P < 0.01.Further examination demonstrated that the activity of NF-κB in SV group was significantly down-regulated as compared with that in control group.Conclusion Salvianolate can attenuate lung injury induced by hepatic IR in mice,the mechanism may inclade

  20. Bupivacaine drug-induced liver injury: a case series and brief review of the literature.

    Science.gov (United States)

    Chintamaneni, Preethi; Stevenson, Heather L; Malik, Shahid M

    2016-08-01

    Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaine-induced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic.

  1. Acute Liver Injury with Severe Coagulopathy in Marasmus Caused by a Somatic Delusional Disorder

    Directory of Open Access Journals (Sweden)

    Lance L. Stein

    2011-01-01

    Full Text Available Marasmus is a severe form of protein-calorie malnutrition characterized by the depletion of fat stores, muscle wasting, and the lack of edema. In developed countries, marasmus is often the result of anorexia nervosa. Abnormal transaminases with liver synthetic dysfunction have rarely been reported with anorexia nervosa. To our knowledge, we report the first detailed case of acute liver injury with severe coagulopathy (INR>1.5 in a patient with marasmus due to self-induced calorie restriction caused by a somatic delusional disorder. This case highlights the severity of liver injury that may occur with significant weight loss from self-induced calorie restriction and the rapid normalization of this injury with treatment. It is important for clinicians to be aware of patterns of acute liver injury in patients with severe protein-calorie malnutrition, regardless of the underlying cause.

  2. anti-retroviral therapy related liver injury (arli): a series of 11 cases

    African Journals Online (AJOL)

    2013-12-02

    Dec 2, 2013 ... Risk factors for liver injury should be evaluated ... Weight (Kg) using a Salter weighing scale and height (Cms) ... ascertain other risk factors which affect ART related ..... associated with an increased propensity to develop.

  3. Liver Injury from Herbal, Dietary, and Weight Loss Supplements: a Review.

    Science.gov (United States)

    Zheng, Elizabeth X; Navarro, Victor J

    2015-06-28

    Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.

  4. Pretreatment with TCDD exacerbates liver injury from Concanavalin A: critical role for NK cells.

    Science.gov (United States)

    Fullerton, Aaron M; Roth, Robert A; Ganey, Patricia E

    2013-11-01

    For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6 mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response.

  5. Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh

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    Grace Guzman

    2009-01-01

    Full Text Available There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa, an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis.

  6. Expression and significance of SOCS3 in liver tissue of rats with severe acute pancreatitis complicated by liver injury

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    Bin WANG

    2012-11-01

    Full Text Available Objective  To investigate the expression and mechanism of action of suppressor of cytokine signaling 3 (SOCS3 in liver tissue of rats with experimental severe acute pancreatitis (SAP concurring with liver injury. Methods  The rat model of SAP was reproduced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Thirty-two male SD rats were randomly assigned into 4 groups (8 each: normal control group (NC, SAP 6h, 12h, and 18h groups. The levels of serum amylase (AMY, alanine aminotransferase (ALT and aspartate aminotransferase (AST were measured dynamically. The concentrations of IL -6 and IL -18 were determined by ELISA. The localization and expression of SOCS3 protein in liver were determined by immunohistochemical staining and Western blotting. Results  Compared with NC group, the serum levels of AMY, ALT and AST increased significantly in SAP groups (P < 0.05, and there was significant difference among SAP groups. The serum concentrations of IL-6 and IL-18 increased significantly in the SAP groups than in NC group (P < 0.05, and there was significant difference among SAP groups. Compared with NC group, the concentration of SOCS3 protein increased significantly in SAP groups, and increased gradually along with the increased duration of pancreatitis (P < 0.05. A minor expression of SOCS3 protein was found in NC group. The change in SOCS3 protein concentration was consistent with the severity of liver injury as well as the serum concentrations of IL-6 and IL-18. Conclusions  The inflammatory action induced by SAP concurring with liver injury may induce the expression of SOCS3 in liver tissue, and it may increase in intensity along with the severity of liver injury and inflammatory reaction. The mechanism may be attributed to a negative feedback regulation of the inflammatory action mediated by JAK/STAT pathway.

  7. The Roles of Innate Immune Cells in Liver Injury and Regeneration

    Institute of Scientific and Technical Information of China (English)

    Zhongjun Dong; Haiming Wei; Rui Sun; Zhigang Tian

    2007-01-01

    For predominant abundance with liver-specific Kupffer cells, natural killer (NK) cells, and natural killer T (NKT)cells and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features.In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A (Con A), lipopolysaccharide (LPS), or polyinosinic-polycytidylic acid (Poly I:C)-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.

  8. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  9. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice

    NARCIS (Netherlands)

    Swelm, R.P.L. van; Laarakkers, J.M.M.; Kuur, E.C. van der; Morava, E.; Wevers, R.A.; Augustijn, K.D.; Touw, D.J.; Sandel, M.H.; Masereeuw, R.; Russel, F.G.M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  10. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  11. Low-dose ATRA Supplementation Abolishes PRM Formation in Rat Liver and Ameliorates Ethanol-induced Liver Injury

    Institute of Scientific and Technical Information of China (English)

    PAN Zhihong; DAN Zili; FU Yu; TANG Wangxian; LIN Jusheng

    2006-01-01

    The effects of all-trans-retinoic acid (ATRA) in low doses supplementation on concentrations of polar retinoid metabolites (PRM) and retinoids in the ethanol-fed rat liver, and on hepatocyte injury were investigated. The rat model of alcoholic liver disease (ALD) was induced by intragastric infusion of ethanol, and then the rats were administrated with ATRA in two different doses (150 μg/kg body weight and 1.5 mg/kg body weight) for 4 weeks. Concentrations of retinoids in rat liver and plasma were determined by using HPLC. Liver tissues pathologic changes were observed under the light microscopy and electron microscopy. The serum transaminases concentrations were measured. The results showed that the HPLC analysis of retinoids revealed that retinoids (vitamin A,RA, retinyl palmitate) concentrations in ethanol-fed rat liver and RA concentration in ethanol-fed rat plasma were markedly diminished (P<0.01) after ethanol feeding for 12 weeks. Furthermore, obvious peaks of PRM were formed in livers of ethanol-fed rats. ATRA 150 μg/kg supplementation in ethanol-fed rats for 4 weeks raised RA concentration in both liver and plasma, and also raised vitamin A concentration in liver to control levels, partially restored retinyl palmitate concentration (P<0.05) in liver. ATRA 1.5 mg/kg supplementation raised not only RA concentrations in liver and plasma but also retinyl palmitate concentrations in liver. However, the vitamin A concentration in liver of ATRA-supplemented rats (1.5 mg/kg) was higher than that of controls (P<0.05). The histologic observation of liver tissues indicated that ATRA treatment notably alleviated hepatocellular swelling,steatosis, the swelling of mitochondria and proliferation of smooth endoplasmic reticulum (SER).ATRA treatment greatly decreased levels of serum transaminases as compared with the only ethanol-fed group (P<0.05). It was concluded that low-dose ATRA treatment could restore retinoids concentrations and abolish the PRM formation

  12. Decoy receptor 3 analogous supplement protects steatotic rat liver from ischemia–reperfusion injury

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    Tzu-Hao Li

    2017-07-01

    Conclusion: Using multimodal in vivo and in vitro approaches, we found that DcR3a analogue was a potential agent to protect steatotic liver against IR injury by simultaneous blockade of the multiple IR injury-related pathogenic changes.

  13. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model

    NARCIS (Netherlands)

    B.H.M. Heijnen; I.H. Straatsburg; N.D. Padilla; G.J. Mierlo; C.E. Hack; T.M. van Gulik

    2006-01-01

    Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 10

  14. Immune-mediated Liver Injury in Hepatitis B Virus Infection

    National Research Council Canada - National Science Library

    In Soo Oh; Su-Hyung Park

    2015-01-01

    Hepatitis B virus (HBV) is responsible for approximately 350 million chronic infections worldwide and is a leading cause of broad-spectrum liver diseases such as hepatitis, cirrhosis and liver cancer...

  15. Effect of adoptive transfer or depletion of regulatory T cells on triptolide-induced liver injury

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    Xinzhi eWang

    2016-04-01

    Full Text Available ObjectiveThe aim of this study is to clarify the role of regulatory T cell (Treg in triptolide (TP-induced hepatotoxicity. MethodsFemale C57BL/6 mice received either adoptive transfer of Tregs or depletion of Tregs, then underwent TP administration and were sacrificed 24 hours after TP administration. Liver injury was determined according to ALT and AST levels in serum and histopathological change in liver tissue. Hepatic frequencies of Treg cells and the mRNA expression levles of transcription factor FoxP3 and RORγt, IL-10, SOCS and Notch/Notch ligand were investigated.ResultsDuring TP-induced liver injury, hepatic Treg and IL-10 decreased, while Th17 cell transcription factor RORγt, SOCS signaling and Notch signaling increased, accompanied with liver inflammation. Adoptive transfer of Tregs ameliorated the severity of TP-induced liver injury, accompanied with increased levels of hepatic Treg and IL-10. Adoptive transfer of Tregs remarkably inhibited the expression of RORγt, SOCS3, Notch1 and Notch3. On the contrary, depletion of Treg cells in TP-administered mice resulted in a notable increase of RORγt, SOCS1, SOCS3 and Notch3, while the Treg and IL-10 of liver decreased. Consistent with the exacerbation of liver injury, higher serum levels of ALT and AST were detected in Treg-depleted mice. ConclusionsThese results showed that adoptive transfer or depletion of Tregs attenuated or aggravated TP-induced liver injury, suggesting that Tregs could play important roles in the progression of liver injury. SOCS proteins and Notch signaling affected Tregs, which may contribute to the pathogenesis of TP-induced hepatotoxicity.

  16. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jie, E-mail: JLiu@kumc.edu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Lu, Yuan-Fu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Zhang, Youcai; Wu, Kai Connie [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Fan, Fang [Cytopathology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D. [University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2013-11-01

    Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential. - Highlights: • Oleanolic acid at higher doses and long-term use may produce liver injury. • Oleanolic acid increased serum ALT, ALP, bilirubin and bile acid concentrations. • OA produced feathery degeneration, inflammation and cell death in the liver. • OA altered bile acid homeostasis, affecting bile acid synthesis and transport.

  17. Injurious effect on rat liver mitochondria by lymphocytes from patients with primary biliary cirrhosis.

    Science.gov (United States)

    Bootello, A; Fernandez-Cruz, E; Escartin, P; Blanco, M F; Gosalvez, M; Segovia De Arana, J M

    1976-01-01

    Lymphocytes from primary biliary cirrhosis (PBC) patients were shown to have an injurious effect on rat liver mitochondria, as was demonstrated by the inhibition of mitochondrial respiratory control by these cells. The incubation of the PBC patients' lymphocytes with isolated rat liver mitochondria produced a significant inhibition of mitochondrial respiration in the presence of ADP. However, no significant effect on respiration was seen with control lymphocytes of normal persons or with lymphocytes from patients with alcoholic cirrhosis and miscellaneous liver diseases. The results suggest that this injurious effect of PBC lymphocytes on mitochondria might be a consequence of sensitization in vivo of the PBC patients' lymphocytes by the mitochondrial antigens. PMID:1277585

  18. Protective effects of ω-3 PUFA on the second liver injury in rats with traumatic brain injury and hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    许会彬

    2014-01-01

    Objective To investigate the effects of preconditioning withω-3 polyunsaturated fatty acid(ω-3 PUFA)on the second liver injury in rats with traumatic brain injury and hemorrhagic shock(TBIS)and explore the underlying mechanism.Methods Total of 36 male Wistar rats were assigned randomly(random number)into 3 groups(n=12 in each):sham

  19. Acute kidney injury in acute on chronic liver failure.

    Science.gov (United States)

    Maiwall, Rakhi; Sarin, S K; Moreau, Richard

    2016-03-01

    Acute on chronic liver failure (ACLF) is a distinct clinical entity; however, there is still debate in the way it is defined in the East as compared to the West, especially with respect to incorporation of kidney dysfunction or failure in the definition of ACLF. Kidney dysfunction is defined as serum creatinine between 1.5 and 1.9 mg/dl and kidney failure as serum creatinine of more than 2 mg/dl or requirement of renal replacement therapy according to the EASL-CLIF Consortium. Kidney dysfunction or failure is universally present in patients with ACLF according to the definition by the EASL-CLIF Consortium while on the contrary the APASL definition of ACLF does not incorporate kidney dysfunction or failure in its definition. Recently, both the diagnosis and management of renal failure in patients with cirrhosis has changed with the advent of the acute kidney injury (AKI) criteria defined as an abrupt decline in renal functions, characterized by an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or an increase of more than 50 % from baseline, which is known or presumed to have occurred in the previous 7 days. Further, recent studies in patients with cirrhosis have shown the utility of biomarkers for the diagnosis of AKI. The present review covers the pathogenetic mechanisms, diagnosis, prognosis as well as management of AKI in patients with ACLF from both a Western as well as an Eastern perspective. The review identifies an unmet need to diagnose AKI and prevent this ominous complication in patients with ACLF.

  20. Internal vacuum-assisted closure device in the swine model of severe liver injury

    Directory of Open Access Journals (Sweden)

    Everett Christopher B

    2012-12-01

    Full Text Available Abstract Objectives The authors present a novel approach to nonresectional therapy in major hepatic trauma utilizing intraabdominal perihepatic vacuum assisted closure (VAC therapy in the porcine model of Grade V liver injury. Methods A Grade V injury was created in the right lobe of the liver in a healthy pig. A Pringle maneuver was applied (4.5 minutes total clamp time and a vacuum assisted closure device was placed over the injured lobe and connected to suction. The device consisted of a perforated plastic bag placed over the liver, followed by a 15 cm by 15cm VAC sponge covered with a nonperforated plastic bag. The abdomen was closed temporarily. Blood loss, cardiopulmonary parameters and bladder pressures were measured over a one-hour period. The device was then removed and the animal was euthanized. Results Feasibility of device placement was demonstrated by maintenance of adequate vacuum suction pressures and seal. VAC placement presented no major technical challenges. Successful control of ongoing liver hemorrhage was achieved with the VAC. Total blood loss was 625 ml (20ml/kg. This corresponds to class II hemorrhagic shock in humans and compares favorably to previously reported estimated blood losses with similar grade liver injuries in the swine model. No post-injury cardiopulmonary compromise or elevated abdominal compartment pressures were encountered, while hepatic parenchymal perfusion was maintained. Conclusion These data demonstrate the feasibility and utility of a perihepatic negative pressure device for the treatment of hemorrhage from severe liver injury in the porcine model.

  1. Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

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    Antonios Douros

    2016-01-01

    Full Text Available Herb-induced liver injury (HILI has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once. Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

  2. Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

    Science.gov (United States)

    Douros, Antonios; Bronder, Elisabeth; Andersohn, Frank; Klimpel, Andreas; Kreutz, Reinhold; Garbe, Edeltraut; Bolbrinker, Juliane

    2016-01-01

    Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. PMID:26784183

  3. The Effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yu-Jie Zhang

    2016-09-01

    Full Text Available Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. The animals were treated daily with alcohol and fruit juices for fifteen days. Chronic treatment with alcohol increased the levels of aspartate transaminase (AST, alanine transaminase (ALT, total bilirubin (TBIL, triglyceride (TG, malondialdehyde (MDA, and decreased total protein (TP. Histopathological evaluation also showed that ethanol induced extensive fat droplets in hepatocyte cytoplasm. Syzygium samarangense and Passiflora edulis normalized various biochemical parameters. Solanum muricatum increased the level of ALT and induced infiltration of inflammatory cells in the liver. These results strongly suggest that treatment with Syzygium samarangense and Passiflora edulis could protect liver from the injury of alcohol, while Solanum muricatum could aggravate the damage.

  4. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.

    Science.gov (United States)

    Deutsch, M; Graffeo, C S; Rokosh, R; Pansari, M; Ochi, A; Levie, E M; Van Heerden, E; Tippens, D M; Greco, S; Barilla, R; Tomkötter, L; Zambirinis, C P; Avanzi, N; Gulati, R; Pachter, H L; Torres-Hernandez, A; Eisenthal, A; Daley, D; Miller, G

    2015-05-07

    Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

  5. Small-for-Size Liver Transplantation Increases Pulmonary Injury in Rats: Prevention by NIM811

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    Qinlong Liu

    2012-01-01

    Full Text Available Pulmonary complications after liver transplantation (LT often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG and quarter-size grafts (QSG, respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5–18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT.

  6. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai Nguyen Thanh; Hue Pham Thi Minh; Tuan Anh Le; Huong Duong Thi Ly; Tung Nguyen Huu; Loi Vu Duc; Thu Dang Kim; Tung Bui Thanh

    2015-01-01

    To investigated the protective potential of ethanol extracts of Scutellaria baicalensis (S. baicalensis ) against lipopolysaccharide (LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS (5 mg/kg of body weight, intraperitoneal injection). Both protein and mRNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. Cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS significantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice. Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  7. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai; Nguyen; Thanh; Hue; Pham; Thi; Minh; Tuan; Anh; Le; Huong; Duong; Thi; Ly; Tung; Nguyen; Huu; Loi; Vu; Duc; Thu; Dang; Kim; Tung; Bui; Thanh

    2015-01-01

    Objective: To investigated the protective potential of ethanol extracts of Scutellaria baicalensis(S. baicalensis) against lipopolysaccharide(LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS(5 mg/kg of body weight, intraperitoneal injection). Both protein and m RNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. C yclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS signifi cantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice.Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  8. Apocynin reduced doxycycline-induced acute liver injury in ovariectomized mice

    Directory of Open Access Journals (Sweden)

    Satoru Mitazaki

    2016-01-01

    Full Text Available To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx mice against doxycycline (DOXY-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip 8 weeks after the operation, 30 min after apocynin (5 mg/kg or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.

  9. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    Science.gov (United States)

    Khurana, Sandeep; Jadeja, Ravirajsinh; Twadell, William; Cheng, Kunrong; Rachakonda, Vikrant; Saxena, Neeraj; Raufman, Jean-Pierre

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced survival and increased liver nodularity and fibrosis. We next assessed AOM-induced liver injury in mice treated with a selective M3R agonist, pilocarpine. After pilocarpine treatment, stimulation of post-M3R signaling in the liver was evidenced by ERK and AKT activation. In contrast to the damaging effects of the M3R antagonist, administering pilocarpine to AOM-treated mice significantly attenuated hepatic stellate cell activation, collagen deposition, bile ductule proliferation, and liver fibrosis and nodularity. As anticipated from these findings, livers from pilocarpine-treated mice exhibited reduced expression of key players in fibrosis (α1 collagen, α-smooth muscle actin, TGF-β1, PGDF, TGF-β1R, PGDFR) and decreased mRNA levels for molecules that regulate extracellular matrix formation (TIMP-1, TIMP-2, MMP-2, MMP-13). Cleaved caspase-3, nitrotyrosine and BrdU immunostaining provided evidence that pilocarpine treatment reduced hepatocyte apoptosis and oxidative stress, while increasing hepatocyte proliferation. Collectively, these findings identify several downstream mechanisms whereby M3R activation ameliorates toxic liver injury. These novel observations provide a proof-of-principle that selectively stimulating M3R activation to prevent or diminish liver injury is a therapeutic strategy worthy of further investigation. PMID:23707755

  10. Impact of asialoglycoprotein receptor deficiency on the development of liver injury

    Institute of Scientific and Technical Information of China (English)

    Serene ML Lee; Carol A Casey; Benita L McVicker

    2009-01-01

    The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the proper trafficking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously,we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease (ALD). The studies revealed profound ethanolmediated impairments to the ASGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations,studies were performed utilizing knockout mice (lacking a functional ASGP receptor) to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of anti-Fas (CD95) antibody, carbon tetrachloride (CCl4) and lipopolysaccharide (LPS)/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels,histopathological scores, as well as hepatocellular death.Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the ASGP receptor may provide protection against various toxinmediated liver diseases.

  11. A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury

    National Research Council Canada - National Science Library

    Hide, Diana; Ortega-Ribera, Martí; Fernández-Iglesias, Anabel; Fondevila, Constantino; Salvadó, M Josepa; Arola, Lluís; García-Pagán, Juan Carlos; Mancini, Aldo; Bosch, Jaime; Gracia-Sancho, Jordi

    2014-01-01

    ...), liver grafts from healthy and steatotic rats, and human liver samples, we aimed to characterize the effects of a new recombinant form of human manganese superoxide dismutase (rMnSOD) on hepatic CS+WR injury. After CS...

  12. The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence.

    Science.gov (United States)

    Orci, Lorenzo A; Lacotte, Stéphanie; Oldani, Graziano; Morel, Philippe; Mentha, Gilles; Toso, Christian

    2014-09-01

    Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence.

  13. S-nitroso-N-acetylcysteine ameliorates ischemia-reperfusion injury in the steatotic liver

    Directory of Open Access Journals (Sweden)

    Wellington Andraus

    2010-01-01

    Full Text Available BACKGROUND: Steatosis is currently the most common chronic liver disease and it can aggravate ischemia-reperfusion (IR lesions. We hypothesized that S-nitroso-N-acetylcysteine (SNAC, an NO donor component, can ameliorate cell damage from IR injury. In this paper, we report the effect of SNAC on liver IR in rats with normal livers compared to those with steatotic livers. METHODS: Thirty-four rats were divided into five groups: I (n=8, IR in normal liver; II (n=8, IR in normal liver with SNAC; III (n=9, IR in steatotic liver; IV (n=9, IR in steatotic liver with SNAC; and V (n=10, SHAN. Liver steatosis was achieved by administration of a protein-free diet. A SNAC solution was infused intraperitoneally for one hour, beginning 30 min. after partial (70% liver ischemia. The volume of solution infused was 1 ml/100 g body weight. The animals were sacrificed four hours after reperfusion, and the liver and lung were removed for analysis. We assessed hepatic histology, mitochondrial respiration, oxidative stress (MDA, and pulmonary myeloperoxidase. RESULTS: All groups showed significant alterations compared with the group that received SHAN. The results from the steatotic SNAC group revealed a significant improvement in liver mitochondrial respiration and oxidative stress compared to the steatotic group without SNAC. No difference in myeloperoxidase was observed. Histological analysis revealed no difference between the non-steatotic groups. However, the SNAC groups showed less intraparenchymal hemorrhage than groups without SNAC (p=0.02. CONCLUSION: This study suggests that SNAC effectively protects against IR injury in the steatotic liver but not in the normal liver.

  14. Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM: To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions. METHODS: Abdominal injection of CCl4 was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was function-ally examined by depletion experiment using ...

  15. Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS: Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d.UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment.RESULTS: At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ± 35.5 U/L, respectively, P < 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION: The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.

  16. Evaluation of liver function and electroacupuncture efficacy of animals with alcoholic liver injury by the novel imaging methods.

    Science.gov (United States)

    Zhang, Dong; Song, Xiao-Jing; Li, Shun-Yue; Wang, Shu-You; Chen, Bing-Jun; Bai, Xiao-Dong; Tang, Li-Mei

    2016-07-22

    Imaging methods to evaluate hepatic microcirculation (HM) and liver function (LF) by directly monitoring overall liver tissue remain lacking. This study establish imaging methods for LF that combines Laser speckle perfusion imaging (LSPI) and in vivo optical imaging (IVOI) technologies to investigate changes of hepatic microcirculation and reserve function in the animals gavaged with 50% ethanol (15 ml/kg·bw) for a model of acute alcoholic liver injury (ALI), and for evaluation of electroacupuncture (EA) effect. The liver blood perfusion and indocyanine green (ICG) distribution were observe by LSPI and IVOI separately. After EA, the livers were collected to measure the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), thromboxane A (TXA2), prostacyclin (PGI2) and endothelin (ET). The acquisitions of newly established LSPI of liver and ICG in vivo fluorescence imaging (ICG-IVFI), combining the results of other indexes showed: hepatic microcirculation perfusion (HMP) significantly reduced, ICG metabolism reduced, and ALT/AST increased in animal model with acute ALI. EA can reverse these changes. The use of LSPI of liver and ICG-IVFI, which was novel imaging methods for LF established in this study, could display the LF characteristics of ALI and the EA efficacy.

  17. Complications of high grade liver injuries: management and outcomewith focus on bile leaks

    Directory of Open Access Journals (Sweden)

    Bala Miklosh

    2012-03-01

    Full Text Available Abstract Background Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to expect an increased risk of hepatic complications following trauma. The aim of the current study was to define hepatic related morbidity in patients sustaining high-grade hepatic injuries that could be safely managed non-operatively. Patients and methods This is a retrospective study of patients with liver injury admitted to Hadassah-Hebrew University Medical Centre over a 10-year period. Grade 3-5 injuries were considered to be high grade. Collected data included the number and types of liver-related complications. Interventions which were required for these complications in patients who survived longer than 24 hours were analysed. Results Of 398 patients with liver trauma, 64 (16% were found to have high-grade liver injuries. Mechanism of injury was blunt trauma in 43 cases, and penetrating in 21. Forty patients (62% required operative treatment. Among survivors 22 patients (47.8% developed liver-related complications which required additional interventional treatment. Bilomas and bile leaks were diagnosed in 16 cases post-injury. The diagnosis of bile leaks was suspected with abdominal CT scan, which revealed intraabdominal collections (n = 6, and ascites (n = 2. Three patients had continuous biliary leak from intraabdominal drains left after laparotomy. Nine patients required ERCP with biliary stent placement, and 2 required percutaneous transhepatic biliary drainage. ERCP failed in one case. Four angioembolizations (AE were performed in 3 patients for rebleeding. Surgical treatment was found to be associated with higher complication rate. AE at admission was associated with a significantly higher rate of biliary complications. There were 24 deaths (37%, the majority from uncontrolled haemorrhage (18 patients. There were only 2 hepatic-related mortalities due to liver failure

  18. Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases

    Science.gov (United States)

    Wunsch, Ewa; Krawczyk, Marcin; Milkiewicz, Malgorzata; Trottier, Jocelyn; Barbier, Olivier; Neurath, Markus F.; Lammert, Frank; Kremer, Andreas E.; Milkiewicz, Piotr

    2016-01-01

    Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival. PMID:27506882

  19. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

    Energy Technology Data Exchange (ETDEWEB)

    Massey, Veronica L. [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Stocke, Kendall S. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Schmidt, Robin H.; Tan, Min [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Ajami, Nadim [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Neal, Rachel E. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Petrosino, Joseph F. [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Barve, Shirish [Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)

    2015-05-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria.

  20. The protective effect of niacinamide on ischemia-reperfusion-induced liver injury.

    Science.gov (United States)

    Chen, C F; Wang, D; Hwang, C P; Liu, H W; Wei, J; Lee, R P; Chen, H I

    2001-01-01

    Reperfusion of ischemic liver results in the generation of oxygen radicals, nitric oxide (NO) and their reaction product peroxynitrite, all of which may cause strand breaks in DNA, which activate the nuclear enzyme poly(ADP ribose)synthase (PARS). This results in rapid depletion of intracellular nicotinamide adenine dinucleotide and adenosine 5'-triphosphate (ATP) and eventually induces irreversible cytotoxicity. In this study, we demonstrated that niacinamide, a PARS inhibitor, attenuated ischemia/reperfusion (I/R)-induced liver injury. Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 min. Thereafter, flow was restored and the liver was reperfused for 90 min. Blood samples collected prior to I and after R were analyzed for methyl guanidine (MG), NO, tumor necrosis factor (TNF-alpha) and ATP. Blood levels of aspartate transferase (AST), alanine transferase (ALT) and lactate dehydrogenase (LDH) which served as indexes of liver injury were measured. This protocol resulted in elevation of the blood NO level (p niacinamide (10 mM), liver injury was significantly attenuated, while blood ATP content was reversed. In addition, MG, TNF-alpha and NO release was attenuated. These results indicate that niacinamide, presumably by acting with multiple functions, exerts potent anti-inflammatory effects in I/R-induced liver injury.

  1. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  2. Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy

    Science.gov (United States)

    Guo, Rui; Lin, Bin; Pan, Jing Fei; Liong, Emily C.; Xu, Ai Min; Youdim, Moussa; Fung, Man Lung; So, Kwok Fai; Tipoe, George L.

    2016-01-01

    Acute liver disease is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long term clinical outcome and lead to liver failure or cancer. Here, we initially demonstrated the beneficial role of caspase-9-dependent autophagy in acute liver injury. Treatment with caspase-9 inhibitor z-LEHD-FMK in HepG2 cells, AML12 cells and C57BL/b6N mice exacerbated CCl4-induced acute hepatocellular damage, and also down-regulated autophagy markers expression levels, indicating that caspase-9 inhibition may aggravate acute liver damage by suppressing cytoprotective autophagy. CCl4 was used as an acute liver injury inducer which caused oxidative stress and apoptosis through up-regulation of HIF-1α, as well as triggered hepatic inflammation and necroptosis via TLR4/NF-κB pathway. Caspase-9 Thr125 site was firstly phosphorylated by ERK1/2 which subsequently activated the cytoprotective autophagy process to attenuate acute CCl4 injury. Caspase-9 inhibition further aggravated hepatic necroptosis through NF-κB expression, leading to increased pro-inflammatory mediators levels, suggesting a protective role of caspase-9-dependent autophagy in the inflammatory process as well as its possibility being a new therapeutic target for the treatment of acute liver injury. PMID:27580936

  3. Total Flavonoids from Mimosa Pudica Protects Carbon Tetrachloride -Induced Acute Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Zhen-qin QIU

    2015-03-01

    Full Text Available Objective: To observe the protective effect of total flavonoids from Mimosa pudica on carbon tetrachloride (CCl4-induced acute liver injury in mice. Methods: CCl4-induced acute liver injury model in mice was established. The activity of ALT and AST, the content of serum albumin (Alb and total antioxidant capacity (T-AOC were determined. The content of malondiadehyde (MDA was measured and the activity of superoxide dismutase (SOD was determined. The histopathological changes of liver were observed.Results: Compared with CCl4 modle group, each dose group of total flavonouida from Mimosa pudica couldreduced the activity of ALT and AST in mice obviously (P<0.01, indicating they had remarkably protective effect on CCl4-induced acute liver injury in mice. high and middle dose groups of total flavonouida from Mimosa pudica couldincrease the content of Alb in mice (P<0.01. Each dose group of total flavonouida from Mimosa pudica could enhance the level of T-AOC (P<0.01. each dose group of total flavonouida from Mimosa pudica could lower the content of liver homogenate MDA but enhance the activity of SOD in a dose-depended manner (P<0.01. Conclusion: Total flavones from Mimosa Pudica have obvious protective effect on CCl4-induced acute liver injury in mice.

  4. Interleukin-23 mediates the pathogenesis of LPS/GalN-induced liver injury in mice.

    Science.gov (United States)

    Bao, Suxia; Zhao, Qiang; Zheng, Jianming; Li, Ning; Huang, Chong; Chen, Mingquan; Cheng, Qi; Zhu, Mengqi; Yu, Kangkang; Liu, Chenghai; Shi, Guangfeng

    2017-05-01

    Interleukin-23 (IL-23) is required for T helper 17 (Th17) cell responses and IL-17 production in hepatitis B virus infection. A previous study showed that the IL-23/IL-17 axis aggravates immune injury in patients with chronic hepatitis B virus infection. However, the role of IL-23 in acute liver injury remains unclear. The purpose of this study was to determine the role of the inflammatory cytokine IL-23 in lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury in mice. Serum IL-23 from patients with chronic hepatitis B virus (CHB), acute-on-chronic liver failure (ACLF) and healthy individuals who served as healthy controls (HCs) was measured by ELISA. An IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody was administered intravenously at the time of challenge with LPS (10μg/kg) and GalN (400mg/kg) in C57BL/6 mice. Hepatic pathology and the expression of Th17-related cytokines, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and the stabilization factor Csf3 were assessed in liver tissue. Serum IL-23 was significantly upregulated in ACLF patients compared with CHB patients and HCs (Pliver tissue histopathology and significant reductions in the expression of Th17-related inflammatory cytokine, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and stabilization factors Csf3 within the liver tissue compared with LPS/GalN mice (Pliver injury in mice. IL-23 neutralizing antibodies attenuated liver injury by reducing the expression of Th17-related inflammatory cytokines, neutrophil chemoattractants and stabilization factors within the liver tissue, which indicated that IL-23 likely functions upstream of Th17-related cytokine and chemokine expression to recruit inflammatory cells into the liver. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Protective effect of nitric oxide induced by ischemic preconditioning on reperfusion injury of rat liver graft

    Institute of Scientific and Technical Information of China (English)

    Jian-Ping Gong; Bing Tu; Wei Wang; Yong Peng; Shou-Bai Li; Lu-Nan Yan

    2004-01-01

    AIM: Ischemic preconditioning (IP) is a brief ischemic episode,which confers a state of protection against the subsequent long-term ischemia-reperfusion injuries. However, little is known regarding the use of IP before the sustained cold storage and liver transplantation. The present study was designed to evaluate the protective effect of IP on the long-term preservation of liver graft and the prolonged anhepatic-phase injury.METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation. All livers underwent 10 min of ischemia followed by 10 min of reperfusion before harvest. Rat liver transplantation was performed with the portal vein clamped for 25 min. Tolerance of transplanted liver to the reperfusion injury and liverdamage were investigated. The changes in adenosineconcentration in hepatic tissue and those of nitric oxide (NO)and tumor necrosis factor (TNF) in serum were also assessed.RESULTS: Recipients with IP significantly improved theirone-week survival rate and liver function, they had increasedlevels of circulating NO and hepatic adenosine, and a reducedlevel of serum TNF, as compared to controls. Histologicalchanges indicating hepatic injuries appeared improved in theIP group compared with those in control group. The protectiveeffect of IP was also obtained by administration of adenosine,while blockage of the NO pathway using Nω-nitro-L-argininemethyl ester abolished the protective effect of IRCONCLUSION: IP appears to have a protective effect onthe long-term preservation of liver graft and the prolongedanhepatic-phase injuries. NO may be involved in this process.

  6. Obesity Increases Sensitivity to Endotoxin Liver Injury: Implications for the Pathogenesis of Steatohepatitis

    Science.gov (United States)

    Yang, Shi Qi; Zhi Lin, Hui; Lane, M. Daniel; Clemens, Mark; Diehl, Anna Mae

    1997-03-01

    Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor α (TNFα ), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon γ , which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.

  7. The protection of meloxicam against chronic aluminium overload-induced liver injury in rats.

    Science.gov (United States)

    Yang, Yang; He, Qin; Wang, Hong; Hu, Xinyue; Luo, Ying; Liang, Guojuan; Kuang, Shengnan; Mai, Shaoshan; Ma, Jie; Tian, Xiaoyan; Chen, Qi; Yang, Junqing

    2017-04-04

    The present study was designed to observe the protective effect and mechanisms of meloxicam on liver injury caused by chronic aluminium exposure in rats. The histopathology was detected by hematoxylin-eosin staining. The levels of prostaglandin E2, cyclic adenosine monophosphate and inflammatory cytokines were detected by enzyme linked immunosorbent assay. The expressions of cyclooxygenases-2, prostaglandin E2 receptors and protein kinase A were measured by western blotting and immunohistochemistry. Our experimental results showed that aluminium overload significantly damaged the liver. Aluminium also significantly increased the expressions of cyclooxygenases-2, prostaglandin E2, cyclic adenosine monophosphate, protein kinase A and the prostaglandin E2 receptors (EP1,2,4) and the levels of inflammation and oxidative stress, while significantly decreased the EP3 expression in liver. The administration of meloxicam significantly improved the impairment of liver. The contents of prostaglandin E2 and cyclic adenosine monophosphate were significantly decreased by administration of meloxicam. The administration of meloxicam also significantly decreased the expressions of cyclooxygenases-2 and protein kinase A and the levels of inflammation and oxidative stress, while significantly increased the EP1,2,3,4 expressions in rat liver. Our results suggested that the imbalance of cyclooxygenases-2 and downstream prostaglandin E2 signaling pathway is involved in the injury of chronic aluminium-overload rat liver. The protective mechanism of meloxicam on aluminium-overload liver injury is attributed to reconstruct the balance of cyclooxygenases-2 and downstream prostaglandin E2 signaling pathway.

  8. Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats

    Science.gov (United States)

    Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

    2016-01-01

    Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti-inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)-induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN-induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor-α, interferon-γ and granulocyte/macrophage colony-stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN-induced liver injury. Therefore, Centella asiatica may be useful in preventing liver damage. PMID:27748812

  9. Innate immune recognition and regulation in liver injury: A brief report from a series of studies

    Institute of Scientific and Technical Information of China (English)

    TIAN ZhiGang

    2009-01-01

    The discovery of innate immune receptors and the emergence of liver Immunology (high content of NK and NKT cells in liver) led to the second research summit in innate immunity since the finding of NK cells in the middle 1970s. Liver disease is one of the most dangerous threats to humans, and the pro-gress in innate immunology and liver immunology made it possible to re-explain the cellular end too-lecular immune mechanisms of liver disease. In the past ten years, we have found that innate recogni-tion of hepatic NK and NKT subsets were involved in murine liver injury. We established a novel NK cell-dependent acute murine hepatitis model by activating Toll-like receptor-3 (TLR-3) with an injection of poly I:C, which may mimic mild viral hepatitis (such as Chronic Hepatitis B). We observed that a network of innate immune cells including NK, NKT and Kupffer cells is involved in liver immune injury in our established NK cell-dependent murine model. We noted that TLR-3 on Kupffer ceils activated by pretreatment with poly I:C might protect against bacterial toxin (LPS)-induced fuIminant hepatitis by down-regulating TLR-4 function, while TLR-3 pre-activation of NK cells might reduce Con A-induced NKT cell-mediated fulminant hepatitis by blocking NKT cell recruitment to the liver. We also found that the oversensitivity to injury by immune stimulation in HBV (hepatitis B virus) transgenic mice (full HBV gene-tg or HBs-tg) correlated to the over-expression of Real, an NKG2D (natural killer cell group 2D) ligand of NK cells or CDld, a ligand of TCR-V14 of NKT cells, on HBV+ hepatocytes, which leads to an innate immune response against hepatocytes and is critical in liver immune injury and regeneration.

  10. Liver manipulation causes hepatocyte injury and precedes systemic inflammation in patients undergoing liver resection.

    NARCIS (Netherlands)

    Poll, M.C. van de; Derikx, J.P.M.; Buurman, W.A.; Peters, W.H.M.; Roelofs, H.M.J.; Wigmore, S.J.; Dejong, C.H.

    2007-01-01

    BACKGROUND: Liver failure following liver surgery is caused by an insufficient functioning remnant cell mass. This can be due to insufficient liver volume and can be aggravated by additional cell death during or after surgery. The aim of this study was to elucidate the causes of hepatocellular injur

  11. Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

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    Yumin Xu

    Full Text Available BACKGROUND: Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF. METHODOLOGY: Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. PRINCIPAL FINDINGS: Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats. CONCLUSIONS: sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  12. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital

    Science.gov (United States)

    Mrzljak, Anna; Kosuta, Iva; Skrtic, Anita; Kanizaj, Tajana Filipec; Vrhovac, Radovan

    2013-01-01

    Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement. PMID:23467452

  13. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital.

    Science.gov (United States)

    Mrzljak, Anna; Kosuta, Iva; Skrtic, Anita; Kanizaj, Tajana Filipec; Vrhovac, Radovan

    2013-01-01

    Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.

  14. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia Juice and Phenobarbital

    Directory of Open Access Journals (Sweden)

    Anna Mrzljak

    2013-01-01

    Full Text Available Noni (Morinda citrifolia juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.

  15. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect from APAP

  16. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    Science.gov (United States)

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (Psesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  17. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

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    H. P. Kopylchuk

    2017-04-01

    Full Text Available Arginase activity and L-arginine content in both cytosolic and mitochondrial fractions of rat liver cells under the conditions of toxic injury on the background of protein deprivation was studied. The most significant reduction of arginase activity in liver cells and depletion of L-arginine pool was found in rats with toxic acetaminophen-induced liver injury maintained on the ration balanced by all nutrients as well as in protein deficiency rats. It was concluded that reduction of the arginase activity in the cytosolic fraction of rat liver cells, combined with simultaneous decrease of L-arginine content, may be considered as one of the mechanisms of ornithine cycle disturbance. The decline of activity of mitochondrial isoform of arginase II, for certain, is related with activation of NO-synthase system.

  18. Hepatoprotective effects of Sapium sebiferum in paracetamol-induced liver injury

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    Liaqat Hussain

    2015-06-01

    Full Text Available Sapium sebiferum leaves were used to determine its hepatoprotective effects against paracetamol-induced hepatotoxicity in mice. A dose dependent study was conducted using two different doses (200 mg/kg and 400 mg/kg of the extract of S. sebiferum against toxic effects of paracetamol (500 mg/kg in experimental animal model. Silymarin (50 mg/kg was used as standard drug to compare therapeutic effects of S. sebiferum with control and paracetamol-treated groups. Paracetamol significantly increased the serum levels of liver enzyme markers like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin. The extract showed protective effects by normalizing the liver enzymes markers in a dose dependent manner. Histopathological results confirmed the hepatoprotective effects of leaves of S. sebiferum. We conclude that leaves of S. sebiferum have strong hepatoprotective effects against paracetamol-induced liver injury and can be used in liver injuries caused by drug-induced toxicity.

  19. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.

    Science.gov (United States)

    Liu, Jie; Lu, Yuan-Fu; Zhang, Youcai; Wu, Kai Connie; Fan, Fang; Klaassen, Curtis D

    2013-11-01

    Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential.

  20. Co-administration of cyclosporine A alleviates thioacetamide-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sabrina Fan; Ching-Feng Weng

    2005-01-01

    AIM: To investigate the effects of cyclosporine A (CsA)on thioacetamide (TAA)-induced liver injury.METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group shows higher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4)in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section,TGFβ-R1 and FGFR4 are more concentrated in rat liver after CsA plus TAA injury.CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.

  1. Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

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    Edith Hochhauser

    2015-07-01

    Full Text Available Background/Aims: Ischemia/reperfusion (I/R injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC, a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70% ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway, the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation. This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. Conclusion: A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.

  2. Effects of cefodizime on chemokines of liver tissues in mice with immunological hepatic injury

    Institute of Scientific and Technical Information of China (English)

    WANG Peng; KAN Quan-cheng; YU Zu-jiang; LI Ling; PAN Xue

    2011-01-01

    Background Chronic hepatic inflammation is characterized by the accumulation of lymphocytes as a consequence of increased recruitment from the blood and retention within the tissue at sites of infection. CXC chemokine ligand 16 (CXCL16) mRNA has been detected in both inflamed and normal liver tissues and is strongly upregulated in the injured liver tissues in a murine model. The aim of this study was to investigate the effect of cefodizime on CXCL16 mRNA of liver tissues in mice with immunological hepatic injury.Methods The murine model of immunological hepatic injury was induced by Bacillus Calmette Guerin and Lipoposaccharide. The mice with immunological hepatic injury were randomly assigned to the model group, the cefodizime group and the ceftriaxone group. The three groups were continuously given agents for seven days and CXCL16 mRNA of liver tissue was determined and contrasted with the control group treated by normal saline. Reverse transcription-polymerase chain reaction was used to assay CXCL16 mRNA levels in liver tissues.Results The expressions of CXCL16 mRNA were significantly higher in the model group and the ceftriaxone group than in the control group and the cefodizime group (P <0.05), indicating the mice in the model group and the ceftriaxone group were immunodeficient. There was no statistical difference in the expressions of CXCL16 mRNA between the control group and the cefodizime group. Similarly, no statistical difference in the expressions of CXCL16 mRNA between the model group and the ceftriaxone group was detected (P >0.05).Conclusion Cefodizime effectively reduces the infiltration of lymphocytes into liver tissues and alleviates the liver damage by decreasing CXCL16 mRNA in liver tissues in mice with immunological hepatic injury.

  3. Role of Hydrogen Sulfide on Autophagy in Liver Injuries Induced by Selenium Deficiency in Chickens.

    Science.gov (United States)

    Wenzhong, Wang; Tong, Zhang; Hongjin, Lin; Ying, Chang; Jun, Xing

    2017-01-01

    Selenium (Se) is an indispensable trace mineral that was associated with liver injuries in animal models. Hydrogen sulfide (H2S) is involved in many liver diseases, and autophagy can maintain liver homeostasis with a stress stimulation. However, little is known about the correlation between H2S and autophagy in the liver injury chicken models induced by Se deficiency. In this study, we aimed to investigate the correlation between H2S and autophagy in the liver injury chicken models. We randomly divided 120 1-day-old chickens into two equal groups. The control group was fed with complete food with a Se content of 0.15 mg/kg, and the Se-deficiency group (lab group) was fed with a Se-deficient diet with a Se content of 0.033 mg/kg. When the time comes to 15, 25, and 35 days, the chickens were sacrificed (20 each). The liver tissues were gathered and examined for pathological observations, the mRNA and protein levels of H2S synthases (CSE, CBS, and 3-MST) and the mRNA and protein levels of autophagy-related genes. The results showed that the expression of CSE, CBS, and 3-MST and H2S production were higher in the lab group than in the control group. Swellings, fractures, and vacuolizations were visible in the mitochondria cristae in the livers of the lab group and autophagosomes were found as well. In addition, the expression of autophagy-related genes (ATG5, LC3-I, LC3-II, Beclin1, and Dynein) was higher in the lab group than in the control group (p liver injury chicken models, and H2S was correlated with autophagy.

  4. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury

    Directory of Open Access Journals (Sweden)

    Henning W Zimmermann

    2012-10-01

    Full Text Available Different etiologies such as drug toxicity, acute viral hepatitis B or acetaminophen poisoning can cause acute liver injury (ALI or even acute liver failure (ALF. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF, interleukin-6 (IL-6, IL-1-beta or monocyte chemoattractant protein 1 (MCP-1, CCL2 as well as activating other non-parenchymal liver cells, e.g. endothelial or hepatic stellate cells (HSC. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g. via caspase activation, but also activate protective signaling pathways, e.g. via nuclear factor kappa B (NF-kB. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+ monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1 are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.

  5. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

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    Maria Ausiliatrice Puglisi

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs, represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

  6. Mitochondrial Roles and Cytoprotection in Chronic Liver Injury

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    Davide Degli Esposti

    2012-01-01

    Full Text Available The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.

  7. Free radical scavenging activity of Berberine in acetaminophen induced liver injury

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    Suhail Ahmed Almani

    2017-01-01

    Full Text Available Objective: Evaluation of free radical scavenging activity of Berberine (BBR in acetaminophen (AAP induced liver injury. Study design: Experimental study Place and Duration: Animal house, Isra University Hyderabad from October 2015 to March 2016. Methodology: A sample of 80 male Wistar rats was selected according to inclusion and exclusion criteria and was divided into a control and three experimental groups. Acetaminophen, N-acetyl cysteine (NAC and BBR were administered in standard doses. Blood samples were collected by cardiac puncture after 18 hours of post experiment period. Liver function test, anti oxidant enzymes and malondialdehyde (MDA were detected by ELISA assay kit (Fortress Diagnostics. The data was analyzed on Statistix 10.0 software (USA at 95% CI (P≤ 0.05. Results: The BBR showed anti oxidant and anti peroxidant activity against acetaminophen induced liver injury. BBR treated animals showed increased serum and tissue SOD, GPX, CAT, and GSSH with a reduction in tissue MDA (p=0.0001. Liver injury ameliorating effect of BBR was superior to N-acetyl cysteine. Conclusion: The present study suggests Berberine protects against acetaminophen-induced liver injury by its free radical scavenging activity.

  8. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q.H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y.X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X.M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-03-03

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  9. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    L. Zong

    2014-03-01

    Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  10. A fatal case of air-bag-mediated liver injury in an unrestrained driver.

    Science.gov (United States)

    Uemura, Koichi; Uchida, Kyoko; Nara, Akina; Ochiai, Eriko

    2009-04-01

    A middle-aged man, who drove a small vehicle while drunken and not wearing a seat belt, crashed head on into a pier wall at a high speed. The rapid air-bag deployment caused abdominal compression of the driver, who was found dead 2 m away from the car. There were facial front-glass injuries and multiple rib fractures, but no head injury. Autopsy disclosed liver laceration with intra-abdominal hemorrhage (2,000 mL), resulting in hemorrhagic shock. This is the first autopsy report of liver laceration caused by the rapid expansion of an air-bag during an automobile crash.

  11. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    OpenAIRE

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced...

  12. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

    OpenAIRE

    Cotter, David G.; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M.; d’Avignon, D. André; Graham, Mark J.; Dietzen, Dennis J.; Brunt, Elizabeth M; Patti, Gary J.; Crawford, Peter A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohe...

  13. Pistacia Terebinthus Coffee Protects against Thioacetamide-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Ibrahim Halil Bahcecioglu

    2015-08-01

    Full Text Available Aim/background: Pistacia terebinthus is used as a coffee substitute in the East and Southern Anatolia regions of Turkey. It contains unsaturated fatty acids, tocopherols, polyphenols and carotenoids. P. terebinthus has anti-inflammatory and potential antioxidant activity. In this study we evaluated the protective effects of P. terebinthus coffee (PTC on thioacetamide (TAA-induced liver injury in rats. Materials and methods: Twenty-eight male Sprague-Dawley rats were equally randomized into four groups. Chronic liver injury was induced with TAA (100 mg/kg i.p. three times weekly. The first group of rats served as control and received only tap water (G1, and the remaining groups of rats received PTC, p.o (G2; TAA (G3; TAA plus PTC, p.o (G4, respectively. Results: After 8 weeks, PTC intake significantly reduced fibrosis/ inflammation scores (p < 0.05 in the livers of TAA-treated group. Compared to control group, PTC intake reduced transforming growth factor beta (TGF-β concentrations in the liver (p < 0.05. Compared to the TAA group, TGF-β, nuclear factor kappa B (NF-κB (p < 0.05, tumor necrosis factor alpha (TNF-α concentrations in the liver tissue were reduced by PTC intake. Discussion and conclusion: PTC intake provided beneficial effects against TAA-induced liver injury in rats. PTC probably suppresses the proinflammatory cytokines through NF-κB signaling pathway.

  14. Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

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    Chengwei Niu

    2017-01-01

    Full Text Available Cisplatin is widely used for the treatment of a variety of cancers but with a high incidence of hepatotoxicity. Baicalein is originally isolated from the root of Scutellaria baicalensis Georgi with broad bioactivities. The present study aims to investigate the protective effect of baicalein against cisplatin-induced acute liver injury and the underlying mechanism of this protective effect. Administration of cisplatin (40 mg/kg for 24 h increased the serum alanine and aspartate aminotransferases and alkaline phosphatase levels, while baicalein could reverse all those changes induced by cisplatin. Liver histological analysis further evidenced the protection of baicalein against cisplatin-induced liver injury. Baicalein counteracted the increased liver malondialdehyde (amount induced by cisplatin, while baicalein could further increase the cisplatin-induced elevation of the amount of reduced glutathione in the liver. Further results showed that baicalein reversed the cisplatin-induced decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S transferase and glutathione reductase. On the other hand, baicalein alleviated the increase in the serum levels of tumour necrosis factor alpha and interleukin 6 induced by cisplatin. Taken together, our results demonstrate that baicalein can inhibit cisplatin-induced hepatic oxidative stress and inflammation, which contributes greatly to the amelioration of cisplatin-induced liver injury.

  15. Surgical intervention for paediatric liver injuries is almost history - a 12-year cohort from a major Scandinavian trauma centre.

    Science.gov (United States)

    Koyama, Tomohide; Skattum, Jorunn; Engelsen, Peder; Eken, Torsten; Gaarder, Christine; Naess, Pål Aksel

    2016-11-29

    Although nonoperative management (NOM) has become standard care, optimal treatment of liver injuries in children is still challenging since many of these patients have multiple injuries. Moreover, the role of angiography remains poorly defined, and a high index of suspicion of complications is warranted. This study reviews treatment and outcomes in children with liver injuries at a major Scandinavian trauma centre over a 12-year period. Patients trauma registry and medical records. A total of 66 children were included. The majority was severely injured as reflected by a median injury severity score of 20.5 (mean 22.2). NOM was attempted in 60 (90.9%) patients and was successful in 57, resulting in a NOM success rate of 95.0% [95% CI 89.3 to 100]. Only one of the three NOM failures was liver related, occurred in the early part of the study period, and consisted in operative placement of drains for bile leak. Two (3.0%) patients underwent angiographic embolization (AE). Complications occurred in 18 (27.3% [95 % CI 16.2 to 38.3]) patients. Only 2 (3.0%) patients had liver related complications, in both cases bile leak. Six (9.1%) patients underwent therapeutic laparotomy for non-liver related injuries. Two (3.0%) patients died secondary to traumatic brain injury. This single institution paediatric liver injury cohort confirms high attempted NOM and NOM success rates even in patients with high grade injuries and multiple accompanying injuries. AE can be a useful NOM adjunct in the treatment of paediatric liver injuries, but is seldom indicated. Moreover, bile leak is the most common liver-related complication and the need for liver-related surgery is very infrequent. NOM is the treatment of choice in almost all liver injuries in children, with operative management and interventional radiology very infrequently indicated.

  16. OLIGOFRUCTOSE PROTECTS AGAINST ARSENIC-INDUCED LIVER INJURY IN A MODEL OF ENVIRONMENT/OBESITY INTERACTION

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    Massey, Veronica L; Stocke, Kendall S; Schmidt, Robin H.; Tan, Min; Ajami, Nadim; Neal, Rachel E.; Petrosino, Joseph F; Barve, Shirish; Arteel, Gavin E.

    2015-01-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 wks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. PMID:25759243

  17. Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases

    NARCIS (Netherlands)

    C. Ferrajolo (Carmen); K.M.C. Verhamme (Katia); G. Trifirò (Gianluca); ‘T Jong, G.W. (Geert W.); G. Picelli (Gino); C. Giaquinto (Carlo); G. Mazzaglia (Giampiero); B.H.Ch. Stricker (Bruno); F. Rossi (Francesco); A. Capuano (Annalisa); M.C.J.M. Sturkenboom (Miriam)

    2016-01-01

    textabstractIntroduction: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. Objective: We assessed risk estimates of liver injury associated with antibi

  18. Biliary tract injury caused by different relative warm ischemia time in liver transplantation in rats

    Institute of Scientific and Technical Information of China (English)

    Hong-Feng Zhao; Guo-Wei Zhang; Jie Zhou; Jian-Hua Lin; Zhong-Lin Cui; Xiang-Hong Li

    2009-01-01

    BACKGROUND: There is a controversy over the degree of liver and biliary injury caused by the period of secondary warm ischemia. A liver autotransplantation model was adopted because it excludes the effects of infection and immunological rejection on bile duct injury. This study was undertaken to assess biliary tract injury caused by relative warm ischemia (secondary warm ischemia time in the biliary tract) and reperfusion. METHODS: One hundred and two rats were randomly divided into 5 groups: groupⅠ (control); groupsⅡ toⅤ, relative warm ischemia times of 0 minute, 30 minutes, 1 hour and 2 hours. In addition to the levels of serum alkaline phosphatase, and total bilirubin, pathomorphology assessment and TUNEL assay were performed to evaluate biliary tract damage. RESULTS: Under the conditions that there were no signiifcant differences in warm ischemia time, cold perfusion time and anhepatic phase, group comparisons showed statistically signiifcant differences. The least injury occurred in groupⅡ (portal vein and hepatic artery reperfused simultaneously) but the most severe injury occurred in groupⅤ (biliary tract relative warm ischemia time 2 hours). CONCLUSIONS: Relative warm ischemia is one of the factors that result in bile duct injury, and the relationship between relative warm ischemia time the bile injury degree is time-dependent. Simultaneous arterial and portal reperfusion is the best choice to avoid the bile duct injury caused by relative warm ischemia.

  19. Subnormothermic ex vivo liver perfusion reduces endothelial cell and bile duct injury after donation after cardiac death pig liver transplantation.

    Science.gov (United States)

    Knaak, Jan M; Spetzler, Vinzent N; Goldaracena, Nicolas; Boehnert, Markus U; Bazerbachi, Fateh; Louis, Kristine S; Adeyi, Oyedele A; Minkovich, Leonid; Yip, Paul M; Keshavjee, Shaf; Levy, Gary A; Grant, David R; Selzner, Nazia; Selzner, Markus

    2014-11-01

    An ischemic-type biliary stricture (ITBS) is a common feature after liver transplantation using donation after cardiac death (DCD) grafts. We compared sequential subnormothermic ex vivo liver perfusion (SNEVLP; 33°C) with cold storage (CS) for the prevention of ITBS in DCD liver grafts in pig liver transplantation (n = 5 for each group). Liver grafts were stored for 10 hours at 4°C (CS) or preserved with combined 7-hour CS and 3-hour SNEVLP. Parameters of hepatocyte [aspartate aminotransferase (AST), international normalized ratio (INR), factor V, and caspase 3 immunohistochemistry], endothelial cell (EC; CD31 immunohistochemistry and hyaluronic acid), and biliary injury and function [alkaline phosphatase (ALP), total bilirubin, and bile lactate dehydrogenase (LDH)] were determined. Long-term survival (7 days) after transplantation was similar between the SNEVLP and CS groups (60% versus 40%, P = 0.13). No difference was observed between SNEVLP- and CS-treated animals with respect to the peak of serum INR, factor V, or AST levels within 24 hours. CD31 staining 8 hours after transplantation demonstrated intact EC lining in SNEVLP-treated livers (7.3 × 10(-4) ± 2.6 × 10(-4) cells/μm(2)) but not in CS-treated livers (3.7 × 10(-4) ± 1.3 × 10(-4) cells/μm(2) , P = 0.03). Posttransplant SNEVLP animals had decreased serum ALP and serum bilirubin levels in comparison with CS animals. In addition, LDH in bile fluid was lower in SNEVLP pigs versus CS pigs (14 ± 10 versus 60 ± 18 μmol/L, P = 0.02). Bile duct histology revealed severe bile duct necrosis in 3 of 5 animals in the CS group but none in the SNEVLP group (P = 0.03). Sequential SNEVLP preservation of DCD grafts reduces bile duct and EC injury after liver transplantation. © 2014 American Association for the Study of Liver Diseases.

  20. Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications.

    Science.gov (United States)

    Gordon, D W; Rosenthal, G; Hart, J; Sirota, R; Baker, A L

    1995-02-08

    Unconventional medical practices, including the use of herbal remedies, are prevalent in the United States. Chaparral is an herbal preparation made from a desert shrub and used for its antioxidant properties. We report the case of a 60-year-old woman who took chaparral for 10 months and developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient deteriorated and required orthotopic liver transplantation. She is now well, more than 1 year after her transplant. This case suggests that chaparral can cause serious liver injury and fulminant hepatic failure. Herbal medications should be considered as potential causes of liver toxicity.

  1. Effects of quercetin on polychlorinated biphenyls-induced liver injury in rats

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    Cléia Rocha de Oliveira

    2014-05-01

    Full Text Available Introduction: Polychlorinated biphenyls (PCBs, used as pesticides in agriculture, can lead to irreversible injuries in living organisms, particularly in liver. Oxidative stress has been implicated in the liver pathogenesis induced by different molecules, including PCBs. It has been demonstrated that quercetin, an antioxidant flavonoid found in the diet, exhibits a potent antioxidant effect in different liver pathologies. Objective: To evaluate oxidative stress caused by PCBs in liver and the antioxidant activity of quercetin. Methodology: We used male Wistar rats (n = 36, divided in 4 groups: control, quercetin (50 mg/kg/day, PCBs (0.4 ml/kg/day, and rats treated with both PCBs and quercetin. On day 25 blood was collected to assess liver integrity (enzymes AST, ALT and ALP, and liver samples to measure oxidative stress (TBARS, activity of antioxidant enzymes (SOD, CAT, GPx and DNA damage (micronucleus assay, and histological damage. Results: TBARS concentration and SOD activity were significantly higher in PCBs animals as compared to the PCB group receiving quercetin. CAT and GPx decreased in PCBs and increased when quercetin was added. The histological analysis showed damage to hepatocytes in PCBs, but quercetin was able to afford protection against such damage. The micronucleus test showed there was an increase in the production of microclenucleus compared to control, and quercetin was able to reduce this effect. Conclusion: Contamination with PCBs led to increased lipid peroxidation and DNA damage, and the use of antioxidant quercetin was effective in reducing PCBs-induced liver injury.

  2. U-74389G PRETREATMENT ATTENUATING WARM ISCHEMIA INJURY IN LIVER TRANSPLANTATION

    Institute of Scientific and Technical Information of China (English)

    严佶祺; 李宏为; 张明钧; 杨卫平; 蔡伟耀; 林言箴

    2002-01-01

    Objective To investigate the protective role of lazaroid U-74389G pretreatment against warm ischemia injury of rat liver transplantation from non-heart-beating donors. Methods Rat othortopic liver transplantation was perfomed in 4 groups (N-45, N-60 , pN-45 and pN-60 ), according to pretreatrnent with U-74389G or not, and the non-heart-beating time 45min or 60min before donor liver harvested. Survival rates, liver functions, MDA values and graft pathology of each group were compared. Results The oneweek survival rates ofGroupN-45, N-60 , pN-45 and pN-60 were25% (2/8), 0% (0/8), 58.3% (7/12)and 33.3% ( 4/12 ), respectively. U-74389G pretreatment significantly increased survival rate of rat liver transplantation from non-heart-beating donors, but also improved liver functions atd graft pathologies, as well as decreased MDA expression. Conclusion U-74389G pretreatment could attenuate warm ischemia reperfusion injury of rat liver transplantation from non-heart-beating donors.

  3. [Method of treatment of combined injuries of the liver and spleen in children].

    Science.gov (United States)

    Babich, I I; Matveev, O L; Panchenko, S N; Poliakova, L P

    2008-01-01

    Since 1980 operations for combined injuries of the liver and spleen have been made on 57 children aged from 5 through 16 years. Autografting of splenic tissue into the liver wound was performed in 17 (29.8%) patients using an original technique developed in experiments. The novelty of the suggested technique is that autografting of splenic tissue into the liver wound was followed by fixing the fragments with Pi-like stitches through the spleen transplant capsule. It ensures the impermeability of the liver wound, adequate hemostasis without applying artificial hemostatic materials and helps to avoid alloplastic materials for additional drainage of the subhepatic space, provides a direct physiological contact between the splenoid and liver tissue that is effective for prevention of hyposplenism following spleenectomy.

  4. TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.

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    Susanne Nicole Weber

    Full Text Available The development of hepatocellular carcinoma (HCC is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN, with HCC formation depending amongst others on interleukin (IL 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6 as well as hepatic apoptosis (TUNEL and proliferation (Ki67 rates.Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.This study demonstrates that liver injury upon DEN challenge

  5. [A clinicopathological study of primary liver cancer associated with alcoholic liver injury].

    Science.gov (United States)

    Kohgo, Y; Ohhira, M; Ono, M

    1996-04-01

    We described a clinicopathological study of primary hepatoma associated with alcoholic liver diseases without viral liver diseases. In 150 patients with primary hepatoma, 6 patients (4%) have hepatoma associated with pure alcoholic liver disease, although 143 hepatoma were associated with chronic viral liver diseases and one was with primary biliary cirrhosis. All patients were male. The diagnosis of hepatoma was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Three cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in 3 cases and liver cirrhosis was in 3 cases. Chronic infections of hepatitis B and C viruses were ruled out by assaying serum virus markers. Autoimmune hepatitis and primary biliary cirrhosis were neglected by serum autoantibody. Hemochromatosis and Wilson's disease were also excluded. Hepatocellular carcinoma was diagnosed histologically in all the cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced hepatocellular carcinoma. In cases with small hepatoma, the tumor was resected surgically in two cases and percutaneous ethanol injection against hepatoma was performed in one case. In these cases with small hepatoma, the patients were alive without tumor recurrence during observation period. In advanced hepatoma, transcatheter arterial infusion of anticancer agent was performed in two cases and no therapy was performed due to poor general condition in one case. One case was alive with recurrent hepatoma for 27 months, during which a therapy was repeated five times. Other 2 cases were died. The clinicopathological features of hepatoma associated with alcoholic liver disease were essentially same as those associated with chronic viral infection, although the incidence of hepatoma in alcoholic liver disease was lower than in viral liver disease. The mechanism of hepatocarcinogenesis in alcoholic liver disease was unclear and, therefore

  6. Drug-Induced Liver Injury Is a Major Risk for New Drugs.

    Science.gov (United States)

    Seeff, Leonard B

    2015-01-01

    Drug-induced liver injury (DILI), a relatively rare condition, is nevertheless a major reason for not approving a drug in development or for removing one already marketed. With a specific diagnostic biomarker lacking, finding elevated serum enzyme [alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase] activities remains an initial signal for incipient liver injury. Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called 'Hy's law') there is a high possibility of serious DILI. In 1997 several drugs were approved by the Food and Drug Administration (FDA) of the USA that were later withdrawn from the market for serious liver toxicity. New drugs in development are now required to be monitored for liver injury, and the data is to be considered in the approval decision. A program called e-DISH (evaluation of drug-induced serious hepatotoxicity) was introduced in 2004 to aid medical reviewers to select from all subjects studied those few who show nontrivial liver injury and estimate the most likely cause. The threshold of enzyme elevation comprising a warning for possibly serious DILI is uncertain, although generally accepted as 3-5 times the 'upper limit of normal'. The new direct-acting antiviral agents for treating chronic hepatitis C virus, which often lead to a reduction of elevated ALTs, mandate that a later increase without viral breakthrough be compared to the new on-treatment level of values. The drug may be discontinued or interrupted for evaluation to exclude other possible causes of liver injury. The FDA has approved no drug since 1997 that has been withdrawn later because of serious hepatotoxicity.

  7. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

    Science.gov (United States)

    Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel

    2014-06-01

    Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury.

  8. Xanthohumol suppresses inflammatory response to warm ischemia-reperfusion induced liver injury.

    Science.gov (United States)

    Dorn, Christoph; Massinger, Sabine; Wuzik, Andreas; Heilmann, Jörg; Hellerbrand, Claus

    2013-02-01

    Liver ischemia/reperfusion (I/R) leads to formation of reactive oxygen species (ROS), which cause hepatic injury and initiate an inflammatory response, which is a critical problem after liver surgery and transplantation. Xanthohumol, the major prenylated chalcone found in hops, has been discussed for its anti-inflammatory and ROS-scavenging properties, and thus, we aimed to investigate the effect of xanthohumol in a model of warm I/R liver injury. Xanthohumol was applied to BALB/c mice orally at a dose of 1 mg/g body weight for 5 days before I/R-injury was induced by clamping the vascular blood supply to the median and left lateral liver lobe for 1 h followed by a 6 h period of reperfusion. At this time, HPLC analysis revealed hepatic xanthohumol levels of approximately 2 μM, a concentration which has been shown to inhibit inflammatory effects in vitro. Assessment of hepatic HMOX1 expression, hepatic glutathione content and immunohistochemical analysis for proteins conjugated with the reactive aldehyde 4-hydroxynonenal indicated that I/R-induced oxidative stress was significantly inhibited in xanthohumol-fed compared to control mice. Histological analysis, TUNEL staining and determination of transaminase serum levels revealed no significant effects of xanthohumol on acute hepatocellular injury. However, at the same time point, pretreatment with xanthohumol almost completely blunted the I/R-induced AKT and NFκB activation and the expression of the proinflammatory genes IL-1alpha, IL-6, MCP-1 and ICAM-1, which are known to play a crucial role in the subacute phase of I/R-induced liver damage. In conclusion, these data indicate the potential of xanthohumol application to prevent adverse inflammatory responses to I/R-induced liver damage such as after surgical liver resection or transplantation.

  9. Ciprofloxacin-induced cholestatic liver injury – A case report

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    Miroslav Vujasinović

    2012-09-01

    Case report: A 19year old man has been treated with ciprofloxacin at a daily dose of 500 mg twice a day due to a mild respiratory infection. After twenty days he was admitted to hospital because of jaundice. Laboratory findings showed a typical pattern of acute cholestatic liver failure, which was additionally confirmed by the liver biopsy. The patient was treated symptomatically. Ten months later the patient’s clinical status is stabile with a normal bilirubin level and mildly elevated alkaline phosphatase and gamma-glutamyltransferase. Conclusion: Although severe hepatotoxicity after the administration of ciprofloxacin is rare, physicians should be cautious and alert to its side-effects.

  10. Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene.

    Science.gov (United States)

    Mojena, M; Hortelano, S; Castrillo, A; Diaz-Guerra, M J; Garcia-Barchino, M J; Saez, G T; Bosca, L

    2001-03-01

    The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.

  11. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

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    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  12. Influence of zinc sulfate intake on acute ethanol-induced liver injury in rats

    Institute of Scientific and Technical Information of China (English)

    Sema Bolkent; Pelin Arda-Pirincci; Sehnaz Bolkent; Refiye Yanardag; Sevim Tunali; Sukriye Yildirim

    2006-01-01

    AIM: To investigate the role of metallothionein and proliferating cell nuclear antigen (PCNA) on the morphological and biochemical effects of zinc sulfate in ethanol-induced liver injury.METHODS: Wistar albino rats were divided into four groups. Group I; intact rats, group Ⅱ; control rats given only zinc, group Ⅲ; animals given absolute ethanol, group Ⅳ; rats given zinc and absolute ethanol.Ethanol-induced injury was produced by the 1 mL of absolute ethanol, administrated by gavage technique to each rat. Animals received 100 mg/kg per day zinc sulfate for 3 d 2 h prior to the administration of absolute ethanol.RESULTS: Increases in metallothionein immunoreactivity in control rats given only zinc and rats given zinc and ethanol were observed. PCNA immunohistochemistry showed that the number of PCNA-positive hepatocytes was increased significantly in the livers of rats administered ethanol + zinc sulfate. Acute ethanol exposure caused degenerative morphological changes in the liver. Blood glutathione levels decreased, serum alkaline phosphatase and aspartate transaminase activities increased in the ethanol group when compared to the control group. Liver glutathione levels were reduced, but lipid peroxidation increased in the livers of the group administered ethanol as compared to the other groups. Administration of zinc sulfate in the ethanol group caused a significant decrease in degenerative changes, lipid peroxidation, and alkaline phosphatase and aspartate transaminase activities, but an increase in liver glutathione.CONCLUSION: Zinc sulfate has a protective effect on ethanol-induced liver injury. In addition, cell proliferation may be related to the increase in metallothionein immunoreactivity in the livers of rats administered ethanol + zinc sulfate.

  13. Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion

    Science.gov (United States)

    Yazdani, Hamza O.; Sud, Vikas; Goswami, Julie; Loughran, Patricia; Huang, Hai; Simmons, Richard L.; Tsung, Allan

    2017-01-01

    Introduction Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Methods Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. Results After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines

  14. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats

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    Sayed M. Mizar

    2015-03-01

    Full Text Available Oxidative stress plays a key role in the pathogenesis of hepatic ischemia/reperfusion (I/R-induced injury, one of the leading causes of liver damage post-surgical intervention, trauma and transplantation. This study aimed to evaluate the protective effect of nebivolol and chrysin against I/R-induced liver injury via their vasodilator and antioxidant effects, respectively. Adult male Wister rats received nebivolol (5 mg/kg and/or chrysin (25 mg/kg by oral gavage daily for one week then subjected to ischemia via clamping the portal triad for 30 min then reperfusion for 30 min. Liver function enzymes, alanine transaminase (ALT and aspartate transaminase (AST, as well as hepatic Myeloperoxidase (MPO, total nitrate (NOx, glutathione (GSH and liver malondialdehyde (MDA were measured at the end of the experiment. Liver tissue damage was examined by histopathology. In addition, the expression levels of nitric oxide synthase (NOS subtypes, endothelial (eNOS and inducible (iNOS in liver samples were assessed by Western blotting and confirmed by immunohistochemical analysis. Both chrysin and nebivolol significantly counteracted I/R-induced oxidative stress and tissue damage biomarkers. The combination of these agents caused additive liver protective effect against I/R-induced damage via the up regulation of nitric oxide expression and the suppression of oxidative stress. Chrysin and nebivolol combination showed a promising protective effect against I/R-induced liver injury, at least in part, via decreasing oxidative stress and increasing nitric oxide levels.

  15. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen.

    Science.gov (United States)

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-02-26

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA(-/-)). We found that MsrA(-/-) mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA(+/+)). The central lobule area of the MsrA(-/-) liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA(-/-) than in MsrA(+/+) mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA(-/-) than in MsrA(+/+) livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA(-/-) than in MsrA(+/+) livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion.

    Science.gov (United States)

    Tohme, Samer; Kameneva, Marina V; Yazdani, Hamza O; Sud, Vikas; Goswami, Julie; Loughran, Patricia; Huang, Hai; Simmons, Richard L; Tsung, Allan

    2017-08-29

    Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines. DRPs significantly attenuated

  17. Hepatoprotective Effect of Trigona spp. Bee Propolis against Carbon Tetrachloride-Induced Liver Injury in Rat

    Directory of Open Access Journals (Sweden)

    Rachel Amelia

    2016-06-01

    Full Text Available Background: Oxidative stress reaction can cause liver injury. This process can be prevented by antioxidant activities which can break the destructive chain caused by free radical substances in the liver. Propolis produced by Trigona spp. bee is known to have a high level of antioxidant. The aim of this study was to examine the effect of Trigona spp. bee propolis on liver histological toxicity caused by carbon tetrachloride-induced oxidative stress. Methods:This experimental study was conducted in September 2013 at the Animal Laboratory of Departement of Pharmacology and Therapy, Faculty of Medicine Universitas Padjadjaran. Twenty-four healthy male Wistar rats as objects were adapted for one week and randomly divided into 3 groups. Group I was the control negative, group II was given carbon tetrachloride on day 14, group III was given Trigona spp. bee propolis on day 1-14. On day 14, group III was injected CCl4 intraperitoneally. The quantitative data were statistically analyzed using the one way ANOVA and Tukey test with p value < 0.05. Results: Group I showed the liver contained normal cells, without significant injury of the membrane, round and complete nucleus. The average number of liver cell was 464 ± 9.59281 cells/field; group II underwent necrosis and the average of the cells was 146 ± 7.56885 cells/field; group III showed some normal liver cells, and some necrotic area with the normal liver cells average was 263 ± 14.10860 cells/field. The p-value=0.00. Conclusions: Trigona spp. bee propolis has a hepatoprotective effect against CCl4-induced liver injury histologically.

  18. Pharmaco-epidemiological, clinical and laboratory characteristics of drug-induced liver injury in tuberculosis

    Directory of Open Access Journals (Sweden)

    M. V. Koroleva

    2015-01-01

    Full Text Available Objective: improving the efficiency of pharmacotherapy of drug-induced liver injury in tuberculosis by clarifying pharmaco-epidemiological, clinical and laboratory features.Materials and Methods: A retrospective analysis of primary medical records of 250 patients with pulmonary tuberculosis, patients «Volgograd Regional Clinical TB Dispensary № 1». We evaluated the dynamics of biochemical parameters characterizing the development of hepatic cytolytic syndrome, examined the impact of gender and age on the incidence of liver damage, we investigated the relationship of clinical tuberculosis and chemotherapy regimen with the incidence of drug-induced liver injury, examined the clinical manifestations of liver disease.Results: Drug-induced liver injury as a complication of a specific anti-TB treatment was diagnosed in 67 patients (26,8%. In 170 patients (68,0% showed increase in alanine aminotransferase and asparaginaminotrasferazy. Hepatotoxicity significantly more common in patients with disseminated tuberculosis with the collapse of the lung tissue, smear, and a high degree of disease severity. Risk factors for drug liver damage were female gender and age older than 50 years. Women develop liver disease at an earlier date, and displays it harder than men. The earliest and most informative routine biochemical tests, reflecting the state of the liver in the dynamics are ALT and AST. It was found that the mode of the standard anti-TB treatment determines the type of liver injury: the first, 2a and 3rd modes prevails cytolytic hepatocellular type, with 2b mode – combined (mixed type 4th – type of cholestatic liver damage. It was found that repeated, after the development of hepatotoxic reactions, the appointment of anti-TB drugs without gepatoprotektsii in 94% of patients leads to repeated drug-induced liver damage. Cancel specific therapy against the background of cytolytic syndrome promotes the formation of

  19. Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat.

    Directory of Open Access Journals (Sweden)

    Ismail Ben Mosbah

    Full Text Available Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP, a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging

  20. Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury.

    Science.gov (United States)

    Irvine, Katharine M; Clouston, Andrew D; Gadd, Victoria L; Miller, Gregory C; Wong, Weng-Yew; Melino, Michelle; Maradana, Muralidhara Rao; MacDonald, Kelli; Lang, Richard A; Sweet, Matthew J; Blumenthal, Antje; Powell, Elizabeth E

    2015-01-01

    Macrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro- and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice). Fibrosis and HPC activation were exacerbated in LysM-Wls mice compared to littermate controls, in the absence of an apparent increase in myofibroblast activation or interstitial collagen mRNA expression, in both the TAA and CDE models of chronic liver disease. Increased Epcam mRNA levels paralleled the increased HPC activation and more mature ductular reactions, in LysM-Wls mice. Increased Epcam expression in LysM-Wls HPC was also observed, consistent with a more cholangiocytic phenotype. No differences in the mRNA expression levels of key pro-inflammatory and pro-fibrotic cytokines or the macrophage-derived HPC mitogen, Tweak, were observed. LysM-Wls mice exhibited increased expression of Timp1, encoding the key Mmp inhibitor Timp1 that blocks interstitial collagen degradation, and, in the TAA model, reduced expression of the anti-fibrotic matrix metalloproteinases, Mmp12 and Mmp13, suggesting a role for macrophage-derived Wnt proteins

  1. Expression of nitric oxide synthase in T-cell-dependent liver injury initiated by ConA in Kunming mice

    Institute of Scientific and Technical Information of China (English)

    张修礼; 曲建慧; 万谟彬; 权启镇; 孙自勤; 王要军; 江学良; 李文波

    2004-01-01

    Objective: To investigate whether nitric oxide synthase (NOS) is expressed in T-cell-dependent liver injury initiated by concanavalin A (ConA) in Kunming mice and study the possible effect of nitric oxide(NO) on liver injury models. Methods: Liver injury in Kunming mice was induced by administration of ConA through tail vein. Expression of NOS in the liver was detected by NADPH diaphorase staining method. The possible effect of NO on liver injury models was obtained by L-NAME injection to suppress synthesis of NO. Results: NOS has a strong expression in hepatocytes after ConA injection, especially in those close to the central vein, while only a weak expression was found in the epithelial cells in control group. Liver injury became more serious when NO synthesis was inhibited by L-NAME, accompanied by great malondialdehyde(MDA) increase in serum and severe intrahepatic vascular thrombosis. Conclusion: NOS markedly expressed in ConAinduced liver injury, which may subsequently promote nitric oxide synthesis. Increasement of nitric oxide has a protective effect on ConA-induced liver injury.

  2. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.; Schlienger, R.; Reynolds, R.; Klungel, O.

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods T

  3. Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury

    Science.gov (United States)

    Lu, Yan; Zhang, Cheng; Chen, Yuan-Hua; Wang, Hua; Zhang, Zhi-Hui; Chen, Xi; Xu, De-Xiang

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury. PMID:28205631

  4. Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

    Science.gov (United States)

    Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

    2014-05-01

    Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response.

  5. Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.

    Science.gov (United States)

    Shin, So Youn; Jeong, Sook-Hyang; Sung, Pil Soo; Lee, Jino; Kim, Hyung Joon; Lee, Hyun Woong; Shin, Eui-Cheol

    2016-05-01

    Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

  6. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.|info:eu-repo/dai/nl/313936455; Schlienger, R.; Reynolds, R.; Klungel, O.|info:eu-repo/dai/nl/181447649

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods T

  7. Application of urine proteomics for biomarker discovery in drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Kramers, Cornelis; Masereeuw, R.; Russel, Frans G M

    2014-01-01

    Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker cand

  8. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.|info:eu-repo/dai/nl/313936455; Schlienger, R.; Reynolds, R.; Klungel, O.|info:eu-repo/dai/nl/181447649

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods

  9. Methylene blue attenuates acute liver injury induced by paraquat in rats.

    Science.gov (United States)

    Chen, Jun-Liang; Dai, Li; Zhang, Peng; Chen, Wei; Cai, Gao-Shan; Qi, Xiao-Wei; Hu, Ming-Zhu; Du, Bin; Pang, Qing-Feng

    2015-09-01

    Paraquat (PQ) poisoning often leads to severe oxidative liver injury. Recent studies have reported that methylene blue (MB) can prevent oxidative stress-induced diseases. This study tested the hypothesis that MB treatment reduced acute liver injury induced by PQ in rats. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: (1) normal group, (2) MB group (2mg/kg i.p.), (3) PQ group (35 mg/kg i.p.) and (4) PQ+MB group (MB 2mg/kg i.p. administrated 2h after PQ). We evaluated the changes of liver histopathology, serum liver enzymatic activities, oxidative stress, heme oxygenase-1 expression, and mitochondrial permeability transition. The rats were injected with PQ produced liver injury, evidenced by histological changes and elevated serum alkaline phosphatase and alanine transaminase levels; PQ also led to oxidative stress, an increase of malondialdehyde content and mitochondrial permeability transition pore opening. Pathological damage and all of the above mentioned markers were reversed in the animals treated with MB than in those who received PQ alone. Meanwhile, MB significantly increased the contents of superoxide dismutase, adenosine triphosphate and the expression of heme oxygenase-1. In conclusion, MB had a protective effect against PQ-induced hepatic damage in rats. The mechanisms of the protection seem to be the inhibition of mitochondrial permeability transition opening and the increase of heme oxygenase-1 expression.

  10. Hepatoprotective effect of Matricaria chamomilla.L in paraquat induced rat liver injury.

    Science.gov (United States)

    Tavakol, H S; Farzad, K; Fariba, M; Abdolkarim, C; Hassan, G; Seyed-Mostafa, H Z; Akram, R

    2015-02-01

    Paraquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ is known to induce injury via a redox cyclic reaction. The purpose of this study was to investigate the effect of aqueous extract Matricaria chamomilla.L (M. chamomilla) against PQ-induced liver injury in association with its antioxidant activity.The male rats were treated by gastric gavage daily with PQ (5 mg/kg/day) and M. chamomilla (50 mg/kg/day) were administered alone or in combination for 7 days. After treatments, total antioxidant capacity (TAC), total thiol molecules (TTG) levels and catalase (CAT) activity in liver tissue were measured. At the end of the experiment, plasma and lung tissue of the animals was separated. The activity of enzymatic scavengers such as CAT, TAC and TTG were measured in liver homogenate.In this sample, the TAC and TTG were lower in the PQ group as compared with control group. Co-administration of PQ with M. chamomilla extract increased TAC and TTG in liver tissue as compared with PQ group.In conclusion, M. chamomilla as natural antioxidant may be considered beneficial for the protection oxidative liver injury in PQ poisoning.

  11. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury.

    Science.gov (United States)

    Frazier, Thomas H; DiBaise, John K; McClain, Craig J

    2011-09-01

    Obesity and its metabolic complications are major health problems in the United States and worldwide, and increasing evidence implicates the microbiota in these important health issues. Indeed, it appears that the microbiota function much like a metabolic "organ," influencing nutrient acquisition, energy homeostasis, and, ultimately, the control of body weight. Moreover, alterations in gut microbiota, increased intestinal permeability, and metabolic endotoxemia likely play a role in the development of a chronic low-grade inflammatory state in the host that contributes to the development of obesity and associated chronic metabolic diseases such as nonalcoholic fatty liver disease. Supporting these concepts are the observations that increased gut permeability, low-grade endotoxemia, and fatty liver are observed in animal models of obesity caused by either high-fat or high-fructose feeding. Consistent with these observations, germ-free mice are protected from obesity and many forms of liver injury. Last, many agents that affect gut flora/permeability, such as probiotics/prebiotics, also appear to affect obesity and certain forms of liver injury in animal model systems. Here the authors review the role of the gut microbiota and metabolic endotoxemia-induced inflammation in the development of obesity and liver injury, with special reference to the intensive care unit setting.

  12. Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

    Institute of Scientific and Technical Information of China (English)

    Banwari; Agarwal; Andrew; Davenport

    2014-01-01

    Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease(MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period.

  13. Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion.

    Directory of Open Access Journals (Sweden)

    Bin Liu

    Full Text Available Hepatic ischemia/reperfusion (I/R injury is an unavoidable consequence of major liver surgery, especially in liver transplantation with bowel congestion, during which endotoxemia is often evident. The inflammatory response aggravated by endotoxin after I/R contributes to liver dysfunction and failure. The purpose of the present study was to investigate the protective effect of butyrate, a naturally occurring four-carbon fatty acid in the body and a dietary component of foods such as cheese and butter, on hepatic injury complicated by enterogenous endotoxin, as well as to examine the underlying mechanisms involved. SD rats were subjected to a total hepatic ischemia for 30 min after pretreatment with either vehicle or butyrate, followed by 6 h and 24 h of reperfusion. Butyrate preconditioning markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathological changes. The inflammatory factors levels, macrophages activation, TLR4 expression, and neutrophil infiltration in live were attenuated by butyrate. Butyrate also maintained the intestinal barrier structures, reversed the aberrant expression of ZO-1, and decreased the endotoxin translocation. We conclude that butyrate inhibition of endotoxin translocation, macrophages activation, inflammatory factors production, and neutrophil infiltration is involved in the alleviation of total hepatic I/R liver injury in rats. This suggests that butyrate should potentially be utilized in liver transplantation.

  14. Epigenetic effects of ethanol on liver and gastrointestinal injury

    Institute of Scientific and Technical Information of China (English)

    Shivendra D Shukla; Annayya R Aroor

    2006-01-01

    Alcohol consumption causes cellular injury. Recent developments indicate that ethanol induces epigenetic alterations, particularly acetylation, methylation of histones, and hypo- and hypermethylation of DNA. This has opened up a new area of interest in ethanol research and is providing novel insight into actions of ethanol at the nucleosomal level in relation to gene expression and patho-physiological consequences. The epigenetic effects are mainly attributable to ethanol metabolic stress (Emess), generated by the oxidative and non-oxidative metabolism of ethanol, and dysregulation of methionine metabolism. Epigenetic changes are important in ethanol-induced hepatic steatosis, fibrosis, carcinoma and gastrointestinal injury. This editorial highlights these new advances and its future potential.

  15. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice.

    Science.gov (United States)

    van der Geest, Rick; Ouweneel, Amber B; van der Sluis, Ronald J; Groen, Albert K; Van Eck, Miranda; Hoekstra, Menno

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; Phypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Intermittent Ischemia but Not Ischemic Preconditioning Is Effective in Restoring Bile Flow After Ischemia Reperfusion Injury in the Livers of Aged Rats

    NARCIS (Netherlands)

    Schiesser, Marc; Wittert, Anna; Nieuwenhuijs, Vincent B.; Morphett, Arthur; Padbury, Robert T. A.; Barritt, Greg J.

    2009-01-01

    BackgroundlAims. Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of t

  17. Protective effect of mycelial polysaccharides from Cordyceps sinensis on immunological liver injury in mice

    Directory of Open Access Journals (Sweden)

    Kai-zhong DONG

    2016-04-01

    Full Text Available Objective  To explore the protective effects of mycelial polysaccharides from Cordyceps sinensis (MPCS on BCG+LPS-induced liver injury in mice. Methods  The immunological liver injury mice model was reproduced by giving bacillus Calmette-Guerin (BCG and lipopolysaccharide (LPS. Sixty NIH mice were randomly assigned into 6 groups (10 each: normal control group, model group, mycelium polysaccharide in high (100mg/kg, medium (50mg/kg and low (25mg/kg dose group, and bifendate (150mg/kg treatment group. The serum transaminase levels of alanine ALT and AST were assayed with ELISA, nitric oxide (NO in serum was measured by nitrate reductase method, and the liver homogenate was prepared for the determination of the contents of interleukin-1β(IL-1β and tumor necrosis factor-α(TNF-α. The mRNA expression levels of IL-6 and iNOS in hepatic tissue were assessed using RT-PCR . Results  In the mice of immunological liver injury, mycelial polysaccharides from Cordyceps sinensis obviously lowered the serum ALT and AST levels (P<0.01, high dose MPCS significantly reduced the serum NO and liver tissue IL-1βand TNF-αlevels (P<0.01. Compared with the model group, high and medium dose MPCS significantly reduced the expression levels of IL-6 and iNOS mRNA in hepatic tissues (P<0.01. Conclusion  MPCS shows a certain protective effect on immunological liver injury induced by BCG plus LPS in mice. DOI: 10.11855/j.issn.0577-7402.2016.04.05

  18. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  19. Ischemia and reperfusion injury of the rat liver: the role of nimodipine.

    Science.gov (United States)

    Chávez-Cartaya, R E; Pino DeSola, G; Ramirez-Romero, P; Calne, R Y; Jamieson, N V

    1996-01-01

    The protective effect of the calcium channel blocker nimodipine on liver ischemia and reperfusion was studied in the rat. The homeostasis of intracellular calcium ions seems to be a determinant factor in the cell injury that appears after ischemia and reperfusion. Nimodipine was used to downregulate the calcium levels in the cytosol of the ischemic cell, the hypothetical role of Ca2+ in the pathogenesis of ischemia and reperfusion injury. The experimental procedure consisted of the temporary interruption of blood flow to the left lateral and medial lobes of the rat liver and subsequent reperfusion after a period of 45 min of ischemia. Nimodipine (10 micrograms/kg body wt) was administered either before or after the onset of ischemia. The postischemic liver blood flow and liver oxyhemoglobin saturation were recorded using a He-Ne laser Doppler flowmeter and photometer, which showed, in the pretreated group, a recovery of reperfusion blood flow (58.1%) and liver reflectance (85.5%) significantly better (P flow (32.8%) and reflectance (70.5%). In the group that received nimodipine after ischemia, the recovery of the blood flow and the postreperfusion liver reflectance were not significantly better than those in the untreated control group. ALT levels (P < 0.05), galactose elimination capacity (P < 0.001), and histological studies also showed a protective effect of calcium antagonist nimodipine when administered before ischemia.

  20. Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury

    Institute of Scientific and Technical Information of China (English)

    Lauren M Aleksunes; Michael Goedken; José E Manautou

    2006-01-01

    AIM: To investigate the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in human liver specimens obtained from patients with liver damage due to acetaminophen (APAP) overdose or primary biliary cirrhosis (PBC).METHODS: NQO1 activity was determined in cytosol from normal, APAP and PBC liver specimens. Western blot and immunohistochemical staining were used to determine patterns of NQO1 expression using a specific antibody against NQO1.RESULTS: NQO1 protein was very low in normal human livers. In both APAP and PBC livers, there was strong induction of NQO1 protein levels on Western blot.Correspondingly, significant up-regulation of enzyme activity (16- and 22-fold, P< 0.05) was also observed in APAP and PBC livers, respectively. Immunohistochemical analysis highlighted injury-specific patterns of NQO1 staining in both APAP and PBC livers.CONCLUSION: These data demonstrate that NQO1 protein and activity are markedly induced in human livers during both APAP overdose and PBC. Up-regulation of this cytoprotective enzyme may represent an adaptive stress response to limit further disease progression by detoxifying reactive species.

  1. Effect of fasting on the metabolic response of liver to experimental burn injury.

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    Mehmet A Orman

    Full Text Available Liver metabolism is altered after systemic injuries such as burns and trauma. These changes have been elucidated in rat models of experimental burn injury where the liver was isolated and perfused ex vivo. Because these studies were performed in fasted animals to deplete glycogen stores, thus simplifying quantification of gluconeogenesis, these observations reflect the combined impact of fasting and injury on liver metabolism. Herein we asked whether the metabolic response to experimental burn injury is different in fed vs. fasted animals. Rats were subjected to a cutaneous burn covering 20% of the total body surface area, or to similar procedures without administering the burn, hence a sham-burn. Half of the animals in the burn and sham-burn groups were fasted starting on postburn day 3, and the others allowed to continue ad libitum. On postburn day 4, livers were isolated and perfused for 1 hour in physiological medium supplemented with 10% hematocrit red blood cells. The uptake/release rates of major carbon and nitrogen sources, oxygen, and carbon dioxide were measured during the perfusion and the data fed into a mass balance model to estimate intracellular fluxes. The data show that in fed animals, injury increased glucose output mainly from glycogen breakdown and minimally impacted amino acid metabolism. In fasted animals, injury did not increase glucose output but increased urea production and the uptake of several amino acids, namely glutamine, arginine, glycine, and methionine. Furthermore, sham-burn animals responded to fasting by triggering gluconeogenesis from lactate; however, in burned animals the preferred gluconeogenic substrate was amino acids. Taken together, these results suggest that the fed state prevents the burn-induced increase in hepatic amino acid utilization for gluconeogenesis. The role of glycogen stores and means to increase and/or maintain internal sources of glucose to prevent increased hepatic amino acid

  2. Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation

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    Xiaxia Cai

    2016-03-01

    Full Text Available Background: Previous studies suggested that nucleotides were beneficial for liver function, lipid metabolism and so on. The present study aimed to investigate the metabolic response of dietary nucleotides supplementation in alcohol-induced liver injury rats. Methods: Five groups of male Wistar rats were used: normal control group (basal diet, equivalent distilled water, alcohol control group (basal diet, 50% alcohol (v/v, dextrose control group (basal diet, isocaloric amount of dextrose, and 0.04% and 0.16% nucleotides groups (basal diet supplemented with 0.4 g and 1.6 g nucleotides kg−1 respectively, 50% alcohol (v/v. The liver injury was measured through traditional liver enzymes, expression of oxidative stress markers and histopathological examination. Ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS was applied to identify liver metabolite profiles. Results: Nucleotides supplementation prevented the progression of hepatocyte steatosis. The levels of total proteins, globulin, alanine aminotransferase, aspartate aminotransferase, total cholesterol triglyceride, as well as the oxidative stress markers altered by alcohol, were improved by nucleotides supplementation. Elevated levels of liver bile acids (glycocholic acid, chenodeoxyglycocholic acid, and taurodeoxycholic acid, as well as lipids (stearic acid, palmitic acid, oleic acid, phosphatidylcholine, and lysophosphatidylethanolamine in alcohol-treated rats were reversed by nucleotides supplementation. In addition, supplementation with nucleotides could increase the levels of amino acids, including valyl-Leucine, l-leucine, alanyl-leucine and l-phenylalanine. Conclusion: These data indicate potential biomarkers and confirm the benefit of dietary nucleotides on alcoholic liver injury.

  3. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

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    Peter Onody

    Full Text Available INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment or 24 hours (late pretreatment before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005, AST (p early = 0.02; p late = 0.004 and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034 and PAR positivity (p early = 0.02; p late = 0.04. Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

  4. A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.

    Directory of Open Access Journals (Sweden)

    Sinem Perk

    Full Text Available With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD. A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD, recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP, and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE as log(SPE >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

  5. A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.

    Science.gov (United States)

    Perk, Sinem; Izamis, Maria-Louisa; Tolboom, Herman; Uygun, Basak; Berthiaume, Francois; Yarmush, Martin L; Uygun, Korkut

    2011-01-01

    With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

  6. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

    Directory of Open Access Journals (Sweden)

    Patricia Rivera

    2017-10-01

    Full Text Available Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE-peroxisome proliferators activated receptor alpha (PPARα system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP, a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM and time-course (2–6–24 h study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH, including the NAEs oleoyl ethanolamide (OEA and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg. The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver

  7. Implication of altered proteasome function in alcoholic liver injury

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The proteasome is a major protein-degrading enzyme,which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels: low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation.Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins.Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling (Ⅰ-κB and SOCS), thereby blocking cytokine signal transduction.Finally, ethanol-elicited blockade of interferon type 1 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class Ⅰ-restricted antigen presentation.

  8. HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

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    Manuela G. Neuman

    2012-01-01

    Full Text Available The present paper describes possible connections between antiretroviral therapies (ARTs used to treat human immunodeficiency virus (HIV infection and adverse drug reactions (ADRs encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication.

  9. A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury.

    Science.gov (United States)

    Kohonen, Pekka; Parkkinen, Juuso A; Willighagen, Egon L; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C

    2017-07-03

    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 10(8) data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy.

  10. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Science.gov (United States)

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of

  11. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

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    Tokiko Ishida

    Full Text Available The pathogenesis of renal impairment in chronic liver diseases (CLDs has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy, autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the

  12. Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Rolf J. Schauer; Sinan Kalmuk; Alexander L. Gerbes; Rosemarie Leiderer; Herbert Meissner; Friedrich W. Schildberg; Konrad Messmer; Manfred Bilzer

    2004-01-01

    AIM: To investigate the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation.METHODS: Livers of male Lewis rats were transplantedafter 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting. During a 2-h reperfusion period either saline (controls, n=8) or GSH administered via the jugular vein.RESULTS: Two hours after starting reperfusion plasma ALT increased to 1 457±281 U/L (mean±SE) in controls but to only 908±187 U/L (P<0.05) in animals treated with morphological findings on electron microscopy: GSH treatment prevented detachment of sinusoidal endothelial cells (SECs) as well as loss of microvilli and mitochondrial swelling of hepatooytes. Accordingly, postischemic bile flow increased 2-fold. Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Following infusion of 50 μmol and and 97±18 mol/L, but to only 20±3 mol/L in untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased untreated controls (1.8±0.5 mol/L vs 2.2±0.2 mol/L).CONCLUSION: Plasma GSH levels above a critical level may act as a "sink" for ROS produced in the hepatic vasculature during reperfusion of liver grafts. Therefore, GSH can be considered a candidate antioxidant for the prevention of reperfusion injury after liver transplantation, in particular since it has a low toxicity in humans.

  13. Dynamical changing pattems of glycogen and enzyme histochemical activities in rat liver graft undergoing warm ischemia injury

    Institute of Scientific and Technical Information of China (English)

    Xiao-Shun He; Yi Ma; Lin-Wei Wu; Jin-Lang Wu; Rui-De Hu; Gui-Hua Chen; Jie-Fu Huang

    2005-01-01

    AIM: To investigate the changing patterns of glycogen and enzyme histochemical activities in rat liver graft under a dif ferent warm ischemia time (WIT) and to predict the tolerant time limitation of the liver graft to warm ischemia injury.METHODS: The rats were randomized into five groups, WTT was 0, 15, 30, 45, 60 min, respectively, and histochemical staining of liver graft specimens was observed. The recovery changes of glycogen and enzyme histochemistry activities were measured respectively 6 and 24 h following liver graft implantation.RESULTS: The activities of succinic dehydrogenase, cytochrome oxidase, apyrase (Mg++-ATPase) and content of glycogen were decreased gradually after different WIT in a time-dependent manner. The changes were significant when WIT was over 30 min.CONCLUSION: Hepatic injury is reversible within 30 min of warm ischemia injury. Glycogen and enzyme histochemistry activities of liver grafts and their recovery potency after reperfusion may serve as criteria to evaluate the quality of liver grafts.

  14. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    OpenAIRE

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in...

  15. Epigallocatechin-3-Gallate Ameliorates Alcohol-Induced Liver Injury in Rats

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    Xi Li

    2006-07-01

    Full Text Available Endotoxemia is a common event in alcoholic liver disease. Elevated intestinalpermeability is the major factor involved in the mechanism of alcoholic endotoxemia andthe pathogenesis of alcoholic liver disease. This study examined the effect ofepigallocatechin-3-gallate (EGCG on alcohol-induced gut leakiness, and explored therelated mechanisms involved in its protection against alcohol-induced liver injury in rats.Four groups of female Sprague-Dawley rats were studied. Alcohol and alcohol/EGCGgroups rats received fish oil along with alcohol daily via gastrogavage for 6 weeks, anddextrose and dextrose/EGCG groups rats were given fish oil along with isocaloric dextroseinstead of alcohol. The dextrose/EGCG and alcohol/EGCG groups received additionaltreatment of EGCG (100mg.kg-1 body weight daily intragastrically by gavage. Intestinalpermeability was assessed by urinary excretion of lactulose and mannitol (L/M ratio. Liverinjury was evaluated histologically and by serum alanine aminotransferase (ALT. Plasmaendotoxin and serum tumor necrosis factor-α (TNF-α levels were assayed; livermalondialdehyde (MDA contents determined. CD14 and inflammatory factors, such asTNF-α, cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS mRNAs inthe liver were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR. Ratsgiven fish oil plus alcohol had gut leakiness (L/M ratio was increased, which wasassociated with both endotoxemia and liver injury. The above responses were accompaniedby increased CD14, TNF-α, COX-2 and iNOS mRNA expressions in the liver. EGCGsupplementation partly blocked the gut leakiness, reduced endotoxemia and lipidperoxidation, and blunted the elevated expressions of CD14, TNF-α, COX-2 and iNOS, allof which were associated with improved liver injury. These results show that EGCG can block alcohol-induced gut leakiness, reduce endotoxemia, and inhibit inflammatory factors expressions in

  16. Effect of WeiJia on carbon tetrachloride induced chronic liver injury

    Institute of Scientific and Technical Information of China (English)

    Pik-Yuen Cheung; Jay Chun; Hsiang-Fu Kung; Meng-su Yang; Qi Zhang; Ya-Ou Zhang; Gan-Rong Bai; Marie Chia-Mi Lin; Bernard Chan; Chi-Chun Fong; Lin Shi; Yue-Feng Shi

    2006-01-01

    AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model.METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week,Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type Ⅳ collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed.RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV,ALT, AST and Y-GT levels after eight weeks of treatment for Group C rats were 58±22 μg/L (P0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in a-SMA expression level was also observed.CONCLUSION: WeiJia could improve liver function and reduce liver fibrosis

  17. Proteomic analysis of protective effects of polysaccharides from Salvia miltiorrhiza against immunological liver injury in mice.

    Science.gov (United States)

    Sun, Xue-Gang; Fu, Xiu-Qiong; Cai, Hong-Bing; Liu, Qiang; Li, Chun-Hua; Liu, Ya-Wei; Li, Ying-Jia; Liu, Zhi-Feng; Song, Yu-Hong; Lv, Zhi-Ping

    2011-07-01

    This study was designed to investigate mechanisms of the protective effects of Salvia miltiorrhiza polysaccharide (SMPS) against lipopolysaccharide (LPS)-induced immunological liver injury (ILI) in Bacille Calmette-Guérin (BCG)-primed mice. Two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis showed that three proteins are down-regulated and six proteins are up-regulated by SMPS. SMPS reduces the degree of liver injury by up-regulating the enzymes of the citric acid cycle, namely malate dehydrogenase (MDH) and 2-oxoglutarate dehydrogenase complex. LPS significantly increases nuclear factor kappa B (NF-κB) activation, inducible nitric oxide synthase (iNOS) expression and MDA level in BCG primed mice liver, whereas SMPS treatment protects against the immunological liver injury through inhibition of the NF-κB activation by up-regulation of PRDX6 and the subsequent attenuation of lipid peroxidation, iNOS expression and inflammation. Copyright © 2011 John Wiley & Sons, Ltd.

  18. Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response

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    Yun-Hee Lee

    2016-07-01

    Full Text Available It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS and cyclooxygenase (COX-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol.

  19. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

    Institute of Scientific and Technical Information of China (English)

    Ignazio Grattagliano; Leonilde Bonfrate; Catia V Diogo; Helen H Wang; David QH Wang; Piero Portincasa

    2009-01-01

    Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O_2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca~(2+)-dependent ATPase, reduced capability to sequester Ca~(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

  20. The protective effect of Nigella sativa against liver injury: a review

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    Hamid Mollazadeh

    2015-12-01

    Full Text Available Nigella sativa (Family Ranunculaceae is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.

  1. Hepatoprotective effect of apple polyphenols against concanavalin A-induced immunological liver injury in mice.

    Science.gov (United States)

    Wang, Fang; Xue, Yang; Yang, Jingyu; Lin, Fang; Sun, Ying; Li, Ting; Wu, Chunfu

    2016-10-25

    Apple polyphenols (AP), a polyphenol extracted from the unripe apple, has been reported to improve acute hepatotoxicity induced by CCl4 in mice due to its significant antioxidant activity. In this study, the hepatoprotective effect of AP against concanavalin A (Con A)-induced immunological liver injury in mice was investigated. Mice were treated with AP daily for seven days prior to a single intravenous administration of Con A. The serum levels of AST, ALT, TP, Alb and histopathological changes were determined and the A/G ratio was calculated. Potential mechanisms were further explored by measuring TNF-α and IFN-γ levels, NO content as well as changes in the levels of endogenous oxidants and antioxidants. AP significantly improved the abnormal levels of ALT, AST, TP and Alb, and the A/G ratio. AP was also associated with improvement of liver histopathological changes after Con A-induced liver injury. Moreover, AP reduced serum levels of TNF-α and IFN-γ, decreased serum NO content, inhibited oxidative DNA single-strand breaks, and improved the abnormalities of MDA content, SOD activity and GSH level. These results suggest that AP exerts a protective effect against Con A-induced immunological liver injury through suppressing pro-inflammatory cytokines and activating the antioxidant system.

  2. The traditional ayurvedic medicine, Eugenia jambolana (Jamun fruit), decreases liver inflammation, injury and fibrosis during cholestasis.

    Science.gov (United States)

    Donepudi, Ajay C; Aleksunes, Lauren M; Driscoll, Maureen V; Seeram, Navindra P; Slitt, Angela L

    2012-04-01

    Cholestasis is a common disease of the liver. Chronic cholestasis eventually leads to hepatic cirrhosis and fibrosis, and rodent chronic cholestasis models are used to study aspects of fibrosis and cirrhosis. Cholestasis-induced liver injury and fibrosis are associated with increased oxidative stress and inflammation. Few pharmacological therapies exist for treatment of cholestasis or cirrhosis, but it is known that humans with better nutritional intake are less likely to develop certain types of cirrhosis. Eugenia jambolana (Jamun) is a tropical berry fruit rich in antioxidant anthocyanin compounds. As anthocyanins decrease cellular lipid peroxidation and oxidative stress, it was hypothesized that Jamun fruit extract (JFE) administration could protect against cholestatic liver injury and inflammation in mice. Starting 24 h after sham or bile-duct ligation (BDL) surgery, male C57Bl/6 mice were administered vehicle or JFE (100 mg/kg, po) for 10 days. Mice that underwent BDL had elevated serum ALT levels, which were reduced to 60% by JFE treatment. Likewise, BDL caused hepatic inflammation, macrophage infiltration, fibrosis and necrosis, all of which were largely improved by JFE. Interestingly, hepatoprotection was observed in JFE-treated BDL mice, despite suppressed transporter expression and increased hepatic bile acid concentrations. Jamun fruit phytochemicals decreased hepatic inflammation and oxidative stress, and protected against hepatocellular injury in mice. Jamun warrants further investigation as a potential antioxidant/anti-inflammatory therapy not only to treat cholestasis but also other liver diseases with an inflammatory component. © 2011 John Wiley & Sons A/S.

  3. Protective effects of apocynin and allopurinol on ischemia/reperfusion-induced liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Ping-Guo Liu; Song-Qing He; Yan-Hong Zhang; Jian Wu

    2008-01-01

    AIM: To determine the effects of allopurinol, an inhibitor of xanthine oxidase, and apocynin, an inhibitor of NADPH oxidase, on oxidant stress and liver injury caused by hepatic ischemia/reperfusion (I/R) procedure in mice. METHODS: Nice were pretreated with a xanthine oxidase inhibitor, allopurinol, or NADPH oxidase (NOX)inhibitor, apocynin before the hepatic I/R procedure. Then treated or untreated mice underwent the hepatic I/R procedure. The effects on hepatic injury and superoxide anions were determined after starting reperfusion. RESULTS: A standard warm hepatic I/R procedure led to a marked increase in superoxide anion production as indicated by a superoxide anion tracer, MCLA. At the same time, the procedure caused profound acute liver injury, as indicated by elevated serum alanine aminotransferase and tumor necrosis factor-αlevels, reduced liver glutathione levels and elevated malondialdehyde contents, as well as a high apoptotic cell count. All these changes were reversed by the use of apocynin or allopurinol prior to the hepatic I/R procedure. CONCLUSION: AIIopurinol and apocynin exerted protective effects on hepatic ischemia/reperfusion injury. The protection is associated with blocking the generation of superoxide anions during the hepatic I/R procedure by inhibiting xanthine oxidase and NADPH oxidase activity.

  4. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Zhou, Lili; Shu, Xugang [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Sun, Xiaohong [College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Mi, Shumei; Yang, Yuhui [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Yin, Yulong, E-mail: yinyulong@isa.ac.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125 (China)

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  5. Adenovirus-mediated eNOS expression augments liver injury after ischemia/reperfusion in mice.

    Directory of Open Access Journals (Sweden)

    Arun P Palanisamy

    Full Text Available Hepatic ischemia/reperfusion (l/R injury continues to be a critical problem. The role of nitric oxide in liver I/R injury is still controversial. This study examines the effect of endothelial nitric oxide synthase (eNOS over-expression on hepatic function following I/R. Adenovirus expressing human eNOS (Ad-eNOS was administered by tail vein injection into C57BL/6 mice. Control mice received either adenovirus expressing LacZ or vehicle only. Sixty minutes of total hepatic ischemia was performed 3 days after adenovirus treatment, and mice were sacrificed after 6 or 24 hrs of reperfusion to assess hepatic injury. eNOS over expression caused increased liver injury as evidenced by elevated AST and ALT levels and decreased hepatic ATP content. While necrosis was not pervasive in any group, TUNEL demonstrated significantly increased apoptosis in Ad-eNOS infected livers. Western blotting demonstrated increased levels of protein nitration and upregulation of the pro-apoptotic proteins bax and p53. Our data suggest that over-expression of eNOS is detrimental in the setting of hepatic I/R.

  6. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2

    Science.gov (United States)

    Ma, Linglan; Zhao, Jinfang; Wang, Jue; Liu, Jie; Duan, Yanmei; Liu, Huiting; Li, Na; Yan, Jingying; Ruan, Jie; Wang, Han; Hong, Fashui

    2009-11-01

    Although it is known that nano-TiO2 or other nanoparticles can induce liver toxicities, the mechanisms and the molecular pathogenesis are still unclear. In this study, nano-anatase TiO2 (5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days, and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nano-anatase TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nano-anatase TiO2 can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity.

  7. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J. [Institute of Microcirculation, Hebei North University, Zhangjiakou, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

    2014-02-17

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na{sup +}-K{sup +}-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na{sup +}-K{sup +}-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na{sup +}-K{sup +}-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  8. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    Directory of Open Access Journals (Sweden)

    Z.G. Zhao

    2014-02-01

    Full Text Available The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL on lipopolysaccharide (LPS-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1, myeloperoxidase (MPO, and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  9. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis.

    Science.gov (United States)

    Hirsova, Petra; Ibrahim, Samar H; Bronk, Steven F; Yagita, Hideo; Gores, Gregory J

    2013-01-01

    Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol) diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.

  10. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Petra Hirsova

    Full Text Available Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.

  11. Cholesterol and sphingolipids in alcohol-induced liver injury.

    Science.gov (United States)

    Fernández, Anna; Colell, Anna; Garcia-Ruiz, Carmen; Fernandez-Checa, José C

    2008-03-01

    The pathogenesis of alcohol-induced liver disease (ALD) is still poorly understood. One of the clues to its progression relates to the alcohol-mediated susceptibility of hepatocytes to cell death by reactive oxygen species (ROS) and inflammatory cytokines. Tumor necrosis factor alpha (TNF) has been considered a key ALD mediator with acidic sphingomyelinase (ASMase)-mediated ceramide generation playing a critical role. TNF receptor 1 and 2 knock-out mice or ASMase(-/-) mice exhibit resistance to alcohol-mediated fatty liver and cell death. Furthermore, alcohol feeding has been shown to sensitize hepatocytes to TNF due to the limitation of mitochondrial glutathione (mGSH) through impaired import of GSH from the cytosol due to altered membrane order parameter caused by mitochondrial cholesterol increase. Selective pharmacological depletion of mGSH sensitizes hepatocytes to TNF-mediated cell death, which reproduces the observations found with alcohol feeding. TNF signaling analyses in hepatocytes with or without mGSH depletion indicate that mGSH prevents cardiolipin peroxidation (CLOOH) formation by TNF-induced ROS via ASMase and that CLOOH cooperates with oligomerized Bax to cause mitochondrial outer membrane permeabilization through destabilization of the lipid bilayer via increased bilayer-to-inverted hexagonal phase transitions. Thus, activation of ASMase and cholesterol-mediated mGSH depletion both collaborate to promote alcohol-induced TNF-mediated hepatocellular damage, suggesting novel therapeutic opportunities in ALD.

  12. Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

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    Ajay Kumar Jain

    2014-01-01

    Full Text Available Total parenteral nutrition (TPN, a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD. PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR in the gut and enhance fibroblast growth factor 19 (FGF19 level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA. Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs. GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.

  13. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats

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    Akiko Kojima-Yuasa

    2016-12-01

    Full Text Available Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme’s activity and reduced intracellular thiobarbituric acid reactive substances (TBARS levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

  14. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats.

    Science.gov (United States)

    Kojima-Yuasa, Akiko; Goto, Mayu; Yoshikawa, Eri; Morita, Yuri; Sekiguchi, Hirotaka; Sutoh, Keita; Usumi, Koji; Matsui-Yuasa, Isao

    2016-12-19

    Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM) on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl₄)-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl₄-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl₄-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1)-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl₄-treated rats increased significantly, but DNSM-treatment suppressed the enzyme's activity and reduced intracellular thiobarbituric acid reactive substances (TBARS) levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

  15. Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose.

    Science.gov (United States)

    Zhang, Zi-feng; Fan, Shao-hua; Zheng, Yuan-lin; Lu, Jun; Wu, Dong-mei; Shan, Qun; Hu, Bin

    2009-09-01

    Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.

  16. Liver regeneration - The best kept secret: A model of tissue injury response

    Directory of Open Access Journals (Sweden)

    Javier A. Cienfuegos

    2014-03-01

    Full Text Available Liver regeneration (LR is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades. LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness and explains the difficulties of reshaping it with therapeutic goals. TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes -cell-cycle transition G0-G1-, and a second phase of proliferation -cell-cycle S/M phases- which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines (TNF-α, IL-1β, IL-6, growth factors (HGF, EGF, VGF and anti-inflammatory factors (IL-10, TGF-β. Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation. The recent induced pluripotential cells (iPS description and the mesenchymal stem cell (CD133+ plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration.

  17. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model

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    Banu Taskin

    2017-01-01

    Full Text Available The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days. The rats were then sacrificed to harvest blood and liver tissue samples in order to determine blood and tissue MDA, serum ALT, plasma TNF-α, TGF-β, and PTX3 levels. Histological specimens were examined via light microscopy. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by relatively worse histopathological scores and increased biochemical marker levels. Lactulose treatment significantly reduced the liver enzyme ALT, plasma TNF-α, TGF-β, PTX3, and MDA levels and also decreased histological changes in the liver tissue with MTX-induced hepatotoxicity in the rat model. We suggest that lactulose has anti-inflammatory and antifibrotic effects on an MTX-induced liver injury model. These effects can be due to the impact of intestinal microbiome.

  18. Oleanolic acid attenuates liver ischemia reper-fusion injury by HO-1/Sesn2 signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Bao-Bin Hao; Xiong-Xiong Pan; Ye Fan; Ling Lu; Xiao-Feng Qian; Xue-Hao Wang; Feng Zhang; Jian-Hua Rao

    2016-01-01

    BACKGROUND: Ischemia reperfusion injury (IRI) is unavoid-able in liver transplantation and hepatectomy. The present study aimed to explore the possible mechanism and the effect of oleanolic acid (OA) in hepatic IRI. METHODS: Mice were randomly divided into 6 groups based on different treatment. IRI model: The hepatic artery, portal vein, and bile duct to the left and median liver lobes (70% of the liver) were occluded with an atraumatic bulldog clamp for 90 minutes and then the clamp was removed for reperfusion. The mice were sacriifced 6 hours after reperfusion, and blood and liver tissues were collected. Liver injury was evaluated by biochemical and histopathologic examinations. The expressions of Sesn2, PI3K, Akt and heme oxygenase-1 (HO-1) were mea-sured with quantitative real-time RT-PCR and Western blotting. RESULTS: The serum aminotransferases level and scores of he-patic histology were increased after reperfusion. The increase was attenuated by pretreatment with OA (P CONCLUSIONS: Our results demonstrate that OA can attenu-ate hepatic IRI. The protective mechanism may be related to the OA-induced HO-1/Sesn2 signaling pathway.

  19. Effect of matrine on Kupffer cell activation in cold ischemia reperfusion injury of rat liver

    Institute of Scientific and Technical Information of China (English)

    Xin-Hua Zhu; Yu-Dong Qiu; Hao Shen; Ming-Ke Shi; Yi-Tao Ding

    2002-01-01

    AIM: To study the effect of matrine on activation of Kupffer cell during cold ischemia and reperfusion injury in rat orthotopic liver transplantation (OLT).METHODS: 168 syngeneic SD rats were randomly divided into four groups: untreated group, small-dose treated group, large-dose treated group and sham operation group. After 5 hours of preservation in Ringer's (LR) solution, orthotopic implantation of the donor liver was performed. At 1 h, 2 h, 4 h and 24 h after reperfusion of the portal vein, 6 rats were killed in each group to collect the serum and the liver for assay and pathology.RESULTS: Matrine markedly inhibited the activation of Kupffer cells and their release of tumor necrosis factor (TNF). TNF cytotoxicity level at 2 h decreased significantly by matrine treatment (7.94±0.42, 2.39±0.19 and 2.01±0.13 U/ml,respectively; P<0.01), so did the other three time points. The level of hylluronic acid (HA) and alanine transaminase (ALT) decreased significantly in both treated groups, and matrine treatment markedly ameliorated focal necrosis of hepatocytes, inflammatory cells aggregating, rounding and detachment of sinusoidal endothelial cells (SEC). And no significant difference was observed between the treated groups.CONCLUSION: Matrine can inhibit the activation of Kupffer cell and prevent the donor liver from cold preservation and reperfusion injury in rat orthotopic liver transplantation.

  20. The effect of gomisin A on immunologic liver injury in mice.

    Science.gov (United States)

    Nagai, H; Yakuo, I; Aoki, M; Teshima, K; Ono, Y; Sengoku, T; Shimazawa, T; Aburada, M; Koda, A

    1989-02-01

    The hepatoprotective effect of Gomisin A (TJN-101), which is a lignan compound isolated from Schizandra fruits, was studied on three immunologic liver injury models in mice. The first liver injury model was produced by the injection of anti-basic liver protein (BLP) antibody into DBA/2 mice which had been previously immunized with rabbit IgG (RGG). Other models were effected by injection of anti-liver specific protein (LSP) antibody into DBA/2 mice or by the injection of bacterial lipopolysaccharide (LPS) into ddY mice pretreated with Corynebacterium parvum (C. parvum). TJN-101 inhibited the elevation of transaminase (GOT and GPT) activities and showed the tendency to inhibit the histopathological changes of the liver in all models. Moreover, TJN-101 inhibited deoxycholic acid-induced release of transaminase from cultured rat hepatocytes in vitro, but did not affect the formation of hemolytic plaque forming cells in immunized mice spleens and hemolytic activity of guinea pig complement in immunohemolysis reaction. These results, therefore, suggested that the hepatoprotective effect of TJN-101 could be related to the protecting effect of hepatocyte plasma membrane rather than the inhibiting effects of the antibody formation and complement activity.

  1. Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

    Institute of Scientific and Technical Information of China (English)

    Hao Chen; Ying-Yan Yu; Ming-Jun Zhang; Xia-Xing Deng; Wei-Ping Yang; Jun Ji; Cheng-Hong Peng; Hong-Wei Li

    2004-01-01

    AIM: To observe the protective effect of heat shock protein 72 (HSP 72) induced by pretreatment of doxorubicin (DXR)on long-term cold preservation injury of rat livers.METHODS: Sprague-Dawley rats were administered intravenously DXR at a dose of 1 mg/kg body mass in DXR group and saline in control group. After 48 h, the rat liver was perfused with cold Linger′s and University of Wisconsin (UW) solutions and then was preserved in UW solution at 4 ℃ for 24, 36 and 48 h. AST, ALT, LDH and hyaluronic acid in preservative solution were determined. Routine HE,immunohistochemical staining for HSP 72 and electron microscopic examination of hepatic tissues were performed.RESULTS: After 24, 36 and 48 h, the levels of AST, ALT and hyaluronic acid in preservative solution were significantly higher in control group than in DXR group (P<0.05), while LDH level was not significantly different between the 2 groups (P>0.05). Hepatic tissues in DXR group were morphologically normal and significantly injured in control group. HSP 72was expressed in hepatocytes and sinusoidal endothelial cells in DXR group but not in control group.CONCLUSION: Pretreatment of DXR may extend the time of rat liver cold preservation and keep liver alive. The expression of HSP 72 in liver can prevent hepatocytes and sinusoidal endothelial cells from long-term cold preservation injury.

  2. Protective Effect of Ghrelin on Isoniazid-induced Liver Injury in Rat

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    Kheyabany, Shadi Sar Kheyr

    2013-02-01

    Full Text Available Ghrelin (GHR is a peptide that has protective effects on many tissues injury. It has anti-inflammatory and anti-oxidant effects. Isoniazid (INH a widely used antituberculosis drug, has hepatotoxic side effect. The aim of this study was to evaluate the protective role of ghrelin in liver toxicity due to isoniazid. Eighteen male rats were used in this study and divided in to three groups. Including: control, isoniazid, isoniazid and ghrelin groups. Nitric oxide (NO, prostaglandin E2 (PGE2, and hepatic enzymes, ALT (alanine aminotransferase, AST (aspartate aminotransferase, ALK(alkaline phosphatas, were assessed and histologic study of liver were performed as indicators of liver damage following isoniazid toxicity. Ghrelin significantly increased NO metabolites and decreased PGE2 level comparison with INH group, but had no significant change compared to the control group. This study showed that ghrelin administration inhibited liver injury in rats due to isoniazid toxicity. The liver protective role of ghrelin may be mediated at least in part by its anti-inflammatory effect.

  3. Impact of acute kidney injury exposure period among liver transplantation patients

    Science.gov (United States)

    2013-01-01

    Background Acute kidney injury is a common complication of liver transplantation. In this single-centre retrospective observational study, we investigated the impact of acute kidney disease on liver recipient survival. Methods The study population consisted of patients who underwent a liver engraftment between January 2002 and November 2006, at a single transplantation centre in São Paulo, Brazil. Acute kidney injury diagnosis and staging were according to the recommendations of the Acute Kidney Injury Network and consisted of scanning the daily serum creatinine levels throughout the hospital stay. Patients requiring renal replacement therapy prior to transplantation, those who developed acute kidney injury before the procedure or those receiving their second liver graft were excluded from the study. Results A total of 444 liver transplantations were performed during the study period, and 129 procedures (29%) were excluded. The remaining 315 patients constituted the study population. In 207 procedures, the recipient was male (65%). The mean age of the population was 51 years. Cumulative incidence of acute kidney injury within 48 h, during the first week after transplantation, and throughout the hospital stay was 32, 81 and 93%, respectively. Renal replacement therapy was required within a week after the transplantation in 31 procedures (10%), and another 17 (5%) required replacement therapy after that period. Mean follow-up period was 2.3 years. Time in days from acute kidney injury diagnosis to initiation of replacement therapy or reaching serum creatinine peak was associated with lower overall survival even when adjusted for significant potential confounders (HR 1.03; 95% CI 1.01, 1.05; p=0.002). Overall, patients experiencing acute kidney injury lasting for a week or more before initiation of replacement therapy experienced a threefold increase in risk of death (HR 3.02; 95% CI 2.04, 4.46; ptransplantation is remarkably frequent and has a substantial impact

  4. The Effects of Two Anesthetics, Propofol and Sevoflurane, on Liver Ischemia/Reperfusion Injury

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    Zhijie Xu

    2016-04-01

    Full Text Available Background: Propofol and sevoflurane are widely used in clinical anesthesia, and both have been reported to exert a protective effect in organ ischemia/reperfusion (IR. This study aims to investigate and compare the effects of propofol and sevoflurane on liver ischemia/reperfusion and the precise molecular mechanism. Methods and Materials: Rats were randomized into four groups: the sham group, I/R group, propofol treatment group (infused with 1% propofol at 500 µg· kg-1· min-1, and sevoflurane treatment group (infused with 3% (2 L/min sevoflurane. The liver ischemia/reperfusion model was used to evaluate the hepatoprotective effect on ischemic injury. Liver enzyme leakage, liver cytokines and histopathological examination were used to evaluate the extent of hepatic ischemia/reperfusion injury. Oxidative stress was investigated by evaluating the levels of Malondialdehyde(MDA, Superoxide Dismutase(SOD and NO. The terminal dexynucleotidyl transferase(TdT-mediated dUTP nick end labeling (TUNEL assay and western blot were applied to detect apoptosis in the ischemic liver tissue and its mechanism. Results: Both propofol and sevoflurane attenuated the extent of hepatic ischemia/reperfusion injury which is evident from the hisopathological studies and alterations in liver enzymes such as AST and LDH by inhibiting Nuclear factor kappa B (NFκB activation and subsequent alterations in inflammatory cytokines interleukin-1(IL-1, interleukin-6(IL-6, tumor necrosis factor-alpha (TNF-a and increased IL10 release. Propofol exhibited a similar protective effect and a lower IL-1 release, while sevoflurane decreased TNF-a leakage more significantly. Meanwhile, oxidative stress was attenuated by reduced MDA and NO and elevated SOD release. The expression of antiapoptotic protein Bcl-2 and Bcl-xl were enhanced while that of apoptotic protein Bax and Bak were reduced by both propofol and sevoflurane to regulate hepatic apoptosis. In addition, propofol

  5. Shikonin Attenuates Concanavalin A-Induced Acute Liver Injury in Mice via Inhibition of the JNK Pathway

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    Tong Liu

    2016-01-01

    Full Text Available Objective. Shikonin possesses anti-inflammatory effects. However, its function in concanavalin A-induced acute liver injury remains uncertain. The aim of the present study was to investigate the functions of shikonin and its mechanism of protection on ConA-induced acute liver injury. Materials and Methods. Balb/C mice were exposed to ConA (20 mg/kg via tail vein injection to establish acute liver injury; shikonin (7.5 mg/kg and 12.5 mg/kg was intraperitoneally administered 2 h before the ConA injection. The serum liver enzyme levels and the inflammatory cytokine levels were determined at 3, 6, and 24 h after ConA injection. Results. After the injection of ConA, inflammatory cytokines IL-1β, TNF-α, and IFN-γ were significantly increased. Shikonin significantly ameliorated liver injury and histopathological changes and suppressed the release of inflammatory cytokines. The expressions of Bcl-2 and Bax were markedly affected by shikonin pretreatment. LC3, Beclin-1, and p-JNK expression levels were decreased in the shikonin-pretreated groups compared with the ConA-treated groups. Shikonin attenuated ConA-induced liver injury by reducing apoptosis and autophagy through the inhibition of the JNK pathway. Conclusion. Our results indicated that shikonin pretreatment attenuates ConA-induced acute liver injury by inhibiting apoptosis and autophagy through the suppression of the JNK pathway.

  6. Failure of P-selectin blockade alone to protect the liver from ischemia-reperfusion injury in the isolated blood-perfused rat liver

    Institute of Scientific and Technical Information of China (English)

    Samuel Wyllie; Neal R Barshes; Feng-Qin Gao; Saul J Karpen; John A Goss

    2008-01-01

    AIM: To determine if blockade of P-selectin in the isolated blood-perfused cold ex vivo rat liver model protects the liver from ischemia-reperfusion injury. METHODS: The effect of P-selectin blockade was assessed by employing an isolated blood-perfused cold ex vivo rat liver with or without P-selectin antibody treatment before and after 6 h of cold storage in University of Wisconsin solution.RESULTS: In our isolated blood-perfused rat liver model, pre-treatment with P-selectin antibody failed to protect the liver from ischemia-reperfusion injury, as judged by the elevated aspartate aminotransferase activity. In addition, P-selectin antibody treatment did not significantly reduced hepatic polymorphonuclear leukocyte accumulation after 120 min of perfusion. Histological evaluation of liver sections obtained at 120 min of perfusion showed significant oncotic necrosis in liver sections of both ischemic control and P-selectin antibody-treated groups. However, total bile production after 120 min of perfusion was significantly greater in P-selectin antibody-treated livers, compared to control livers. No significant difference in P-selectin and ICAM-1 mRNAs and proteins, GSH, GSSG, and nuclear NF-κB was found between control and P-selectin antibody-treated livers.CONCLUSION: In conclusion, we have shown that blockade of P-selectin alone failed to reduced polymorphonuclear leukocyte accumulation in the liver and protect hepatocytes from ischemia-reperfusion injury in the isolated blood-perfused cold-ex vivo rat liver model.

  7. Alleviation of Ischemia-Reperfusion Injury in Liver Steatosis by Augmenter of Liver Regeneration Is Attributed to Antioxidation and Preservation of Mitochondria.

    Science.gov (United States)

    Weng, Junhua; Li, Wen; Jia, Xiaowei; An, Wei

    2017-10-01

    Fatty liver is one of the major impediments to liver surgery and liver transplantation because steatotic hepatocytes are more susceptible to ischemia-reperfusion injury (IRI). In this study, the effects of augmenter of liver regeneration (ALR) on hepatic IRI in steatotic mice were investigated. In vivo, liver steatosis of mice was induced by feeding a methionine-choline-deficient diet for 2 weeks. Three days before hepatic partial warm IRI, mice were transfected with the ALR-containing adenovirus. In an in vitro study, the protective effect of ALR on steatotic HepG2 cells was analyzed after hypoxia/reoxygenation (HR) treatment. The transfection of the ALR gene into steatotic mice attenuated liver injury, inhibiting hepatic oxidative stress, increasing antioxidation capacities, promoting liver regeneration, and consequently suppressing cell apoptosis/death. Furthermore, resistance to HR injury was notably increased in ALR-transfected cells compared with the vector-transfected cells. The HR-induced rise in the mitochondrial reactive oxygen species was reduced, and cellular antioxidant activities were enhanced. The ALR transfection prevented cells from apoptosis, which can be attributed to the preservation of the mitochondrial membrane potential, enhancement of oxygen consumption rate and production of adenosine triphosphate. ALR protects steatotic hepatocytes from IRI by attenuating oxidative stress and mitochondrial dysfunction, as well as improving antioxidant effect. ALR may be used as a potential therapeutic agent when performing surgery and transplantation of steatotic liver.

  8. Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset.

    Science.gov (United States)

    Metushi, Imir G; Cai, Ping; Dervovic, Dzana; Liu, Feng; Lobach, Alexandra; Nakagawa, Tetsuya; Uetrecht, Jack

    2015-01-01

    Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1(-/-) mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.

  9. Erythropoietin reduces ischemia-reperfusion injury after liver transplantation in rats.

    Science.gov (United States)

    Schmeding, Maximilian; Hunold, Gerhard; Ariyakhagorn, Veravoorn; Rademacher, Sebastian; Boas-Knoop, Sabine; Lippert, Steffen; Neuhaus, Peter; Neumann, Ulf P

    2009-07-01

    Human recombinant Erythropoietin (rHuEpo) has recently been shown to be a potent protector of ischemia- reperfusion injury in warm-liver ischemia. Significant enhancement of hepatic regeneration and survival after large volume partial hepatic resection has also been demonstrated. It was the aim of this study to evaluate the capacities of rHuEpo in the setting of rat liver transplantation. One-hundred-and-twenty Wistar rats were used: 60 recipients received liver transplantation following donor organ treatment (60 donors) with either 1000 IU rHuEpo or saline injection (controls) into portal veins (cold ischemia 18 h, University of Wisconsin (UW) solution). Recipients were allocated to two groups, which either received 1000 IU rHuEpo at reperfusion or an equal amount of saline (control). Animals were sacrificed at defined time-points (2, 4.5, 24, 48 h and 7 days postoperatively) for analysis of liver enzymes, histology [hematoxylin-eosin (HE) staining, periodic acid Schiff staining (PAS)], immunostaining [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Hypoxyprobe] and real-time polymerase chain reaction (RT-PCR) of cytokine mRNA (IL-1, IL-6). Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) values were significantly reduced among the epo-treated animals 24 and 48 h after liver transplantation (LT). The TUNEL and Hypoxyprobe analyses as well as necrotic index evaluation displayed significant reduction of apoptosis and necrosis in rHuEpo-treated graft livers. Erythropoietin reduces ischemia-reperfusion injury after orthotopic liver transplantation in rats.

  10. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    Science.gov (United States)

    Zhang, Youcai; Csanaky, Iván L; Cheng, Xingguo; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2012-06-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis.

  11. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning.

    Science.gov (United States)

    Williams, C David; McGill, Mitchell R; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

  12. Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

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    Paul H. Hayashi

    2016-02-01

    Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

  13. Effects of rifaximin on bacterial translocation in thioacetamide-induced liver injury in rats.

    Science.gov (United States)

    Harputluoglu, Murat M M; Demirel, Ulvi; Gul, Mehmet; Temel, Ismail; Gursoy, Sule; Selcuk, Engin Burak; Aladag, Murat; Bilgic, Yilmaz; Gunduz, Ercan; Seckin, Yuksel

    2012-08-01

    Intestinal bacterial overgrowth (IBO) and increased mucosal permeability are suggested to increase bacterial translocation (BT) in liver injury. Rifaximin (RIF) is a minimally absorbed oral antimicrobial agent that restores gut microflora imbalance. The aim of the present study was to investigate the effects of RIF on BT frequency in thioacetamide (TAA)-induced liver injury. Group 1 was the control. In group 2 (TAA), rats received TAA daily for 3 days. In group 3 (TAA + RIF), RIF was commenced on the same day as the first dose of TAA. In group 4 (RIF), rats received only RIF. Ileal aspirate Escherichia coli counts were significantly lower in the TAA + RIF group than in TAA group. There was no difference in BT frequency between the TAA and TAA + RIF groups. Our results suggest that factors such as intestinal barrier dysfunction and impaired host immune shield, apart from IBO, play an important role in BT in this model.

  14. Investigation on injury of liver and kindey among the workers exposed to terephthalic acid, ethylene glycol and (or) dowtherm A.

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objective: To study injury of liver and kidney among the workers exposed to terephthalic acid (TPA), ethylene glycol(EG) and (or) dowtherm A(DOW), and to research for the early biological monitoring indexes.

  15. Tetrahydroxystilbene glucoside protects against ethanol-induced liver injury in mice by inhibition of expression of inflammatuion-related factors

    Institute of Scientific and Technical Information of China (English)

    熊章鄂

    2013-01-01

    Objective To investigate the protective effects of tetrahydroxystilbene glucoside(TSG)against acute ethanol-induced liver injury in mice and to explore the possible mechanisms involved.Methods Kunming mice were

  16. Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism.

    Science.gov (United States)

    Yu, Chuan; Mei, Xue-Ting; Zheng, Yan-Ping; Xu, Dong-Hui

    2014-03-01

    Curcumin can chelate metal ions, forming metallocomplexes. We compared the effects of Zn(II)-curcumin with curcumin against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Oral administration of Zn(II)-curcumin dose-dependently prevented the ethanol-induced elevation of serum malondialdehyde (MDA) content and reductions in glutathione level and superoxide dismutase (SOD) activity. Zn(II)-curcumin also inhibited ethanol-induced liver injury. Additionally, Zn(II)-curcumin dose-dependently inhibited hemorheological abnormalities, including the ethanol-induced elevation of whole blood viscosity, plasma viscosity, blood viscosity at corrected hematocrit (45%), erythrocyte aggregation index, erythrocyte rigidity index and hematocrit. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively elevated SOD activity, ameliorated liver injury and improved hemorheological variables. These results suggest that Zn(II)-curcumin protected the rats from ethanol-induced liver injury and hemorheological abnormalities via the synergistic effect of curcumin and zinc.

  17. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

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    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  18. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Papadimas, George K.; Kondyli, Vasiliki G.; Kourentzi, Kalliopi T.; Hereti, Rosa I.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi 151 27, Attiki (Greece)

    2004-06-01

    The hepatoprotective effect of putrescine against cadmium liver injury was investigated. Male Wistar rats were injected with a dose of cadmium (6.5 mg CdCl{sub 2}/kg bodyweight, intraperitoneally). Normal saline (group I) or putrescine (300 {mu}mol/kg bodyweight; group II) were injected 2, 5 and 8 h later. A number of animals of both groups were killed 0, 12, 16, 24, 48 or 60 h after cadmium intoxication. Liver tissue was histologically assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay for hepatocytes and nonparenchymal liver cells. The discrimination between hepatic cell subpopulations was achieved histochemically. The mitotic index in hematoxylin-eosin-stained sections and by the immunochemical detection of Ki67 nuclear antigen, {sup 3}H-thymidine incorporation into hepatic DNA, and hepatic thymidine kinase activity were all used as indices of liver regeneration. Both hepatocyte apoptosis and liver necrosis evolved in a biphasic temporal pattern. Nonparenchymal cell apoptosis and peliosis hepatis evolved in a monophasic pattern and were correlated closely. Putrescine administration totally reversed liver necrosis and hepatocyte apoptosis. The time profile of nonparenchymal apoptosis was altered and peliosis hepatis was also totally attenuated. In conclusion, putrescine protected hepatocytes and modulated the mechanism of cadmium-induced acute hepatotoxicity. (orig.)

  19. Prevalence and predictors of acute renal injury in liver transplant recipients.

    Science.gov (United States)

    Rymarz, A; Serwacki, M; Rutkowski, M; Pakosiński, K; Grodzicki, M; Patkowski, W; Kacka, A; Ołdakowska-Jedynak, U; Krawczyk, M

    2009-10-01

    Renal failure is a major factor impacting liver transplant outcomes. Renal functional impairment predicts decreased survival, leading to increased morbidity and mortality. The aim of this study was to estimate the incidence, risk factors, and resolution of acute kidney injury (AKI) among liver transplant recipients during the operative hospital stay. We analyzed data from 99 orthotopic liver transplantations (OLT) performed at our center in 2008. Posttransplantation occurrence of AKI was defined as an increase in serum creatinine (SCr) concentration of 0.3 mg/dL or more, namely, 1.5-fold from baseline. AKI was observed among 31.31% of liver transplant recipients (n = 31). The mean increase in SCr was 2.49 +/- 0.78-fold from baseline. The mean posttransplant SCr level was 2.59 +/- 0.92 mg/dL. Renal replacement therapy was introduced to 16.12% (n = 5) liver recipients developing AKI. Among them, 2 subjects (6.45%) died. The mean SCr level at the time of discharge from the hospital was 1.17 +/- 0.57 mg/dL among the AKI group compared with 0.77 +/- 0.32 mg/dL among the group without AKI. Pretransplant renal impairment expressed by an elevated SCr concentration (relative risk [RR] = 1.25; P = .0386) and treatment with exogenous vasoconstrictors during the operation (RR = 2.27; P = .016) were identified as risk factors for developing AKI after liver transplantation.

  20. Drug-Induced Liver Injury Caused by Adalimumab: A Case Report and Review of the Bibliography

    Directory of Open Access Journals (Sweden)

    Bernardo Frider

    2013-01-01

    Full Text Available The most serious adverse drug reaction of adalimumab (ADR is tuberculosis reactivation. We describe a case of a 35-year-old man, with rheumatoid arthritis (RA and hepatitis C virus genotype 1a with a liver biopsy in 2001 with a METAVIR score pattern A1 F0; he received interferon alpha 2b for six months, but treatment was suspended because of reactivation of RA. Liver function tests after treatment were similar to previous ones showing a minimal cholestatic pattern. In 2008, methotrexate was prescribed, but the drug was withdrawn at the third month because of the appearance of pruritus and Ggt rise. Viral load at that moment was 9300000 UI/mL, log 6,9. The liver biopsy showed a Metavir Score A2 F1. Adalimumab was started in 2010, and at the third month of treatment, Ggt showed a rise of 23 times normal value (NV, alkaline phosphatase 2,5 times NV with AST and ALT with no change. A new liver biopsy showed portal inflammation with eosinophils and a METAVIR A1 F2. We think that adalimumab appears to be responsible for the liver injury, because of temporal relationship, liver biopsy findings, other clinical conditions being discarded, and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended.

  1. Liver, biliary and pancreatic injuries in pancre-aticobiliary maljunction model in cats

    Institute of Scientific and Technical Information of China (English)

    Feng Chen; Lin Tang; Zhi-Qi Zhang; Bing-Wei Jin; Wei-Feng Dong; Jian Wang; Shun-Gen Huang

    2015-01-01

    BACKGROUND: Pancreaticobiliary maljunction is a high risk factor of pancreatitis and biliary tract cancer. How this mal-junction affects the liver remains obscure. This study aimed to examine the effects of pancreaticobiliary maljunction on the liver, pancreas and gallbladder in a cat model. METHODS: A model of choledocho-pancreatic side-to-side ductal anastomosis was created in ten cats.Before the procedure, a small piece of tissue from the liver, pancreas and gallbladder was collected as a control. The common channel formation was checked by cholecystography. The livers, pancreases and gall-bladders of these cats were harvested for histological examina-tion. The expression of proliferating cell nuclear antigen in the gallbladder was examined with immunohistochemistry. RESULTS: Seven of the 10 cats survived for 6 months after surgery. The color of the liver was darker in the PBM model than the control specimen, with nodules on the surface. His-tological examination showed ballooning changes and inflam-matory infiltrations and the histopathological score increased significantly (P CONCLUSION: The present study demonstrated that pancreatico-biliary maljunction can lead to the injuries of the liver, pancreas and gallbladder.

  2. Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.

    Science.gov (United States)

    Yue, Shi; Rao, Jianhua; Zhu, Jianjun; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

    2014-06-01

    Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.

  3. 肝爆震伤的救治%Treatment of liver blast injury

    Institute of Scientific and Technical Information of China (English)

    牟洪超; 周辉; 姜小清; 蔡岩; 孙茂; 董立军

    2015-01-01

    Objective:To investigate the clinical treatment mode of liver blast injury. Methods:The clinical data of 18 patients with liver blast injury who had been treated in our department from May 1998 to December 2013 were studied retrospectively. We summarized the causes of injury, mechanisms,merger injury and compound injury as well as clinical treatment methods and experi-ence to explore the emergency mode of liver blast injury. Results:Wthin 18 cases of liver burst injury, there are pressure cooker ex-plosion (1 case),gas tank explosion (3 cases),fireworks explosion (6 cases), mine gas explosion (8 cases). 14 cases were in hospital-ized immediately within 30minutes-4hours after injury,another 4 cases undergoing initial treatment in other hospital were hospital-ized after the injury within 8 hours. All cases were diagnosed with liver blast injury and merger injury and compound injury.18 cases were variable degrees of shock,there were no single liver blast injury cases . There were 11 cases with varying degrees of burns (5 cases with inhalation injury),2 cases with open fractures,7 cases with lung blast injury,2 cases with spleen rupture,1 case with pan-creatic contusion,3 cases with bowel contusion. All cases were treated by the methods of basical congulation, dressing, fixing ,air ex-haustering of pneumothorax ,oxygen taking and anti shock treatment. 6 cases were cured by non-surgical treatment,the cure rate was 100%(6/6).11 cases were cured by surgical treatment of 12 cases. the cure rate was 91.7%. 1 case died,the mortality rate was 8.3%. Conclusion:The uninterrupted rescue chain model including pre-hospital emergency life-saving,critical evacuation,in-hospi-tal treatment is very important for the patients with liver blast injury. Surgical selection should be differed from conventional surgery for liver blast injury. Treatment of associated injuries should be emphasised.%目的:探讨肝爆震伤的临床救治模式。方法:回顾性分析我科1998年5

  4. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    OpenAIRE

    Hai Nguyen Thanh; Hue Pham Thi Minh; Tuan Anh Le; Huong Duong Thi Ly; Tung Nguyen Huu; Loi Vu Duc; Thu Dang Kim; Tung Bui Thanh

    2015-01-01

    Objective: To investigated the protective potential of ethanol extracts of Scutellaria baicalensis (S. baicalensis) against lipopolysaccharide (LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS (5 mg/kg of body weight, intraperitoneal injection). Both protein ...

  5. Fibrin Sealant Foam Sprayed Directly on Liver Injuries Decreases Blood Loss in Resuscitated Rats

    Science.gov (United States)

    2000-08-01

    based on the dry fibrin sealant dressing concept. This material could potentially be intro- duced into a body cavity by a trocar , spread throughout...Special Operations Command, Biomedical Initiatives Steering Committee. The foam material and funding for a research technician was provided by the...was performed to evaluate the effectiveness of FSF when sprayed directly on a severe liver injury in rats. MATERIALS AND METHODS Thirty-six Sprague

  6. Mechanism for Prevention of Alcohol-Induced Liver Injury by Dietary Methyl Donors

    OpenAIRE

    Powell, Christine L.; Bradford, Blair U.; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O’Connell, Thomas M.; Pogribny, Igor P.; Melnyk, Stepan; Koop, Dennis R.; Bleyle, Lisa; Threadgill, David W.; Rusyn, Ivan

    2010-01-01

    Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors ...

  7. Effects of anti-histamine treatment on liver injury triggered by small intestinal ischemia reperfusion in rats.

    Science.gov (United States)

    Huang, Pin-Jie; Gan, Xiao-Liang; Liu, Jian-Pei; Liu, De-Zhao; Wang, Yan-Ling; Hei, Zi-Qing

    2014-10-31

    Mast cell (MC) degranulation has been implicated in small intestinal ischemia reperfusion (IIR) injury, therein, inhibiting overproduction of histamine released from activated MC may provide promising strategies against IIR-mediated liver injuries. The aim of the present study was to explore whether anti-histamine treatment contribute to attenuating IIR-mediated liver injury. Adult SD rats were randomized into sham-operated group (S group), sole IIR group (IIR group), and IIR treated with Ketotifen, a histamine antagonist (IIR+K group), Cromolyn Sodium, a MC stabilizer (IIR+C group), and Compound 48/80, a MC degranulator (IIR+CP group), respectively. IIR was induced by superior mesenteric artery occlusion for 75 min followed by 4 h of reperfusion. The agents were intravenously administrated 5 min before reperfusion to induce different levels of histamine. Subsequently, serum concentrations of ALT, AST and histamine; levels of LDH,TNF-α, IL-8 and MDA as well as SOD activities in the liver were assessed. Histopathologic changes were also evaluated. IIR resulted in severe liver injury as demonstrated by significant increases in injury scores, with concomitant significant increases in serum ALT, AST and histamine levels, as well as LDH, TNF-α, IL-8, and MDA levels in the liver, accompanied by reduction in SOD activities (all P IIR vs. S). Treatments by Ketotifen and Cromolyn Sodium similarly markedly alleviated IIR-mediated liver injury as confirmed by significant reduction of the above biomedical changes whereas Compound 48/80 further aggravated IIR-mediated liver injury by dramatically enhancing the above biomedical changes. Data of our study suggest that anti-histamine treatments may provide promising benefits in alleviating liver injury triggered by IIR.

  8. 2, 3, 7, 8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury

    OpenAIRE

    Fullerton, Aaron M.; Roth, Robert A.; Ganey, Patricia E.

    2012-01-01

    Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30µg/kg TCDD or vehicle cont...

  9. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Tong Zhou

    2017-01-01

    Full Text Available Chronic excessive alcohol consumption (more than 40–80 g/day for males and more than 20–40 g/day for females could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT, aspartate transaminase (AST, hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

  10. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice.

    Science.gov (United States)

    Zhou, Tong; Zhang, Yu-Jie; Xu, Dong-Ping; Wang, Fang; Zhou, Yue; Zheng, Jie; Li, Ya; Zhang, Jiao-Jiao; Li, Hua-Bin

    2017-01-01

    Chronic excessive alcohol consumption (more than 40-80 g/day for males and more than 20-40 g/day for females) could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG) contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT), aspartate transaminase (AST), hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

  11. Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Xin Liu

    2017-04-01

    Full Text Available The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

  12. CORAL: Binary classifications (active/inactive) for drug-induced liver injury.

    Science.gov (United States)

    Toropova, Alla P; Toropov, Andrey A

    2017-02-15

    The data on human hepatotoxcity (drug-induced liver injury) is extremely important information from point of view of drug discovery. Experimental clinical data on this endpoint is scarce. Experimental way to extend databases on this endpoint is extremely difficult. Quantitative structure - activity relationships (QSAR) is attractive alternative of the experimental approach. Predictive models for human hepatotoxicity (drug-induced liver injury) have been built up by the Monte Carlo method with using of the CORAL software (http://www.insilico.eu/coral). These models are the binary classifications into active class and inactive class. These models are calculated with so-called "semi correlations" described in this work. The Mattews correlation coefficient of these models for external validation sets ranged from 0.52 to 0.62. The approach has been checked up with a group of random splits into the training and validation sets. These stochastic experiments have shown the stability of results: predictability of the models for various splits. Thus, the attempt to build up the classification QSAR model by means of the Monte Carlo technique, based on representation of the molecular structure via simplified molecular input line entry systems (SMILES) and hydrogen suppressed graph (HSG) using the CORAL software (http://www.insilico.eu/coral) has shown ability of this approach to provide quite good prediction of the examined endpoint (drug-induced liver injury). Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Hepatoprotective Effects of Panus giganteus (Berk.) Corner against Thioacetamide- (TAA-) Induced Liver Injury in Rats.

    Science.gov (United States)

    Wong, Wei-Lun; Abdulla, Mahmood Ameen; Chua, Kek-Heng; Kuppusamy, Umah Rani; Tan, Yee-Shin; Sabaratnam, Vikineswary

    2012-01-01

    Panus giganteus, a culinary and medicinal mushroom consumed by selected indigenous communities in Malaysia, is currently being considered for large scale cultivation. This study was undertaken to investigate the hepatoprotective effects of P. giganteus against thioacetamide- (TAA-) induced liver injury in Sprague-Dawley rats. The rats were injected intraperitoneally with TAA thrice weekly and were orally administered freeze-dried fruiting bodies of P. giganteus (0.5 or 1 g/kg) daily for two months, while control rats were given vehicle or P. giganteus only. After 60 days, rats administered with P. giganteus showed lower liver body weight ratio, restored levels of serum liver biomarkers and oxidative stress parameters comparable to treatment with the standard drug silymarin. Gross necropsy and histopathological examination further confirmed the hepatoprotective effects of P. giganteus. This is the first report on hepatoprotective effects of P. giganteus. The present study showed that P. giganteus was able to prevent or reduce the severity of TAA-induced liver injury.

  14. Hepatoprotective Effects of Panus giganteus (Berk. Corner against Thioacetamide- (TAA- Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Wei-Lun Wong

    2012-01-01

    Full Text Available Panus giganteus, a culinary and medicinal mushroom consumed by selected indigenous communities in Malaysia, is currently being considered for large scale cultivation. This study was undertaken to investigate the hepatoprotective effects of P. giganteus against thioacetamide- (TAA- induced liver injury in Sprague-Dawley rats. The rats were injected intraperitoneally with TAA thrice weekly and were orally administered freeze-dried fruiting bodies of P. giganteus (0.5 or 1 g/kg daily for two months, while control rats were given vehicle or P. giganteus only. After 60 days, rats administered with P. giganteus showed lower liver body weight ratio, restored levels of serum liver biomarkers and oxidative stress parameters comparable to treatment with the standard drug silymarin. Gross necropsy and histopathological examination further confirmed the hepatoprotective effects of P. giganteus. This is the first report on hepatoprotective effects of P. giganteus. The present study showed that P. giganteus was able to prevent or reduce the severity of TAA-induced liver injury.

  15. Coffee and caffeine protect against liver injury induced by thioacetamide in male Wistar rats.

    Science.gov (United States)

    Furtado, Kelly S; Prado, Monize G; Aguiar E Silva, Marco A; Dias, Marcos C; Rivelli, Diogo P; Rodrigues, Maria A M; Barbisan, Luis F

    2012-11-01

    Coffee intake has been inversely related to the incidence of liver diseases, although there are controversies on whether these beneficial effects on human health are because of caffeine or other specific components in this popular beverage. Thus, this study evaluated the protective effects of coffee or caffeine intake on liver injury induced by repeated thioacetamide (TAA) administration in male Wistar rats. Rats were randomized into five groups: one untreated group (G1) and four groups (G2-G5) treated with the hepatotoxicant TAA (200 mg/kg b.w., i.p.) twice a week for 8 weeks. Concomitantly, rats received tap water (G1 and G2), conventional coffee (G3), decaffeinated coffee (G4) or 0.1% caffeine (G5). After 8 weeks of treatment, rats were killed and blood and liver samples were collected. Conventional and decaffeinated coffee and caffeine intake significantly reduced serum levels of alanine aminotransferase (ALT) (p coffee and caffeine intake significantly reduced proliferating cellular nuclear antigen (PCNA) S-phase indexes (p coffee reduced cleaved caspase-3 indexes (p coffee and 0.1% caffeine intake presented better beneficial effects than decaffeinated coffee against liver injury induced by TAA in male Wistar rats. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

  16. Hepatoprotective effect of Centella asiatica (L in carbon tetrachloride-induced liver injury in rats

    Directory of Open Access Journals (Sweden)

    Antony B

    2006-01-01

    Full Text Available The present study was conducted to evaluate the hepatoprotective effects of the Centella asiatica extract in carbon tetrachloride-induced liver injury in rats. Sprague Dawley rats were treated with alcohol extract of Centella asiatica orally in two doses (20 and 40 mg/kg/day for 3 mo along with intraperitoneal injection of carbon tetrachloride (1 ml/kg. Biochemical parameters such as serum total protein, albumin and marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were estimated both before and after the experiment. Histopathological studies of liver were also carried out to confirm the biochemical changes. Carbon tetrachloride-induced hepatotoxic effects were evident by a significant (p < 0.05 increase in the serum marker enzymes and a decrease in the total serum protein and albumin. Administration of extract of Centella asiatica effectively inhibited these changes in a dose-dependent manner; maximum effect was with 40 mg/kg. Histopathological examination of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in carbon tetrachloride-treated group, while these were completely absent in the treatment group. Centella asiatica extract exhibited hepatoprotective action against carbon tetrachloride-induced liver injury. This effect is attributed to the presence of asiaticoside (14.5% in the extract.

  17. Therapeutic potential of cannabidiol against ischemia/reperfusion liver injury in rats.

    Science.gov (United States)

    Fouad, Amr A; Jresat, Iyad

    2011-11-16

    The therapeutic potential of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated in rats exposed to ischemia/reperfusion liver injury. Ischemia was induced by clamping the pedicle of the left hepatic lobe for 30 min, and cannabidiol (5mg/kg, i.v.) was given 1h following the procedure and every 24h thereafter for 2 days. Ischemia/reperfusion caused significant elevations of serum alanine aminotransferase and hepatic malondialdehyde, tumor necrosis factor-α and nitric oxide levels, associated with significant decrease in hepatic reduced glutathione. Cannabidiol significantly attenuated the deterioration in the measured biochemical parameters mediated by ischemia/reperfusion. Histopathological examination showed that cannabidiol ameliorated ischemia/reperfusion-induced liver damage. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, cyclooxygenase-2, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin protein in ischemic/reperfused liver tissue. These results emphasize that cannabidiol represents a potential therapeutic option to protect the liver against hypoxia-reoxygenation injury.

  18. Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue.

    Science.gov (United States)

    Terzi, Alpaslan; Iraz, Mustafa; Sahin, Semsettin; Ilhan, Atilla; Idiz, Nuri; Fadillioglu, Ersin

    2004-09-01

    Rotenone, an insecticide of botanical origin, causes toxicity through inhibition of complex I of the respiratory chain in mitochondria. This study was undertaken to determine whether rotenone-induced liver oxidant injury is prevented by erdosteine, a mucolytic agent showing antioxidant properties. There were four groups of Male Wistar Albino rats: group one was untreated as control; the other groups were treated with erdosteine (50 mg/kg per day, orally), rotenone (2.5 mg/mL once and 1 mL/kg per day for 60 days, i.p.) or rotenone plus erdosteine, respectively. Rotenone treatment without erdosteine increased xanthine oxidase (XO) enzyme activity and also increased lipid peroxidation in liver tissue (P erdosteine produced a significant decrease in lipid peroxidation and XO activities in comparison with rotenone group (P Erdosteine treatment with rotenone led to an increase in catalase (CAT) and superoxide dismutase (SOD) activities in comparison with the rotenone group (P erdosteine group, there was a negative correlation between XO activity and NO level in liver tissue (r = -0.833, P erdosteine may be a protective agent for rotenone-induced liver oxidative injury in rats.

  19. Visualization of acetaminophen-induced liver injury by time-of-flight secondary ion mass spectrometry.

    Science.gov (United States)

    Murayama, Yohei; Satoh, Shuya; Hashiguchi, Akinori; Yamazaki, Ken; Hashimoto, Hiroyuki; Sakamoto, Michiie

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid-Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications.

  20. Protective Effect of Ghrelin on Sodium Valproate-induced Liver Injury in Rat

    Directory of Open Access Journals (Sweden)

    Sadeghi Niaraki, Mandana

    2013-02-01

    Full Text Available Ghrelin is a peptide that has protective effects on many tissues injury. It has anti-inflammatory and anti-oxidant effects. Sodium valproate is widely used anticonvuisant and anti-depression drug with hepatotoxic side effects. The aim of this study was to evaluated the protective role of ghrelin in liver toxicity due to sodium valproate overdose. Eighteen rats were used in this study and divided in to three groups, containing: control, sodium valproate, and sodium valproate and ghrelin groups. Nitric oxide (NO, prostaglandin E2 (PGE2 and hepatic enzymes AST (aspartate aminotransferase and ALT (alanine aminotransferase, were assessed and histologic study of liver were performed as indicators of liver damage following sodium valproate toxicity. This study showed the ghrelin decreased ALT and AST to the normal level. Our results show that ghrelin significantly increased NO metabolites and decreased PGE2 level comparison with sodium valproate group, but had no significant change compared to the control group. we showed that ghrelin administration inhibited liver injury in rats due to sodium valproate toxicity.

  1. 1-methylmalate from camu-camu (Myrciaria dubia) suppressed D-galactosamine-induced liver injury in rats.

    Science.gov (United States)

    Akachi, Toshiyuki; Shiina, Yasuyuki; Kawaguchi, Takumi; Kawagishi, Hirokazu; Morita, Tatsuya; Sugiyama, Kimio

    2010-01-01

    To evaluate the protective effects of fruit juices against D-galactosamine (GalN)-induced liver injury, lyophilized fruit juices (total 12 kinds) were fed to rats for 7 d, and then we evoked liver injury by injecting GalN. The juice of camu-camu (Myrciaria dubia) significantly suppressed GalN-induced liver injury when the magnitude of liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, although some other juices (acerola, dragon fruit, shekwasha, and star fruit) also tended to have suppressive effects. An active compound was isolated from camu-camu juice by solvent fractionation and silica gel column chromatography. The structure was determined to be 1-methylmalate. On the other hand, malate, 1,4-dimethylmalate, citrate, and tartrate had no significant effect on GalN-induced liver injury. It is suggested that 1-methylmalate might be a rather specific compound among organic acids and their derivatives in fruit juices in suppressing GalN-induced liver injury.

  2. Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver

    Institute of Scientific and Technical Information of China (English)

    Fahrettin Yildiz; Alpaslan Terzi; Sacit Coban; Mustafa Ares,; Nurten Aksoy; Hale Cakir; Ali Riza Ocak; Muharrem Bitiren,

    2008-01-01

    AIM:To determine whether Nigella sativa prevents hepatic ischemia-reperfusion injury to the liver.METHODS:Thirty rats were divided into three groups as sham(Group 1),control(Group 2),and Nigella sativa(NS)treatment group(Group 3).All rats underwent hepatic ischemia for 45 min followed by 60 min period of reperfusion.Rats were intraperitoneally infused with only 0.9% saline solution in group 2.Rats in group 3 received NS(0.2 mL/kg)intraperitoneally,before ischemia and before reperfusion.Blood samples and liver tissues were harvested from the rats,and then the rats were sacrificed.Serum aspartate aminotransferase(AST),alanine aminotransferase(ALT),and lactate dehydrogenase(LDH)Ievels were determined.Total antioxidant capacity(TAC),catalase(CAT),total oxidative status(TOS),oxidative stress index(OSI)and myeloperoxidase(MPO)in hepatic tissue were measured.Also liver tissue histopathology was evaluated by light microscopy.RESULTS:The levels of liver anzymes in group 3 were significantly lower than those in the group 2.TAC in liver tissue was significantly higher in group 3 than in group 2.TOS,OSI and MPO in hepatic tissue were significantly lower in group 3 than the group 2.Histo logical tissue damage was milder in the NS treatment group than that in the control group.CONCLUSION:Our results suggest that Nigella sativa treatment protects the rat liver against to hepatic ischemia-reperfusion injury.(C)2008 The WJG Press.All rights reserved.

  3. In situ metabolic flux analysis to quantify the liver metabolic response to experimental burn injury.

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    Izamis, Maria-Louisa; Sharma, Nripen S; Uygun, Basak; Bieganski, Robert; Saeidi, Nima; Nahmias, Yaakov; Uygun, Korkut; Yarmush, Martin L; Berthiaume, Francois

    2011-04-01

    Trauma such as burns induces a hypermetabolic response associated with altered central carbon and nitrogen metabolism. The liver plays a key role in these metabolic changes; however, studies to date have evaluated the metabolic state of liver using ex vivo perfusions or isotope labeling techniques targeted to specific pathways. Herein, we developed a unique mass balance approach to characterize the metabolic state of the liver in situ, and used it to quantify the metabolic changes to experimental burn injury in rats. Rats received a sham (control uninjured), 20% or 40% total body surface area (TBSA) scald burn, and were allowed to develop a hypermetabolic response. One day prior to evaluation, all animals were fasted to deplete glycogen stores. Four days post-burn, blood flow rates in major vessels of the liver were measured, and blood samples harvested. We combined measurements of metabolite concentrations and flow rates in the major vessels entering and leaving the liver with a steady-state mass balance model to generate a quantitative picture of the metabolic state of liver. The main findings were: (1) Sham-burned animals exhibited a gluconeogenic pattern, consistent with the fasted state; (2) the 20% TBSA burn inhibited gluconeogenesis and exhibited glycolytic-like features with very few other significant changes; (3) the 40% TBSA burn, by contrast, further enhanced gluconeogenesis and also increased amino acid extraction, urea cycle reactions, and several reactions involved in oxidative phosphorylation. These results suggest that increasing the severity of injury does not lead to a simple dose-dependent metabolic response, but rather leads to qualitatively different responses.

  4. Prevention of liver fibrosis by intrasplenic injection of high-density cultured bone marrow cells in a rat chronic liver injury model.

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    Jie Lian

    Full Text Available Endothelial progenitor cells (EPCs from bone marrow have proven to be functional for the prevention of liver fibrosis in chronic liver injury. However, expansion of EPCs in culture is complicated and expansive. Previously, we have established a simple method that could enrich and expand EPCs by simple seeding bone marrow cells in high density dots. The purpose of this study is to evaluate whether cells derived from high-density (HD culture of rat bone marrow cells could prevent the liver fibrosis in a chronic liver injury rat model, induced by carbon tetrachloride (CCl4. Flow cytometric analysis showed that cells from HD culture were enriched for EPCs, expressing high levels of EPC markers. Intrasplenic injection of HD cultured bone marrow cells in the CCl4-induced liver injury rat showed an enhanced antifibrogenic effect compared with animals treated with cells from regular-density culture. The antifibrogenic effect was demonstrated by biochemical and histological analysis 4 weeks post-transplantation. Furthermore, cells from HD culture likely worked through increasing neovascularization, stimulating liver cell proliferation, and suppressing pro-fibrogenic factor expression. HD culture, which is a simple and cost-effective procedure, could potentially be used to expand bone marrow cells for the treatment of liver fibrosis.

  5. Validity of diagnostic codes and laboratory measurements to identify patients with idiopathic acute liver injury in a hospital database

    DEFF Research Database (Denmark)

    Udo, Renate; Maitland-van der Zee, Anke H; Egberts, Toine C G;

    2016-01-01

    of liver enzyme values (ALT > 2× upper limit of normal (ULN); AST > 1ULN + AP > 1ULN + bilirubin > 1ULN; ALT > 3ULN; ALT > 3ULN + bilirubin > 2ULN; ALT > 10ULN) and (II) algorithms based on solely liver enzyme values (ALT > 3ULN + bilirubin > 2ULN; ALT > 10ULN). Hospital medical records were reviewed......PURPOSE: The development and validation of algorithms to identify cases of idiopathic acute liver injury (ALI) are essential to facilitate epidemiologic studies on drug-induced liver injury. The aim of this study is to determine the ability of diagnostic codes and laboratory measurements...... 32% (13/41) to 48% (43/90) with the highest PPV found with ALT > 2ULN. The PPV for (II) algorithms with liver test abnormalities was maximally 26% (150/571). CONCLUSIONS: The algorithm based on ICD-9-CM codes indicative of ALI combined with abnormal liver-related laboratory tests is the most...

  6. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice

    NARCIS (Netherlands)

    Hoekstra, H; Porte, RJ; Tian, Y; Jochum, W; Stieger, B; Moritz, W; Slooff, MJH; Graf, R; Clavien, PA

    2006-01-01

    Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resista

  7. Stem cell injury and restitution after ionizing irradiation in intestine, liver, salivary gland, mesenteric lymph node

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    Lee, Jae Hyun; Cho, Kyung Ja; Lee, Sun Joo; Jang, Won Suk [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1998-01-01

    There is little information about radiation injury on stem cell resident in other organs. In addition there is little experimental model in which radiation plays a role on proliferation stem cell in adult organ. This study was carried out to evaluate the early response of tissue injury and restitution in intestine, liver, salivary gland and lymph node, and to develop in vivo model to investigate stem cell biology by irradiation. The study is to assay the early response to radiation and setup an animal model for radiation effect on cellular response. Duodenal intestine, liver, submandibular salivary gland and mesenteric lymph node were selected to compare apoptosis and proliferating cell nuclear antigen (PCNA) expression to radiosensitivity. For the effect of radiation on cellular responses, rats were irradiated during starvation. Conclusionly, this study showed the value of apoptosis in detection system for evaluating cellular damage against radiation injury. Because apoptosis was regularly inducted depending on tissue-specific pattern, dose and time sequence as well as cellular activity. Furthermore in vivo model in the study will be helped in the further study to elucidate the relationship between radiation injury and starvation or malnutrition. (author). 22 refs., 6 figs

  8. Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver.

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    Shimada, Shingo; Wakayama, Kenji; Fukai, Moto; Shimamura, Tsuyoshi; Ishikawa, Takahisa; Fukumori, Daisuke; Shibata, Maki; Yamashita, Kenichiro; Kimura, Taichi; Todo, Satoru; Ohsawa, Ikuroh; Taketomi, Akinobu

    2016-12-01

    Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter. Copyright © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  9. The inflammasome in liver injury and non-alcoholic fatty liver disease.

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    Mehal, Wajahat Zafar

    2014-01-01

    The liver possesses a strong inflammatory response, as seen experimentally and clinically with liver inflammation due to toxic and metabolic stress, sepsis and ischemia. Initiation of this inflammatory response requires the interaction of two types of extracellular signals which collectively upregulate and activate a cytosolic molecular complex termed the inflammasome. Signal 1 is via activation of pattern recognition receptors, and signal 2 is delivered by diverse stimuli including particulates and adenosine triphosphate. The common end result of inflammasome activation is the activation of the protease caspase-1 with release of active interleukin-1β. The inflammasome is important in a wide range of conditions including alcoholic and non-alcoholic steatohepatitis. Kupffer cells are known to be important, but the consequences of inflammasome activation in other hepatic immune cells have not been well characterized. The inflammasome pathway is also known to be required for a full fibrotic response, as demonstrated by reduced lung, skin and liver fibrosis in inflammasome-deficient mice. Identification of the inflammasome machinery has opened up novel therapeutic avenues by the use of antagonists for Toll-like receptors as well as the adenosine triphosphate receptor P2X7, and the interleukin-1 receptor. There is now great interest in how inflammasome pathways are regulated. The initial challenge is to understand how an acute inflammatory response is sustained. This is a significant issue as the known stimuli result in an acute response that is self-limited to under 24 h. This suggests that there are significant regulators which allow sustained inflammasome activation in conditions such as non-alcoholic steatohepatitis and alcoholic hepatitis.

  10. BML-111 Protected LPS/D-GalN-Induced Acute Liver Injury in Rats

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    Dan Yan

    2016-07-01

    Full Text Available Lipoxins (LXs display unique pro-resolving and anti-inflammatory functions in a variety of inflammatory conditions. The present study was undertaken to investigate the effects of BML-111 (5(S,6(R,7-trihydroxyheptanoic acid methyl ester, the agonist of lipoxin A4 receptor, in a model of Lipopolysaccharides (LPS and d-Galactosamine (d-GalN induced acute liver injury, and to explore the mechanisms. Histopathological analyses were carried out to quantify liver injury degree. The activities of myeloperoxidase (MPO were examined to evaluate the levels of neutrophil infiltration. The activities of aspartate aminotransferase (AST and alanine aminotransferase (ALT in serum were detected to evaluate the functions of the liver. The amounts of tumor necrosis factor-α (TNF-α, interleukin-10 (IL-10, and interleukin-1β (IL-1β were measured using enzyme-linked immunosorbent assay (ELISA, and the expression levels of transforming growth factor-β1(TGF-β1 and cyclooxygenase-2 (COX-2 were examined using Western blotting. The antioxidant capacity, the activities of inducible nitric oxide synthase (iNOS, the contents of malondialdehyde (MDA and nitric oxide (NO were analyzed with the kits via biochemical analysis. We established the model of acute liver injury with lipopolysaccharide and d-Galactosamine (LPS/d-GalN: (1 histopathological results and MPO activities, with the activities of AST and ALT in serum, consistently demonstrated LPS and d-GalN challenge could cause severe liver damage, but BML-111 could prevent pathological changes, inhibit neutrophil infiltration, and improve the hepatic function; (2 LPS/d-GalN increased TNF-α, IL-1β, COX-2, and IL-10, while decreasing TGF-β1. However, BML-111 could repress LPS/d-GalN -induced TNF-α, IL-1β and COX-2, meanwhile increasing the expression levels of TGF-β1 and IL-10; (3 LPS/d-GalN inhibited the activities of superoxide dismutase (SOD, catalase (CAT, total antioxidant capacity (T-AOC, and hydroxyl

  11. A comprehensive five-step surgical management approach to penetrating liver injuries that require complex repair.

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    Ordoñez, Carlos Alberto; Parra, Michael W; Salamea, Juan Carlos; Puyana, Juan Carlos; Millán, Mauricio; Badiel, Marisol; Sanjuán, Juán; Pino, Luis F; Scavo, David; Botache, Wilmer; Ferrada, Ricardo

    2013-08-01

    The objective of this study was to describe a comprehensive five-step surgical management approach for patients with penetrating liver trauma based on our collective institutional experience. A prospective consecutive study of all penetrating liver traumas from January 2003 to December 2011 at a regional Level I trauma center in Cali, Colombia, was conducted. A total of 538 patients with penetrating thoracoabdominal trauma were operated on at our institution. Of these, 146 had penetrating liver injuries that satisfied the inclusion criteria for surgical intervention to manage their hepatic and/or associated injuries. Eighty-eight patients (60%) had an American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) of Grade III (54 patients, 37%), Grade IV (24 patients, 16%), and Grade V (10 patients, 7%). This group of patients required advanced "complex" techniques of hemostasis such as the Pringle maneuver (PM), perihepatic liver packing (PHLP), and/or hepatotomy with selective vessel ligation (SVL). The focus of our study was this subgroup of patients, which we further divided into two as follows: those who required only PM + PHLP (55 patients, 63%) to obtain control of their liver hemorrhage and those who required PM + PHLP + SVL (33 patients, 37%). Of the patients who required PM + PHLP + SVL, 10 (27%) required ligation of major intrahepatic branches, which included suprahepatic veins (n = 4), portal vein (n = 4), retrohepatic vena cava (n = 1), and hepatic artery (n = 1). The remaining 23 patients (73%) required direct vessel ligation of smaller intraparenchymal vessels. The overall mortality was 15.9% (14 of 88), with 71.4% (10 of 14) related to coagulopathy. Mortality rates for Grade III was 3.7% (2 of 54), for Grade IV was 20.8% (5 of 24), and for Grade V was 70% (7 of 10). The mortality in the PM + PHLP + SVL group was higher compared with the PM + PHLP group (12 [36.4%] vs. 2 [3.6%], p = 0.001]. For those patients who fail to respond to PM

  12. Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury

    NARCIS (Netherlands)

    Olthof, Pim B.; Golen, van Rowan F.; Meijer, Ben; Beek, van Adriaan A.; Bennink, Roelof J.; Verheij, Joanne; Gulik, van Thomas M.; Heger, Michal

    2017-01-01

    Background

    Hepatic ischemia/reperfusion (I/R) injury is characterized by hepatocellular damage, sterile inflammation, and compromised postoperative liver function. Generally used mouse I/R models are too severe and poorly reflect the clinical injury profile. The aim was to establish a mouse

  13. Glycine blunts transplantative liver ischemia-reperfusion injury by downregulating interleukin 1 receptor associated kinase-4

    Institute of Scientific and Technical Information of China (English)

    Zuo-jin LIU; Lu-nan YAN; Shen-wei LI; Hai-bo YOU; Jian-ping GONG

    2006-01-01

    Aim: To determine whether glycine could downregulate interleukin 1 receptor associated kinase-4 (IRAK-4) expression to interfere with lipopolysaccharides (LPS) signal transduction and blunt transplantative liver ischemia-reperfusion injury (I/RI). Methods: SD rats were randomly divided into two groups: donor animals of the glycine group (n=40) were given glycine (1.5 mL; 300 mmol/L, iv) 1 h before harvest, and the control group were treated with 1.5 mL physiological saline (n= 40). Orthotropic liver transplantation was then performed according to the Kamada technique. Ten animals in each group were followed up for 7 d after surgery to assess survival. The remaining animals in each group were divided into 3 subgroups (n=10) at 1h, 2 h and 6 h after portal vein reperfusion. Levels of LPS, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin in portal circulation, as well as IRAK-4 and TNF-α expression, NF-кB transcriptional activity and morphological study of liver tissues were analyzed. Results: Reperfusion resulted in a significant elevation of LPS concentrations in each group persisting to the end of our study. However, glycine, which led to improved survival rate and liver function, significantly alleviated liver parenchyma cell damage by downregulating IRAK-4, TNF-α expression and NF-кB transcriptional activity compared with the control group. Conclusion: Glycine can attenuate hepatic I/RI by downregulating IRAK-4 to interfere with LPS signal transduction.

  14. High preoperative bilirubin values protect against reperfusion injury after live donor liver transplantation.

    Science.gov (United States)

    Spetzler, Vinzent N; Goldaracena, Nicolas; Kaths, Johann M; Marquez, Max; Selzner, Nazia; Cattral, Mark S; Greig, Paul D; Lilly, Les; McGilvray, Ian D; Levy, Gary A; Ghanekar, Anand; Renner, Eberhard L; Grant, David R; Selzner, Markus

    2015-11-01

    Heme Oxygenase-1 and its product biliverdin/bilirubin have been demonstrated to protect against ischemia/reperfusion injury (IRI). We investigated whether increased preoperative bilirubin values of transplant recipients decrease IRI. Preoperative bilirubin levels of live donor liver recipients were correlated to postoperative liver transaminase as a marker of IRI. Additionally, two recipient groups with pretransplant bilirubin levels >24 μmol/l (n = 348) and ≤24 μmol/l (n = 118) were compared. Post-transplant liver function, complications, length of hospital stay, and patient and graft survival were assessed. Preoperative bilirubin levels were negatively correlated to the postoperative increase in transaminases suggesting a protective effect against IRI. The maximal rise of ALT after transplantation in high versus low bilirubin patients was 288 (-210-2457) U/l vs. 375 (-11-2102) U/l, P = 0.006. Bilirubin remained a significant determining factor in a multivariate linear regression analysis. The MELD score and its individual components as a marker of severity of chronic liver disease were significantly higher in the high versus low bilirubin group (P bilirubin levels of liver recipients before live donor transplantation is associated with decreased postoperative IRI.

  15. Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate-induced liver injury in rats.

    Science.gov (United States)

    Hfaiedh, Mbarka; Brahmi, Dalel; Zourgui, Lazhar

    2016-03-01

    Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases.

  16. Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway.

    Science.gov (United States)

    Suciu, Maria; Gruia, Alexandra T; Nica, Dragos V; Azghadi, Seyed M R; Mic, Ani A; Mic, Felix A

    2015-12-05

    Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis--were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen-induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology.

  17. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

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    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  18. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation.

    Science.gov (United States)

    Henry, S D; Nachber, E; Tulipan, J; Stone, J; Bae, C; Reznik, L; Kato, T; Samstein, B; Emond, J C; Guarrera, J V

    2012-09-01

    Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function. Molecular data to date has been limited to extrapolation of animal studies. We analyzed liver tissue and serum collected during our Phase 1 trial of liver HMP. Grafts preserved with HMP were compared to static cold stored (SCS) transplant controls. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and transmission electron microscopy (TEM) were performed on liver biopsies. Expression of inflammatory cytokines, adhesion molecules and chemokines, oxidation markers, apoptosis and acute phase proteins and the levels of CD68 positive macrophages in tissue sections were evaluated. RT-PCR of reperfusion biopsy samples in the SCS group showed high expression of inflammatory cytokines, adhesion molecules and chemokines, oxidative markers and acute phase proteins. This upregulation was significantly attenuated in livers that were preserved by HMP. Immunofluorescence showed larger numbers of CD68 positive macrophages in the SCS group when compared to the HMP group. TEM samples also revealed ultrastructural damage in the SCS group that was not seen in the HMP group. HMP significantly reduced proinflammatory cytokine expression, relieving the downstream activation of adhesion molecules and migration of leukocytes, including neutrophils and macrophages when compared to SCS controls.

  19. Brain expression of the water channels Aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema

    DEFF Research Database (Denmark)

    Eefsen, Martin; Jelnes, Peter; Schmidt, Lars E;

    2010-01-01

    Cerebral edema is a feared complication to acute liver failure (ALF), but the pathogenesis is still poorly understood. The water channels Aquaporin-1 (Aqp1) and -4 (Aqp4) has been associated with brain edema formation in several neuropathological conditions, indicating a possible role of Aqp1 and....../or Aqp4 in ALF mediated brain edema. We induced acute liver injury and hyperammonemia in mice, to evaluate brain edema formation and the parallel expression of Aqp1 and Aqp4 in ALF. Liver injury and hyperammonemia were induced by +D-galactosamine (GLN) plus lipopolysaccharide (LPS) intraperitoneally......(6266) (p edema in mice with ALF....

  20. Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation.

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    J Kirk Harris

    Full Text Available Parenteral nutrition (PN has been a life-saving treatment in infants intolerant of enteral feedings. However, PN is associated with liver injury (PN Associated Liver Injury: PNALI in a significant number of PN-dependent infants. We have previously reported a novel PNALI mouse model in which PN infusion combined with intestinal injury results in liver injury. In this model, lipopolysaccharide activation of toll-like receptor 4 signaling, soy oil-derived plant sterols, and pro-inflammatory activation of Kupffer cells (KCs played key roles. The objective of this study was to explore changes in the intestinal microbiome associated with PNALI.Microbiome analysis in the PNALI mouse identified specific alterations within colonic microbiota associated with PNALI and further association of these communities with the lipid composition of the PN solution. Intestinal inflammation or soy oil-based PN infusion alone (in the absence of enteral feeds caused shifts within the gut microbiota. However, the combination resulted in accumulation of a specific taxon, Erysipelotrichaceae (23.8% vs. 1.7% in saline infused controls, in PNALI mice. Moreover, PNALI was markedly attenuated by enteral antibiotic treatment, which also was associated with significant reduction of Erysipelotrichaceae (0.6% and a Gram-negative constituent, the S24-7 lineage of Bacteroidetes (53.5% in PNALI vs. 0.8%. Importantly, removal of soy oil based-lipid emulsion from the PN solution resulted in significant reduction of Erysipelotrichaceae as well as attenuation of PNALI. Finally, addition of soy-derived plant sterol (stigmasterol to fish oil-based PN restored Erysipelotrichaceae abundance and PNALI.Soy oil-derived plant sterols and the associated specific bacterial groups in the colonic microbiota are associated with PNALI. Products from these bacteria may directly trigger activation of KCs and promote PNALI. Furthermore, the results indicate that lipid modification of PN solutions may

  1. Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy.

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    Yun Wang

    Full Text Available BACKGROUND: Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR. Heme oxygenase-1 (HO-1 is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC. The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. METHODS: RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II. The HO-1/extracellular signal-related kinase (ERK/p38/mitogen-activated protein kinase (MAPK pathway was detected in an autophagy model and mineral oil-induced IR in vitro. RESULTS: In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. CONCLUSIONS: RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.

  2. Effects of Shark Hepatic Stimulator Substance on the Function and Antioxidant Capacity of Liver Mitochondria in an Animal Model of Acute Liver Injury

    Institute of Scientific and Technical Information of China (English)

    Qiu-Ling FAN; Cai-Guo HUANG; Yan JIN; Bo FENG; Hui-Nan MIAO; Wen-Jie LI; Bing-Hua JIAO; Qin-Sheng YUAN

    2005-01-01

    This study was carried out to investigate whether shark hepatic stimulator substance (HSS) can prevent acute liver injury and affect mitochondrial function and antioxidant defenses in a rat model of thioacetamide (TAA)-induced liver injury. The acute liver injury was induced by two intraperitoneal injections of TAA (400 mg/kg) in a 24 h interval. In the TAA plus shark HSS group, rats were treated with shark HSS (80 mg/kg) 1 h prior to each TAA injection. In this group, serum liver enzyme activities were significantly lower than those in the TAA group. The mitochondrial respiratory control ratio was improved, and the mitochondrial respiratory enzyme activities were increased in the TAA plus shark HSS group. The mitochondrial antioxidant enzyme activities and glutathione level were higher in the TAA plus shark HSS group than in the TAA group. These results suggest that the protective effect of shark HSS against TAA-induced acute liver injury may be a result of the restoration of the mitochondrial respiratory function and antioxidant defenses and decreased oxygen stress.

  3. Liver Injury Indicating Fatty Liver but Not Serologic NASH Marker Improves under Metformin Treatment in Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    Susanne Tan

    2015-01-01

    Full Text Available Objective. Polycystic ovary syndrome (PCOS is associated with obesity and insulin resistance (IR, key features of nonalcoholic steatohepatitis (NASH. Cytokeratin 18 fragments (M30 have been established as a serum marker for NASH. The insulin sensitizer metformin improves hepatic IR. This study evaluates the influence of MF on serologic NASH (sNASH in patients with PCOS. Patients and Methods. In 89 patients, metabolic parameters, liver injury indicating fatty liver (LIFL, and M30 were assessed at baseline and after metformin treatment. Patients with initial IR were subdivided into dissolved (PCOS-exIR and persistent IR (PCOS-PIR after treatment and compared to an initially insulin sensitive PCOS group (PCOS-C. Results. Improvement of LIFL prevalence could be seen in PCOS-C and PCOS-exIR compared to PCOS-PIR (−19.4, resp., −12.0% versus 7.2%, Chi2 = 29.5, P<0.001 without change in sNASH prevalence. In PCOS-PIR, ALT levels increased significantly accompanied by a nominal, nonsignificant M30 increase. Conclusions. Metformin improves LIFL in subgroups of patients with PCOS without influencing sNASH. This could either indicate a missing effect of metformin on NAFLD or slowed disease progression. Further studies are needed to elucidate NAFLD in the context of PCOS and potential therapeutic options.

  4. A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

    Science.gov (United States)

    Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

    2017-01-01

    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a ‘big data compacting and data fusion’—concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a ‘predictive toxicogenomics space’ (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID:28671182

  5. Biochemical and histological study of rat liver and kidney injury induced by Cisplatin.

    Science.gov (United States)

    Palipoch, Sarawoot; Punsawad, Chuchard

    2013-09-01

    Cisplatin is a chemotherapeutic agent widely used in treatment of several cancers. It is documented as a major cause of clinical nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the involvement of oxidative stress in the pathogenesis of cisplatin-induced liver and kidney injury. Wistar rats were divided into four groups. Group 1 (control) was intraperitoneally (IP) injected with a single dose of 0.85% normal saline. Groups 2, 3 and 4 were IP injected with single doses of cisplatin at 10, 25 and 50 mg/kg body weight (BW), respectively. At 24, 48, 72, 96 and 120 h after injection, BW, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and activity of superoxide dismutase (SOD) and histology of the liver and kidney were evaluated. Cisplatin caused a reduction in BW of rats in groups 2, 3 and 4 at all post injection intervals. The levels of serum ALT, AST, BUN and creatinine and MDA of the kidney and liver were markedly increased especially at 48 and 72 h, whereas the activity of SOD was decreased after cisplatin injection. Liver sections revealed moderate to severe congestion with dilation of the hepatic artery, portal vein and bile duct and disorganization of hepatic cords at 50 mg/kg of cisplatin. Kidney sections illustrated mild to moderate tubular necrosis at 25 and 50 mg/kg of cisplatin. Therefore, oxidative stress was implicated in the pathogenesis of liver and kidney injury causing biochemical and histological alterations.

  6. Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress.

    Science.gov (United States)

    Lu, Yongke; Leung, Tung Ming; Ward, Stephen C; Nieto, Natalia

    2012-02-01

    Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the L-citrulline/nitric oxide (NO·) salvage pathway to continually supply L-arginine from L-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/- mice (Ass+/+ mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/- mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/- compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration.

  7. Prediction of Drug-Induced Liver Injury in HepG2 Cells Cultured with Human Liver Microsomes.

    Science.gov (United States)

    Choi, Jong Min; Oh, Soo Jin; Lee, Ji-Yoon; Jeon, Jang Su; Ryu, Chang Seon; Kim, Young-Mi; Lee, Kiho; Kim, Sang Kyum

    2015-05-18

    Drug-induced liver injury (DILI) via metabolic activation by drug-metabolizing enzymes, especially cytochrome P450 (CYP), is a major cause of drug failure and drug withdrawal. In this study, an in vitro model using HepG2 cells in combination with human liver microsomes was developed for the prediction of DILI. The cytotoxicity of cyclophosphamide, a model drug for bioactivation, was augmented in HepG2 cells cultured with microsomes in a manner dependent on exposure time, microsomal protein concentration, and NADPH. Experiments using pan- or isoform-selective CYP inhibitors showed that CYP2B6 and CYP3A4 are responsible for the bioactivation of cyclophosphamide. In a metabolite identification study employing LC-ESI-QTrap and LC-ESI-QTOF, cyclophosphamide metabolites including phosphoramide mustard, a toxic metabolite, were detected in HepG2 cells cultured with microsomes, but not without microsomes. The cytotoxic effects of acetaminophen and diclofenac were also potentiated by microsomes. The potentiation of acetaminophen cytotoxicity was dependent on CYP-dependent metabolism, and the augmentation of diclofenac cytotoxicity was not mediated by either CYP- or UDP-glucuronosyltransferase-dependent metabolism. The cytotoxic effects of leflunomide, nefazodone, and bakuchiol were attenuated by microsomes. The detoxication of leflunomide by microsomes was attributed to mainly CYP3A4-dependent metabolism. The protective effect of microsomes against nefazodone cytotoxicity was dependent on both CYP-mediated metabolism and nonspecific protein binding. Nonspecific protein binding but not CYP-dependent metabolism played a critical role in the attenuation of bakuchiol cytotoxicity. The present study suggests that HepG2 cells cultured with human liver microsomes can be a reliable model in which to predict DILI via bioactivation by drug metabolizing enzymes.

  8. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

    Science.gov (United States)

    Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

    2015-01-01

    Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients

  9. Anti-lipid peroxidation and protection of liver mitochondria against injuries by picroside Ⅱ

    Institute of Scientific and Technical Information of China (English)

    Hua Gao; Ya-Wei Zhou

    2005-01-01

    AIM: To investigate the anti-lipid peroxidation and protection of liver mitochondria against injuries in mice with liverdamage by picroside Ⅱ.METHODS: Three animal models of liver damageinduced by carbon tetrachloride (CCl4:0.1 mL/10 g, ip),D-galactosamine (D-GalN: 500 mg/kg,ip) and acetaminophen (AP: 0.15 g/kg, ip) were respectively treated with various concentrations of picroside Ⅱ (5, 10, 20 mg/kg, ig). Then we chose the continuously monitoring method (recommended by International Clinical Chemistry League) to analyze serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values, Marland method to detect the activity of manganese-superoxide dismutase (SOD) in liver mitochondria, TBA colorimetry to determine the content of malonicdialdehyde (MDA) in liver tissue, DTNB method to evaluate the activity of glutathioneperoxidase (GSH-Px) and Lowry method to detect protein level in liver tissue. Meanwhile, effects of picroside Ⅱ on the activity of ATPase and swelling extent of mitochondria in hepatocytes damaged by AP were also evaluated.RESULTS: Picroside Ⅱ could significantly prevent liver toxicity in the three models of liver damage. It decreased the high levels of ALT and AST in serum induced by theadministration of CCl4, D-GalN and AP, reduced the cellular damage of liver markedly, and appeared to be even more potent than the positive control drug of biphenyl dimethyl dicarboxylate pilules (DDB). In groups treated with different doses of picroside Ⅱ, compared to the model group, the content of MDA in serum decreased evidently, whereas the content of SOD and GSH-Px increased in a dosedependent manner, and the difference was statistically significant. Further, in the study of AP model, picroside Ⅱinhibited AP-induced liver toxicity in mice, enhanced the activity of ATPase, improved the swelling extent of mitochondria and helped to maintain a normal balance of energy metabolism.CONCLUSION: Picroside Ⅱ can evidently relieve

  10. Adiponectin deficiency exacerbates lipopolysaccharide/ D-galactosamine-induced liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hitoshi Matsumoto; Yuji Matsuzawa; Iichiro Shimomura; Norio Hayashi; Shinji Tamura; Yoshihiro Kamada; Shinichi Kiso; Juichi Fukushima; Akira Wada; Norikazu Maeda; Shinji Kihara; Tohru Funahashi

    2006-01-01

    AIM: To examine the effects of adiponectin on the functions of Kupffer cells, key modulators of lipopolysaccharide (LPS) -induced liver injury.METHODS: D-galactosamine (GaIN) and LPS were injected intraperitoneally into adiponectin-/- mice and wild type mice. Kupffer cells, isolated from Sprague-Dawley rats, were preincubated with or without adiponectin, and then treated with LPS.RESULTS: In knockout mice, GalN/LPS injection significantly lowered the survival rate, significantly raised the plasma levels of alanine transaminase and tumor necrosis factor-α (TNF-α) and significantly reduced IL-10 levels compared with wild type mice. TNF-α gene expression in the liver was which higher and those of IL-10 were lower in knockout mice than in wild type mice. In cultured adiponectin-pre-treated Kupffer cells, LPS significantly lowered TNF-α levels and raised IL-10 levels in the culture media and their respective gene expression levels, compared with Kupffer cells without adiponectinpre-treatment.CONCLUSION: Adiponectin supresses TNF-α production and induces IL-10 production by Kupffer cells in response to LPS stimulation, and a lack of adiponectin enhances LPS-induced liver injury.

  11. Antioxidant effects of aqueous extract of Salep on Paraquat-induced rat liver injury

    Science.gov (United States)

    Atashpour, Shekoufeh; Kargar Jahromi, Hossein; Kargar Jahromi, Zahra; Zarei, Sanaz

    2017-01-01

    AIM To evaluate the effects of aqueous extract of Salep on Paraquat-mediated liver injury. METHODS In this experimental study, 56 adult male Wistar rats were divided randomly to 7 groups as control, sham, and 5 experimental groups. In control group, rats did not receive any substance during experiment. In Sham group, rats were given distilled water according to their body weight and in experimental groups, Paraquat alone and with different doses of Salep aqueous extract (40, 80, 160 and 320 mg/kg) was given intraperitoneal daily for 14 d. After that, liver biochemical parameter and histologic changes were analyzed and compared in different groups. RESULTS Paraquat compared to control and sham groups, significantly (P Paraquat. Salep at doses of 80, 160 and 320 mg/kg significantly decreased serum level of ALT, AST, ALP, bilirubin, MDA and TOC and significantly increased total protein, albumin and TAC level as compared to Paraquat exposed group in dose dependent manner. Aqueous extract of Salep at doses of 40 mg/kg made no significant changes in serum level of mentioned biochemical parameters. Liver microscopic observation revealed that Paraquat could cause hepatocyte necrosis, degenerative changes, proliferation and activation of Kupffer cells (sporadically) which were reduced by Salep treatment. CONCLUSION Salep possesses remarkable hepatoprotection activity against Paraquat-induced hepatic injury by having antioxidant activity and reducing lipid peroxidation and oxidative stress. PMID:28217258

  12. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

    Science.gov (United States)

    Iorga, Andrea; Dara, Lily; Kaplowitz, Neil

    2017-01-01

    Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death. PMID:28486401

  13. Burn injury induces histopathological changes and cellproliferation in liver of rats

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    AIM To investigate effects of severe burn injury (BI) inrat liver through the histopathological and inflammatorymarkers analysis.METHODS: Forty-two male Wistar rats were distributedinto two groups, control (C) and subjected to scaldBI (SBI). The animals were euthanized one, four and14 d post sham or 45% of the total body surface BI.Liver fragments were submitted to histopathological,morphoquantitative (hepatocyte area and cell density),ciclooxigenase-2 (COX-2) immunoexpression, and geneexpression [real-time polymerase chain reaction fortumor necrosis factor (TNF)-α, inducible nitric oxidesynthase (iNOS) and caspase-3] methods.RESULTS: Histopathological findings showed inflammatoryprocess in all periods investigated and hepatocytedegeneration added to increased amount of connectivetissue 14 d post injury. Hepatocyte area, the density ofbinucleated hepatocytes and density of sinusoidal cellsof SBI groups were increased when compared withcontrol. COX-2 immunoexpression was stronger in SBIgroups. No differences were found in TNF-α, iNOS andcaspase-3 gene expression.CONCLUSION: BI induces histopathological changes,upregulation of COX-2 immunoexpression, and cellproliferation in liver of rats.

  14. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis.

    Science.gov (United States)

    Iorga, Andrea; Dara, Lily; Kaplowitz, Neil

    2017-05-09

    Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

  15. Carvacrol attenuates N-nitrosodiethylamine induced liver injury in experimental Wistar rats

    Directory of Open Access Journals (Sweden)

    Balan Rajan

    2015-06-01

    Full Text Available Carvacrol is a main constituent in the essential oils of countless aromatic plants including Origanum Vulgare and Thymus vulgari, which has been assessed for substantial pharmacological properties. In recent years, notable research has been embarked on to establish the biological actions of Carvacrol for its promising use in clinical applications. The present study is an attempt to reveal the protective role of Carvacrol against N-Nitrosodiethylamine (DEN induced hepatic injury in male Wistar albino rats. DEN is an egregious toxin, present in numerous environmental factors, which enhances chemical driven liver damage by inducing oxidative stress and cellular injury. Administration of DEN (200 mg/kg bodyweight, I.P to rats results in elevated marker enzymes (in both serum and tissue. Carvacrol (15 mg/kg body weight suppressed the elevation of marker enzymes (in both serum and tissue and augmented the antioxidants levels. The hoisted activities of Phase I enzymes and inferior activities of Phase II enzymes were observed in DEN-administered animals, whereas Carvacrol treated animals showed improved near normal activity. Histological observations also support the protective role of Carvacrol against DEN induced liver damage. Final outcome from our findings intimate that Carvacrol might be beneficial in attenuating toxin induced liver damage.

  16. Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

    Institute of Scientific and Technical Information of China (English)

    Matthias Froh; Ronald G Thurman; Lars Conzelmann; Peter Walbrun; Susanne Netter; Reiner Wiest; Michael D Wheeler; Mark Lehnert; Takehiko Uesugi; Jurgen Scholmerich

    2007-01-01

    AIM: To investigate the effects of heme oxygenase-1(HO-1) against oxidant-induced injury caused by bile duct ligation (BDL).METHODS: Either cobalt protoporphyrin (CoPP), a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis.Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and cytokine and collagen- Ⅰα (Col- Ⅰα) mRNA expression was detected using RNase protection assays.RESULTS: Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly,enzyme release was not reduced in rats receiving CoPP.Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius redpositive areas were increased to about 11.7% after BDL.Collagen- Ⅰα and TGF-β mRNA increased significantly by BDL. Again, this effect was increased by HO-1overexpression.CONCLUSION: Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.

  17. Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Emma Folch-Puy

    2016-05-01

    Full Text Available The endoplasmic reticulum (ER is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS. This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR, which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.

  18. Hepatoprotective role of ganoderma lucidum polysaccharide against BCG-induced immune liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Guo-Liang Zhang; Ye-Hong Wang; Wei Ni; Hui-Ling Teng; Zhi-Bin Lin

    2002-01-01

    AIM: To examine the effect of ganoderma lucidumpolysaccharide (GLP) on the immune liver injuryinduced by BCG infection, and investigate therelationship between degrees of hepatic damage andNO production in mice.METHODS: Immune hepatic injury was markedlyinduced by BCG-pretreatment (125 mg.kg-1, 2-week, iv)or by BCG-pretreatment plus lipopolysaccharide (LPS,125 μg.kg-1, 12-hour, iv) in mice in vivo.Hepatocellulardamage induced by BCG-pretreated plus inflammatorycytokines mixture (CM), which was included TNF-α, IL1β, IFN-γ and LPS in culture medium in vitro.Administration of GLP was performed by oral orincubating with culture medium at immune stimulisimultaneity. Liver damage was determined by activityof alanine aminotransferase (ALT) in serum and inhepatocytes cultured supernatant, by liver weightchanges and histopathological examination. NOproduction in the cultured supematant was determinedby the Griess reaction. Moreover, inducible nitric oxidesynthase (iNOS) protein expression was alsoexaminated by immunohistochemi1cal method.RESULTS: Immune hepatic injury was markedly inducedby BCG or BCG plus inflammatory cytokines in BALB/cmice in vivoand in vitro. Under BCG-stimulated condition,augment of the liver weight and increase of the serum/supernatant ALT level were observed, as well asgranuloma forming and inflammatory cells soakage wereobserved by microscopic analysis within liver tissues.Moreover, NO production was also increased by BCG or/and CH stimuli in the culture supernatant, and a lot ofiNOS positive staining was observed in BCG-prestimulated hepatic sections. Application of GLPsignificantly mitigated hepatic tumefaction, decreasedALT enzyme release and NO production in serum/supernatant, improved the pathological changes ofchronic and acute inflammation induced by BCG-stimuliin mice. Moreover, the immunohistochemical resultshowed that GLP inhibited iNOS protein expression inBCG-immune hepatic damage model.CONCLUSION: The present study indicates that

  19. ADVANCED LIVER INJURY IN PATIENTS WITH CHRONIC HEPATITIS B AND VIRAL LOAD BELOW 2,000 IU/mL

    Science.gov (United States)

    de OLIVEIRA, Valter Oberdan Borges; OLIVEIRA, Juliana Passos Rocha; de FRANÇA, Eloy Vianey Carvalho; BRITO, Hugo Leite de Farias; NASCIMENTO, Tereza Virgínia; FRANÇA, Alex

    2016-01-01

    SUMMARY Introduction: According to the guidelines, the viral load of 2,000 IU/mL is considered the level to differentiate between inactive carriers and HBeAg(-) chronic hepatitis B patients. Even so, liver damage may be present in patients with lower viral load levels, mainly related to regional variations. This study aims to verify the presence of liver injury in patients with viral load below 2,000 IU/mL. Methods: Patients presenting HBsAg(+) for more than six months, Anti-HBe(+)/HBeAg(-), viral load below 2,000 IU/mL and serum ALT levels less than twice the upper limit of normality underwent liver biopsy. Clinical and laboratory characteristics were evaluated in relation to the degree of histologic alteration. Liver injury was considered advanced when F ≥ 2 and/or A ≥ 2 by the METAVIR classification. Results: 11/27 (40.7%) patients had advanced liver injury, with a mean viral load of 701.0 (± 653.7) IU/mL versus 482.8 (± 580.0) IU/mL in patients with mild injury. The comparison between the mean values of the two groups did not find a statistical difference (p = 0.37). The average of serum aminotransferases was not able to differentiate light liver injury from advanced injury. Conclusions: In this study, one evaluation of viral load did not exclude the presence of advanced liver damage. Pathologic assessment is an important tool to diagnose advanced liver damage and should be performed in patients with a low viral load to indicate early antiviral treatment. PMID:27680170

  20. ADVANCED LIVER INJURY IN PATIENTS WITH CHRONIC HEPATITIS B AND VIRAL LOAD BELOW 2,000 IU/mL

    Directory of Open Access Journals (Sweden)

    Valter Oberdan Borges de OLIVEIRA

    Full Text Available SUMMARY Introduction: According to the guidelines, the viral load of 2,000 IU/mL is considered the level to differentiate between inactive carriers and HBeAg(- chronic hepatitis B patients. Even so, liver damage may be present in patients with lower viral load levels, mainly related to regional variations. This study aims to verify the presence of liver injury in patients with viral load below 2,000 IU/mL. Methods: Patients presenting HBsAg(+ for more than six months, Anti-HBe(+/HBeAg(-, viral load below 2,000 IU/mL and serum ALT levels less than twice the upper limit of normality underwent liver biopsy. Clinical and laboratory characteristics were evaluated in relation to the degree of histologic alteration. Liver injury was considered advanced when F ≥ 2 and/or A ≥ 2 by the METAVIR classification. Results: 11/27 (40.7% patients had advanced liver injury, with a mean viral load of 701.0 (± 653.7 IU/mL versus 482.8 (± 580.0 IU/mL in patients with mild injury. The comparison between the mean values of the two groups did not find a statistical difference (p = 0.37. The average of serum aminotransferases was not able to differentiate light liver injury from advanced injury. Conclusions: In this study, one evaluation of viral load did not exclude the presence of advanced liver damage. Pathologic assessment is an important tool to diagnose advanced liver damage and should be performed in patients with a low viral load to indicate early antiviral treatment.

  1. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model.

    Science.gov (United States)

    Heijnen, B H M; Straatsburg, I H; Padilla, N D; Van Mierlo, G J; Hack, C E; Van Gulik, T M

    2006-01-01

    Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 100, 200 or 400 IU/kg bodyweight, 5 min before 60 min ischaemia (pre-I) or 5 min before 24 h reperfusion (end-I). One hundred IU/kg bodyweight significantly reduced the increase of plasma levels of activated C4 as compared to albumin-treated control rats and attenuated the increase of alanine aminotransferase (ALT). These effects were not better with higher doses of C1-inh. Administration of C1-inh pre-I resulted in lower ALT levels and higher bile secretion after 24 h of reperfusion than administration at end-I. Immunohistochemical assessment indicated that activated C3, the membrane attack complex C5b9 and C-reactive protein (CRP) colocalized in hepatocytes within midzonal areas, suggesting CRP is a mediator of I/R-induced, classical complement activation in rats. Pre-ischaemic administration of C1-inh is an effective pharmacological intervention to protect against liver I/R injury.

  2. Blood oxygenation during hyperpressure intraperitoneal fluid administration in a rabbit model of severe liver injury: Evaluation of a novel concept for control of pre-hospital liver bleeding.

    Science.gov (United States)

    Ahmadi-Noorbakhsh, Siavash; Azizi, Saeed; Dalir-Naghadeh, Bahram; Maham, Masoud

    2012-01-01

    Oxygen is an essential part of the most important metabolic pathways in aerobic organisms. Oxygen delivery is merely dependent on blood, rendering blood loss a devastating event. Traumatic pre-hospital liver bleeding is a major cause of early trauma deaths in human and animals, with no established therapeutic method yet. Increasing intra-abdominal pressure (IAP) has been shown to reduce liver bleeding by half. Although reduction of blood loss could be in favor of blood oxygen delivery, however, the complex interaction between increased IAP and respiratory mechanics during severe hemorrhagic shock remained unclear. We used a novel model of liver trauma in 16 rabbits and randomly assigned them to either normotensive abdomen group or increased IAP by fluid infusion (HA) groups (n=8 each). Liver size and the amount of liver injury were evaluated. Various blood oxygenation parameters were recorded. Both groups were identical in terms of the liver size and injury. The HA group had significantly lower shock index. Arterial oxygen capacity and oxygen content were higher in the HA group. No significant statistical difference was seen between groups in terms of abdominal perfusion pressure; alveolar pressure of oxygen; dissolved oxygen in blood plasma; alveolar to arterial oxygen tension gradient; arterial to alveolar oxygen pressure ratio; the ratio between partial pressure of arterial oxygen and fraction of inspired oxygen; and respiratory index. In conclusion, the novel therapeutic method of increasing IAP by fluid infusion in a rabbit model of liver hemorrhage preserved blood oxygenation better than the classic therapeutic method.

  3. Blood oxygenation during hyperpressure intraperitoneal fluid administration in a rabbit model of severe liver injury: Evaluation of a novel concept for control of pre-hospital liver bleeding

    Directory of Open Access Journals (Sweden)

    Siavash Ahmadi-Noorbakhsh

    2012-06-01

    Full Text Available Oxygen is an essential part of the most important metabolic pathways in aerobic organisms. Oxygen delivery is merely dependent on blood, rendering blood loss a devastating event. Traumatic pre-hospital liver bleeding is a major cause of early trauma deaths in human and animals, with no established therapeutic method yet. Increasing intra-abdominal pressure (IAP has been shown to reduce liver bleeding by half. Although reduction of blood loss could be in favor of blood oxygen delivery, however, the complex interaction between increased IAP and respiratory mechanics during severe hemorrhagic shock remained unclear. We used a novel model of liver trauma in 16 rabbits and randomly assigned them to either normotensive abdomen group or increased IAP by fluid infusion (HA groups (n=8 each. Liver size and the amount of liver injury were evaluated. Various blood oxygenation parameters were recorded. Both groups were identical in terms of the liver size and injury. The HA group had significantly lower shock index. Arterial oxygen capacity and oxygen content were higher in the HA group. No significant statistical difference was seen between groups in terms of abdominal perfusion pressure; alveolar pressure of oxygen; dissolved oxygen in blood plasma; alveolar to arterial oxygen tension gradient; arterial to alveolar oxygen pressure ratio; the ratio between partial pressure of arterial oxygen and fraction of inspired oxygen; and respiratory index. In conclusion, the novel therapeutic method of increasing IAP by fluid infusion in a rabbit model of liver hemorrhage preserved blood oxygenation better than the classic therapeutic method.

  4. Protective effect of Cordyceps militaris polypeptide against acute alcoholic liver injury in rats

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    CAI Qi

    2016-04-01

    Full Text Available ObjectiveTo investigate the protective effect of Cordyceps militaris polypeptide against acute alcoholic liver injury in rats and related mechanism. MethodsA total of 60 Wistar rats were randomly divided into blank control group, model group, and low-, medium-, and high-dose Cordyceps militaris polypeptide groups. All rats except those in the blank control group were given 10 ml/kg 56° liquor by gavage once a day; the rats in the blank control group were given distilled water of the same dose by gavage once a day. At 1 hour after gavage with liquor, the rats in the model group and low-, medium-, and high-dose Cordyceps militaris polypeptide groups were given distilled water or Cordyceps militaris polypeptide solution (6 ml/kg by gavage. Blood samples were collected from the orbit 4 weeks later. The serum levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST and the activity of superoxide dismutase (SOD and level of malondialdehyde (MDA in the liver were measured for each group, and the pathological changes in the liver were observed under a light microscope. Analysis of variance was applied for comparison between multiple groups, and the SNK-q test was applied for comparison between any two groups. ResultsCompared with the model group, the low-, medium-, and high-dose Cordyceps militaris polypeptide groups showed significant reductions in the serum levels of ALT and AST and the level of MDA in the liver (all P<0.05, as well as a significant increase in the activity of SOD in the liver (all P<0.05, while these indices showed significant differences between the low-, medium-, and high-dose Cordyceps militaris polypeptide groups (all P<0.05. The liver pathological sections from the low-, medium-, and high-dose Cordyceps militaris polypeptide groups showed alleviated hepatocyte fatty degeneration and necrosis induced by alcohol under a light microscope. ConclusionCordyceps militaris polypeptide has a protective effect

  5. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

    Science.gov (United States)

    Vliegenthart, A D B; Shaffer, J M; Clarke, J I; Peeters, L E J; Caporali, A; Bateman, D N; Wood, D M; Dargan, P I; Craig, D G; Moore, J K; Thompson, A I; Henderson, N C; Webb, D J; Sharkey, J; Antoine, D J; Park, B K; Bailey, M A; Lader, E; Simpson, K J; Dear, J W

    2015-10-22

    Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

  6. Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice.

    Science.gov (United States)

    McVicker, Benita L; Thiele, Geoffrey M; Casey, Carol A; Osna, Natalia A; Tuma, Dean J

    2013-05-01

    T cell activation and associated pro-inflammatory cytokine production is a pathological feature of inflammatory liver disease. It is also known that liver injury is associated with marked impairments in the function of many hepatic proteins including a hepatocyte-specific binding protein, the asialoglycoprotein receptor (ASGPR). Recently, it has been suggested that hepatic ASGPRs may play an important role in the physiological regulation of T lymphocytes, leading to our hypothesis that ASGPR defects correlate with inflammatory-mediated events in liver diseases. Therefore, in this study we investigated whether changes in hepatocellular ASGPR expression were related to the dysregulation of intrahepatic T lymphocytes and correlate with the development of T-cell mediated hepatitis. Mice lacking functional ASGPRs (receptor-deficient, RD), and wild-type (WT) controls were intravenously injected with T-cell mitogens, Concanavalin A (Con A) or anti-CD3 antibody. As a result of T cell mitogen treatment, RD mice lacking hepatic ASGPRs displayed enhancements in liver pathology, transaminase activities, proinflammatory cytokine expression, and caspase activation compared to that observed in normal WT mice. Furthermore, FACS analysis demonstrated that T-cell mitogen administration resulted in a significant rise in the percentage of CD8+ lymphocytes present in the livers of RD animals versus WT mice. Since these two mouse strains differ only in whether they express the hepatic ASGPR, it can be concluded that proper ASGPR function exerts a protective effect against T cell mediated hepatitis and that impairments to this hepatic receptor could be related to the accumulation of cytotoxic T cells that are observed in inflammatory liver diseases.

  7. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

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    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  8. Hepatoprotective effects of baicalein against CCl4-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai-Li Huang; Ya-Jing Wang; Qing-Yu Zhang; Bin Liu; Fang-Yuan Wang; Jing-Jing Li; Run-Zhi Zhu

    2012-01-01

    AIM:To investigate the hepatoprotective effect of baicalein against carbon tetrachloride (CCl4)-induced liver damage in mice.METHODS:Mice were orally administered with baicalein after CCl4 injection,and therapeutic baicalein was given twice a day for 4 d.The anti-inflammation effects of baicalein were assessed directly by hepatic histology and serum alanine aminotranferease and aspartate aminotransferase measurement.Proliferating cell nuclear antigen was used to evaluate the effect of baicalein in promoting hepatocyte proliferation.Serum interleukin (IL)-6,IL-1β and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay and liverIL-6,TNF-α,transforming growth factor-α (TGF-α),hepatocyte growth factor (HGF) and epidermal growth factor (EGF) genes expression were determined by quantitative real-time polymerase chain reaction.RESULTS:CCl4-induced acute liver failure model offers a survival benefit in baicalein-treated mice.The data indicated that the mRNA levels of IL-6 and TNF-α significantly increased within 12 h after CCl4 treatment in baicalein administration groups,but at 24,48 and 72h,the expression of IL-6 and TNF-α was kept at lower levels compared with the control.The expression of TGF-α,HGF and EGF was enhanced dramatically in baicalein administration group at 12,24,48 and 72 h.Furthermore,we found that baicalein significantly elevated the serum level of TNF-α and IL-6 at the early phase,which indicated that baicalein could facilitate the initiating events in liver regeneration.CONCLUSION:Baicalein may be a therapeutic candidate for acute liver injury.Baicalein accelerates liver regeneration by regulating TNF-α and IL-6 mediated pathways.

  9. Immunohistochemical Analysis of Platelet Extract Effects on Liver Injury Induced by CCl4 in Male Rats

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    Zahra Hesami

    2016-01-01

    Full Text Available Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4, we used immunohistochemical analysis in male rats. Methods: In this project the 28 male Wistar rats (250-300 g were randomly divided into 4 groups, each consisting of 7 animals. The rats were divided into four experimental groups as follows: the first group (sham intraperitoneally received only olive oil as the solvent of carbon tetrachloride; second group (CCl4 intraperitoneally received carbon tetrachloride dissolved in olive oil (ratio of about 1: 1 at a concentration of 1 ml/kg and a twice a week for eight weeks; third group subcutaneously received only platelet extract at a concentration of 0.5 ml/kg twice a week for three weeks; and fourth group received both CCl4 intraperitoneally for eight weeks and platelet extract subcutaneously for last three weeks. After 8 weeks of trial blood and liver sampling were done. Blood samples sent for enzymatic (AST, ALT tests and liver samples tested for histological and immunohistochemical studies. The data were analyzed using  one-way ANOVA followed by Tukey test by Graph pad Prism 5 software and data were considered significant at p≤ 0.05. Results: The results show that platelet extract causes a significant (p≤ 0.001 decrease in liver enzymes and albumin improves the function of liver. The level of alfa smooth muscle actin (α-SMA as an index of hepatic stellate cell activation was decreased by platelet extract administration which eventually reduced the necrosis and fibrosis induced by carbon tetrachloride in studied rats

  10. A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis

    Directory of Open Access Journals (Sweden)

    Thomas B

    2016-12-01

    Full Text Available Binny Thomas,1-3 Mahmoud Mohamed,1,3,4 Moza Al Hail,1-3 Fatma Alzahra Y Awwad,1 Ramy M Wahba,1 Sabir B Hassan,1 Khalid Omar,1 Wessam El Kassem,1 Palivalappila Abdul Rouf1 1Hamad Medical Corporation, Doha, Qatar; 2Robert Gordon University, Aberdeen, Scotland, UK; 3Qatar University, Doha, 4Weill Cornell Medical College, Ar-Rayyan, Qatar Abstract: We report a case of 22-year-old primigravida presented to Women’s Hospital – Hamad Medical Corporation emergency with severe epigastric pain, nausea, and vomiting. On admission, she was dehydrated with remarkably worsening symptoms. Laboratory findings revealed significantly elevated liver enzymes with unknown etiology. Her past medical history showed an admission for nausea and vomiting 3 weeks previously and she was discharged on antiemetics, and esomeprazole for the first time. Due to the predominantly elevated liver enzymes, the clinical pharmacist discussed the possibility of esomeprazole-induced adverse effects and suggested to suspend esomeprazole based on the evidence from literature review. The liver enzymes showed a substantial improvement within days after the discontinuation of the drug; however, a rechallenge was not done since it could have adversely affected the mother or the fetus. Using the Naranjo Adverse Drug Reaction Probability scales, the adverse reaction due to esomeprazole was classified as “probably”. Keywords: hyperemesis, drug-induced liver injury, esomeprazole, adverse drug reaction, ADR, proton pump inhibitor

  11. Involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis

    Institute of Scientific and Technical Information of China (English)

    Natalia A Osna; Paul G Thomes; Terrence M Donohue Jr

    2011-01-01

    This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracellular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers.

  12. Metabolomic Characterizations of Liver Injury Caused by Acute Arsenic Toxicity in Zebrafish.

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    Caixia Li

    Full Text Available Arsenic is one of the most common metalloid contaminants in groundwater and it has both acute and chronic toxicity affecting multiple organs. Details of the mechanism of arsenic toxicity are still lacking and profile studies at metabolic level are very limited. Using gas chromatography coupled with mass spectroscopy (GC/MS, we first generated metabolomic profiles from the livers of arsenic-treated zebrafish and identified 34 significantly altered metabolite peaks as potential markers, including four prominent ones: cholic acid, glycylglycine, glycine and hypotaurine. Combined results from GC/MS, histological examination and pathway analyses suggested a series of alterations, including apoptosis, glycogenolysis, changes in amino acid metabolism and fatty acid composition, accumulation of bile acids and fats, and disturbance in glycolysis related energy metabolism. The alterations in glycolysis partially resemble Warburg effect commonly observed in many cancer cells. However, cellular damages were not reflected in two conventional liver function tests performed, Bilirubin assay and alanine aminotransferase (ALT assay, probably because the short arsenate exposure was insufficient to induce detectable damage. This study demonstrated that metabolic changes could reflect mild liver impairments induced by arsenic exposure, which underscored their potential in reporting early liver injury.

  13. Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management.

    Science.gov (United States)

    Mosedale, M; Watkins, P B

    2016-11-09

    Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

  14. Effect of ONO-4057 and tacrolimus on ischemia-reperfusion injury of the liver

    Institute of Scientific and Technical Information of China (English)

    Takayuki Takeichi; Shinji Uemoto; Sachiko Minamiguchi; Izumi Takeyoshi; Yukihiro Inomata; Koichi Tanaka; Eiji Kobayashi

    2009-01-01

    AIM: To investigate the effects of a novel Leukotriene B4 receptor antagonist and/or tacrolimus on ischemiareperfusion in a rat liver model.METHODS: Male Lewis rats were pretreated with ONO-4057 (100 mg/kg) and/or tacrolimus (1 mg/kg) orally, and divided into four experimental groups; group 1 (control), group 2 (ONO-4057), group 3 (tacrolimus),group 4 (ONO-4057 + tacrolimus).RESULTS: There was a tendency for long survival in the groups treated with tacrolimus alone and ONO-4057 plus tacrolimus. Post-reperfusion serum aspartate aminotransferase levels decreased more significantly in ONO-4057 plus tacrolimus group ( P < 0.01), than in the tacrolimus alone group ( P < 0.05), compared to controls. CONCLUSION: This study demonstrated that pretreatment with ONO-4057 in combination with tacrolimus produced additive effects in a rat model of liver ischemia- reperfusion injury.

  15. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  16. ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury.

    Science.gov (United States)

    Liao, Chia-Chih; Day, Yuan-Ji; Lee, Hung-Chen; Liou, Jiin-Tarng; Chou, An-Hsun; Liu, Fu-Chao

    2017-01-01

    Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

  17. Ethanol induced mitochondria injury and permeability transition pore opening: Role of mitochondria in alcoholic liver disease

    Institute of Scientific and Technical Information of China (English)

    Ming Yan; Ping Zhu; Hui-Min Liu; Hai-Tao Zhang; Li Liu

    2007-01-01

    AIM: To observe changes of mitochondria and investigate the effect of ethanol on mitochondrial permeability transition pore (PTP), mitochondrial membrane potential (MMP, Δψm) and intracellular calcium concentration in hepatocytes by establishing an animal model of alcoholic liver disease (ALD).METHODS: Fourty adult male Wistar rats were randomly divided into two groups, the model group (20) was administered alcohol intragastrically plus an Oliver oil diet to establish an ALD model, and the control group (20) was given an equal amount of normal saline. The ultramicrostructural changes of mitochondria were observed under electron microscopy. Mitochondria of liver was extracted, and patency of PTP, mitochondrial membrane potential (Δψm), mitochondrial mass and intracellular calcium concentration of isolated hepacytes were detected by flow cytometry using rhodamine123 (Rh123), Nonyl-Acridine Orange and calcium fluorescent probe Fluo-3/AM, respectively.RESULTS: Membrane and cristae were broken or disappeared in mitochondria in different shapes under electron microscopy. Some mitochondria showed U shape or megamitochondrion. In the model group, liver mitochondria PTP was broken, and mitochondria swelled, the absorbance at 450 nm, A540 decreased (0.0136 ± 0.0025 vs 0.0321 ± O.0013,model vs control,P<O.01);mitochondria transmembrane potential (239.4638 ± 12.7263 vs 377.5850 ± 16.8119,P<0.01) was lowered;mitochondrial mass (17.4350 ± 1.9880 vs 31.6738 ± 3.4930,P<0.01);and [Ca2+]i was increased in liver cells (7.0020 ± 0.5008 vs 10.2050 ± 0.4701,P<0.01).CONCLUSION:Chronic alcohol intake might lead to broken mitochondria PTP,decreased mitochondria membrane potential and injury,and elevated intracellular Ca2+ production.Ethanol-induced chondriosome injury may be an important mechanism of alcoholic diseases.

  18. Sulforaphane protects liver injury induced by intestinal ischemia reperfusion through Nrf2-ARE pathway

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM: To investigate the effect of sulforaphane (SFN) on regulation of NF-E2-related factor-2 (Nrf2)-antiox-idant response element (ARE) pathway in liver injury induced by intestinal ischemia/reperfusion (I/R). METHODS: Rats were divided randomly into four ex-perimental groups: control, SFN control, intestinal I/R and SFN pretreatment groups (n = 8 in each group). The intestinal I/R model was established by clamping the superior mesenteric artery for 1 h and 2 h reperfu-sion. In the SFN pretreatment group, s...

  19. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat

    OpenAIRE

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate ...

  20. Betaine inhibits Toll-like receptor 4 expression in rats with ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To test whether ethanol feeding could induce Toll-like receptor 4(TLR4)responses,assess the hepatoprotective effect of betaine and its inhibitive effect on TLR4 in animal models of alcoholic liver injury.METHODS:Forty-eight female Sprague-Dawley rats were randomly divided into four groups as control,model,low and high dose betaine groups.Except control group,all rats were fed with high fat-containing diet plus ethanol and fish oil gavages for 8 wk.Betaine was administered intragastrically after exposure...

  1. EARLY ALLOGRAFT DYSFUNCTION AND ACUTE KIDNEY INJURY AFTER LIVER TRANSPLANTATION: DEFINITIONS, RISK FACTORS AND CLINICAL SIGNIFICANCE

    Directory of Open Access Journals (Sweden)

    L. Y. Moysyuk

    2012-01-01

    Full Text Available This review discusses issues related to intensive care in recipients of transplanted liver in the early postoperative period, with an emphasis on contemporary conditions and attitudes that are specific for this group of patients. Early allograft dysfunction (EAD requires immediate diagnosis and appropriate treatment in case. The causes of the EAD and therapeutic tactics are discussed. Acute kidney injury (AKI and renal failure are common in patients after transplantation. We consider etiology, risk factors, diagnosis and treatment guidelines for AKI. The negative impact of EAD and AKI on the grafts survival and recipients is demonstrated. 

  2. Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini-infected and N-nitrosodimethylamine-treated hamsters.

    Science.gov (United States)

    Laothong, Umawadee; Pinlaor, Porntip; Boonsiri, Patcharee; Pairojkul, Chawalit; Priprem, Aroonsri; Johns, Nutjaree Pratheepawanit; Charoensuk, Lakhanawan; Intuyod, Kitti; Pinlaor, Somchai

    2013-10-01

    The human liver fluke Opisthorchis viverrini infection and N-nitrosodimethylamine (NDMA) administration induce cholangiocarcinoma (CCA) and liver injury in hamsters. Melatonin protects against liver injury and reduces the alteration of mitochondrial structure, mitochondrial membrane potential, and mitochondrial pro- and anti-apoptotic pathways in various cancer types. To investigate the chemopreventive effect of melatonin on CCA genesis and liver injury, hamsters were treated with a combination of O. viverrini infection and NDMA concurrently administered with melatonin (10 mg/kg and 50 mg/kg) for 120 days. Melatonin treatment at 50 mg/kg caused a significant reduction in liver/body weight ratios and decreased tumor volumes leading to an increase in the survival of animals. In the tumorous tissues, the high-dose melatonin reduced DNA fragmentation and mitochondrial apoptosis by inducing anti-apoptotic protein (Bcl-2) in the mitochondrial fraction and down-regulating cytochrome c, pro-apoptotic protein (Bax), and caspase-3 in tumor cytosol. Moreover, a high-dose melatonin treatment significantly increased mitochondrial antioxidant enzymes and prevented mitochondrial ultrastructure changes in the tumor. Overall, melatonin has potent chemopreventive effects in inhibiting CCA genesis and also reduces liver injury in hamster CCA, which, in part, might involve in the suppression of CCA by reducing tumor mitochondria alteration.

  3. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

    Institute of Scientific and Technical Information of China (English)

    Rolf; Teschke; Albrecht; Wolff; Christian; Frenzel; Alexander; Schwarzenboeck; Johannes; Schulze; Axel; Eickhoff

    2014-01-01

    Causality assessment of suspected drug induced liver injury(DILI) and herb induced liver injury(HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences(CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. 2014 Baishideng Publishing Group Co., Limited. All rights

  4. Prediction Model of Drug-Induced Liver Injury in Patients with Pulmonary Tuberculosis: Evaluation of the Incidence and Risk Factors

    Directory of Open Access Journals (Sweden)

    Farzaneh Dastan

    2017-03-01

    Full Text Available Introduction and objectives:Tuberculosis (TB still remains a major health concern both in developing and developed countries. The rate of the liver injury due to anti-TB drugs in developed countries has been reported up to 4%. The goal of this study is to assess the rate and risk factors for anti-tuberculosis drug-induced liver injury (DILI. Also, a model has been designed to predict DILI in patients with pulmonary tuberculosis.Methods:We conducted an observational study. The investigation was carried out in the National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran. Anti-tuberculosis drug treatment course and patients’ demographic data, medical and drug history, and social habits were extracted from their medical records. DILI was defined as an increase in serum alanine aminotransfrase (ALT or aspartate aminotransfrase (AST greater than three times of the upper limit of normal (ULN, with symptoms of liver injury, or five times of the ULN without symptoms.Results:In this study, 87 patients (33 male, 54 female, mean age 54.29±21.79 years with tuberculosis diagnosis were followed. Anti-tuberculosis induced liver injury was detected in 14 (16.1% patients. Concomitant use of hepatotoxic drugs (Isoniazid, Rifampin and Pyrazinamide and the abnormal baseline serum liver enzyme levels before the initiation of therapy were found as risk factors for anti-tuberculosis induced liver injury.Conclusion:Anti-tuberculosis induced liver injury is a major problem in tuberculosis patients which lead to treatment interruption in 14 (16.1% patients. Due to the lack of evidence regarding the mechanism of this side effect, we recommend to monitor anti-tuberculosis drug levels in order to study their probable correlations with DILI.   

  5. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury.

    Science.gov (United States)

    Tsutsui, Akemi; Nakanuma, Yasuni; Takaguchi, Kouichi; Nakamura, Satoko; Shibata, Hiroshi; Baba, Nobuyuki; Senoh, Tomonori; Nagano, Takuya; Ikeda, Hiroko

    2015-01-01

    The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated (κ = 0.60). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  6. Metallothionein (MT -I and MT-II expression are induced and cause zinc sequestration in the liver after brain injury.

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    Michael W Pankhurst

    Full Text Available UNLABELLED: Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR and enzyme-linked immunosorbent assay (ELISA with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II(-/- mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II(-/- mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. CONCLUSION: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.

  7. Hepatoprotective Effects of Total Triterpenoids and Total Flavonoids from Vitis vinifera L against Immunological Liver Injury in Mice

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    Tao Liu

    2012-01-01

    Full Text Available Suosuo grape (the fruits of Vitis vinifera L has been used for prevention and treatment of liver diseases in Uighur folk medicine in China besides its edible value. In this study, the hepatoprotective effects of total triterpenoids (VTT and total flavonoids (VTF from Suosuo grape were evaluated in Bacille-Calmette-Guerin- (BCG- plus-lipopolysaccharide- (LPS- induced immunological liver injury (ILI in mice. Various dose groups (50, 150, and 300 mg/kg of VTT and VTF alleviated the degree of liver injury of ILI mice, effectively reduced the BCG/LPS-induced elevated liver index and spleen index, hepatic nitric oxide (NO, and malondialdehyde (MDA content, increased liver homogenate alanine aminotransferase (ALT and aspartate aminotransferase (AST levels, and restored hepatic superoxide dismutase (SOD activity in ILI mice. VTT and VTF also significantly inhibited intrahepatic expression of Th1 cytokines (IFN-γ and IL-2 in ILI mice and increased intrahepatic expression of Th2 cytokines (IL-4 and IL-10. Moreover, the increased Bax/Bcl-2 ratio was significantly downregulated by VTT and VTF in liver tissue of ILI mice. These results are comparable to those of biphenyl dicarboxylate (DDB, the reference hepatoprotective agent and suggest that VTT and VTF play a protective role against immunological liver injury, which may have important implications for our understanding of the immunoregulatory mechanisms of this plant.

  8. Hepatoprotective Effects of Total Triterpenoids and Total Flavonoids from Vitis vinifera L against Immunological Liver Injury in Mice.

    Science.gov (United States)

    Liu, Tao; Zhao, Jun; Ma, Long; Ding, Yusong; Su, Deqi

    2012-01-01

    Suosuo grape (the fruits of Vitis vinifera L) has been used for prevention and treatment of liver diseases in Uighur folk medicine in China besides its edible value. In this study, the hepatoprotective effects of total triterpenoids (VTT) and total flavonoids (VTF) from Suosuo grape were evaluated in Bacille-Calmette-Guerin- (BCG-) plus-lipopolysaccharide- (LPS-) induced immunological liver injury (ILI) in mice. Various dose groups (50, 150, and 300 mg/kg) of VTT and VTF alleviated the degree of liver injury of ILI mice, effectively reduced the BCG/LPS-induced elevated liver index and spleen index, hepatic nitric oxide (NO), and malondialdehyde (MDA) content, increased liver homogenate alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and restored hepatic superoxide dismutase (SOD) activity in ILI mice. VTT and VTF also significantly inhibited intrahepatic expression of Th1 cytokines (IFN-γ and IL-2) in ILI mice and increased intrahepatic expression of Th2 cytokines (IL-4 and IL-10). Moreover, the increased Bax/Bcl-2 ratio was significantly downregulated by VTT and VTF in liver tissue of ILI mice. These results are comparable to those of biphenyl dicarboxylate (DDB, the reference hepatoprotective agent) and suggest that VTT and VTF play a protective role against immunological liver injury, which may have important implications for our understanding of the immunoregulatory mechanisms of this plant.

  9. Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury.

    Science.gov (United States)

    Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Zhai, Yuan

    2017-05-01

    Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. Copyright © 2017 by The American Association of Immunologists, Inc.

  10. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

    Energy Technology Data Exchange (ETDEWEB)

    Mosedale, Merrie [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Wu, Hong [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Kurtz, C. Lisa [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Schmidt, Stephen P. [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Adkins, Karissa, E-mail: Karissa.Adkins@pfizer.com [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Harrill, Alison H. [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); University of Arkansas for Medical Sciences, Little Rock, AR72205 (United States)

    2014-10-01

    A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis

  11. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. YKL-40 expression in CD14+ liver cells in acute and chronic injury

    Institute of Scientific and Technical Information of China (English)

    Oscar Pizano-Martínez; Vidal Delgado-Rizo; Irinea Ya(n)ez-Sánchez; Pilar Alatorre-Carranza; Alejandra Miranda-Díaz; Pablo C Ortiz-Lazareno; Trinidad García-Iglesias; Adrian Daneri-Navarro; Mónica Vázquez-Del Mercado; Mary Fafutis-Morris

    2011-01-01

    AIM: To demonstrate that CD14+ cells are an important source of the growth factor YKL-40 in acute and chronic liver damage.METHODS: Rats were inoculated with one dose of CCl4 to induce acute damage. Liver biopsies were obtained at 0, 6, 12, 24, 48 and 72 h. For chronic damage, CCl4 was administered three days per week for 6 or 8 wk. Tissue samples were collected, and cellular populations were isolated by liver digestion and purified by cell sorting. YKL-40 mRNA and protein expression were evaluated by real-time polymerase chain reaction and western blot. RESULTS: Acute liver damage induced a rapid increase of YKL-40 mRNA beginning at 12 h. Expression peaked at 24 h, with a 26-fold increase over basal levels. By 72 h however, YKL-40 expression levels had nearly returned to control levels. On the other hand, chronic damage induced a sustained increase in YKL-40 expression, with 7- and 9-fold higher levels at 6 and 8 wk, respectively. The pattern of YKL-40 expression in different subpopulations showed that CD14+ cells, which include Kupffer cells, are a source of YKL-40 after acute damage at 72 h [0.09 relative expression units (REU)] as well as after chronic injury at 6 wk (0.11 REU). Hepatocytes, in turn, accounted for 0.06 and 0.01 REU after 72 h (acute) or 6 wk (chronic), respectively. The rest of the CD14- cells (including T lymphocytes, B lymphocytes, natural killer and natural killer T cells) yielded 0.07 and 0.15 REU at 72 h and 6 wk, respectively. YKL-40 protein expression in liver was detected at 72 h as well as 6 and 8 wk, with the highest expression relative to controls (11-fold; P ≤ 0.05) seen at 6 wk. Macrophages were stimulated by lipopolysaccharide. We demonstrate that under these conditions, these cells showed maximum expression of YKL-40 at 12 h, with P < 0.05 compared with controls.CONCLUSION: Hepatic CD14+ cells are an YKL-40 mRNA and protein source in acute and chronic liver injury, with expression patterns similar to growth factors implicated

  13. [Effects of gomisin A, a lignan component of Schizandra fruits, on experimental liver injuries and liver microsomal drug-metabolizing enzymes].

    Science.gov (United States)

    Takeda, S; Maemura, S; Sudo, K; Kase, Y; Arai, I; Ohkura, Y; Funo, S; Fujii, Y; Aburada, M; Hosoya, E

    1986-02-01

    Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

  14. 他汀类药物引起的肝损害%Statin-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    邓华; 雷招宝

    2012-01-01

    他汀类药物是3-羟基3-甲基戊二酰辅酶A还原酶抑制剂,是目前临床上广泛应用的降脂药物.他汀类药物所致肝损害(SILI)无特殊临床特征,与其他药物所致肝损害类似.SILI以肝细胞型多见,胆汁淤积型不常见,混合型少见.SILI的发生机制可能与药物本身的毒性、继发性效应及免疫机制等有关.高剂量、联合用药、肝病史等是SILI的危险因素.应用他汀类药物期间发生轻度肝损害者可减小药物剂量继续使用;发生中度肝损害者应在减量的同时使用保肝药物;发生严重肝损害者则需停药并采取相应的对症治疗措施.临床医师处方他汀类药物要注意严格掌握用药剂量,加强用药期间的实验室监测,尽量避免联合用药,并应嘱咐患者加强营养、注意休息.肝病患者慎用他汀类药物.大部分患者的SILI是可逆的.%Statins are hydroxymethyl glutarate coenzyme A reductase inhibitors, which have been used widely in clinical practice as lipid-lowering drugs currently. The clinical features of statin-induced liver injury ( SILI) are not special and similar to that of other drug-induced liver injury. The hepatocellular type of SILI is more common, the cholestatic type is less common, and mixed type is rare. The mechanisms of SILI may be associated with toxicity of statins, secondary pharmacological effects of statins, immune mechanisms, and so on. The risk factors for SILI are high-dose, drug combination, a history of liver disease, etc. If the liver damage is mild, the drug dosage should be reduced and the drug is continued; if the liver damage is moderate, the drug dosage of statins should be reduced and hepatoprotective treatment should be given at the same time; if the liver damage is severe, statins should be stopped at once and symptomatic treatments should be given. During treatment with statins, clinicians should control strictly the dosage of statins, enhance laboratory monitoring, avoid

  15. Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

    Science.gov (United States)

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-10-01

    Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. Copyright © 2016 by the Research Society on Alcoholism.

  16. Pentoxifylline enhances the protective effects of hypertonic saline solution on liver ischemia reperfusion injury through inhibition of oxidative stress Pentoxifylline enhances the protective effects of hypertonic saline solution on liver ischemia reperfusion injury through inhibition of oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Vinicius Rocha-Santos; Estela RR Figueira; Joel A Rocha-Filho; Ana MM Coelho; Rafael Soraes Pinheiro; Telesforo Bacchella; Marcel CC Machado; Luiz AC D'Albuquerque

    2015-01-01

    BACKGROUND:Liver ischemia reperfusion (IR) injury trig-gers a systemic inlfammatory response and is the main cause of organ dysfunction and adverse postoperative outcomes after liver surgery. Pentoxifylline (PTX) and hypertonic saline solution (HTS) have been identiifed to have beneifcial effects against IR injury. This study aimed to investigate if the addi-tion of PTX to HTS is superior to HTS alone for the preven-tion of liver IR injury. METHODS:Male Wistar rats were allocated into three groups. Control rats underwent 60 minutes of partial liver ischemia, HTS rats were treated with 0.4 mL/kg of intravenous 7.5%NaCl 15 minutes before reperfusion, and HPTX group were treated with 7.5% NaCl plus 25 mg/kg of PTX 15 minutes be-fore reperfusion. Samples were collected after reperfusion for determination of ALT, AST, TNF-α, IL-6, IL-10, mitochondrial respiration, lipid peroxidation, pulmonary permeability and myeloperoxidase. RESULTS:HPTX signiifcantly decreased TNF-α 30 minutes after reperfusion. HPTX and HTS signiifcantly decreased ALT, AST, IL-6, mitochondrial dysfunction and pulmonary myelo-peroxidase 4 hours after reperfusion. Compared with HTS only, HPTX signiifcantly decreased hepatic oxidative stress 4 hours after reperfusion and pulmonary permeability 4 and 12 hours after reperfusion. CONCLUSION:This study showed that PTX added the beneifcial effects of HTS on liver IR injury through decreases of hepatic oxidative stress and pulmonary permeability.

  17. Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice.

    Directory of Open Access Journals (Sweden)

    Hong Zhang

    Full Text Available Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl(4 and the mechanisms involved were investigated. Intraperitoneal injection of CCl(4 (50 µl/kg resulted in a significant increase in the levels of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT and hepatic malondialdehyde (MDA, also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-α, interleukin-1 beta (IL-1β, cyclooxygenase-2 (COX-2, inducible nitric oxide synthase (iNOS and nuclearfactor-kappa B (NF-κB. On the other hand, decreased glutathione (GSH content and activities of glutathione transferase (GST, superoxide dismutase (SOD, catalase (CAT and glutathione peroxidase (GPx were observed following CCl(4 exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-β(1 were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl(4-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases.

  18. Proteomic analysis of plasma from rats following total parenteral nutrition-induced liver injury.

    Science.gov (United States)

    Tsai, Jai-Jen; Kuo, Hsing-Chun; Lee, Kam-Fai; Tsai, Tung-Hu

    2015-11-01

    Total parenteral nutrition (TPN) is provided as the primary nitrogen source to manage patients with intestinal failure who were not able to sustain themselves on enteral feeds. The most common complication of long-term TPN use is hepatitis. A proteomic approach was used to identify proteins that are differentially expressed in the plasma of rats following TPN-related acute liver injury. Six male rats were randomly assigned to either the saline infusion control group or the TPN infusion group. Our results demonstrate that TPN infusion in rats resulted in hepatic dysfunction and hepatocyte apoptosis. Five proteins that were differentially expressed between TPN infusion and normal rats were determined and validated in vivo. Fascinatingly, the proteomic differential displays, downregulated proteins included peroxiredoxin 2 (PRDX2), alpha-1-antiproteinase (A1AT), and fibrinogen gamma chain (FIBG), which were involved in oxidative stress, inflammatory respondence and cells apoptosis. After TPN infusion, two protein spots showed increased expression, namely, the glucagon receptor (GLR) protein and apolipoprotein A-1 (APOA1), which may mediate the effects of TPN administration on glycogen and lipid metabolism. In this study, proteomic analysis suggested TPN-related acute liver injury could be involved in limiting cellular protection mechanisms against oxidative stress-induced apoptosis. On the basis of the results, we also give molecular evidences replying TPN-related hepatitis.

  19. The protective effect of ENA Actimineral resource A on CCl4-induced liver injury in rats.

    Science.gov (United States)

    Hong, Il-Hwa; Ji, Hoon; Hwa, Sung-Yong; Jeong, Won-Il; Jeong, Da-Hee; Do, Sun-Hee; Kim, Ji-Min; Ki, Mi-Ran; Park, Jin-Kyu; Goo, Moon-Jung; Hwang, Ok-Kyung; Hong, Kyung-Sook; Han, Jung-Youn; Chung, Hae-Young; Jeong, Kyu-Shik

    2011-06-01

    ENA Actimineral Resource A (ENA-A) is alkaline water that is composed of refined edible cuttlefish bone and two different species of seaweed, Phymatolithon calcareum and Lithothamnion corallioides. In the present study, ENA-A was investigated as an antioxidant to protect against CCl(4)-induced oxidative stress and hepatotoxicity in rats. Liver injury was induced by either subacute or chronic CCl(4) administration, and the rats had free access to tap water mixed with 0% (control group) or 10% (v/v) ENA-A for 5 or 8 weeks. The results of histological examination and measurement of antioxidant activity showed that the reactive oxygen species production, lipid peroxidation, induction of CYP2E1 were decreased and the antioxidant activity, including glutathione and catalase production, was increased in the ENA-A groups as compared with the control group. On 2-DE gel analysis of the proteomes, 13 differentially expressed proteins were obtained in the ENA-A groups as compared with the control group. Antioxidant proteins, including glutathione S-transferase, kelch-like ECH-associated protein 1, and peroxiredoxin 1, were increased with hepatocyte nuclear factor 3-beta and serum albumin precursor, and kininogen precursor decreased more in the ENA-A groups than compared to the control group. In conclusion, our results suggest that ENA-A does indeed have some protective capabilities against CCl(4)-induced liver injury through its antioxidant function.

  20. A diet rich in cocoa attenuates N-nitrosodiethylamine-induced liver injury in rats.

    Science.gov (United States)

    Granado-Serrano, Ana Belén; Martín, María Angeles; Bravo, Laura; Goya, Luis; Ramos, Sonia

    2009-10-01

    The effects of cocoa feeding against N-nitrosodiethylamine (DEN)-induced liver injury were studied in rats. Animals were divided into five groups. Groups 1 and 2 were fed with standard and cocoa-diet, respectively. Groups 3 and 4 were injected with DEN at 2 and 4 weeks, and fed with standard and cocoa-diet, respectively. Group 5 was treated with DEN, received the standard diet for 4 weeks and then it was replaced by the cocoa-diet. DEN-induced hepatic damage caused a significant increase in damage markers, as well as a decrease in the hepatic glutathione, diminished levels of p-ERK and enhanced protein carbonyl content, caspase-3 activity and values of p-AKT and p-JNK. The cocoa-rich diet prevented the reduction of hepatic glutathione concentration and catalase and GPx activities in DEN-injected rats, as well as diminished protein carbonyl content, caspase-3 activity, p-AKT and p-JNK levels, and increased GST activity. However, cocoa administration did not abrogate the DEN-induced body weight loss and the increased levels of hepatic-specific enzymes and LDH. These results suggested that cocoa-rich diet attenuates the DEN-induced liver injury.

  1. Protective effect of prednisolone on ischemia-induced liver injury in rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To investigate the effects of prednisolone on cell membrane bleb formation, calpain μ activation and talin degradation during hepatic ischemia-reperfusion injury in rats. METHODS: The hilar area of the left lateral and median lobes of rat liver (68%) was clamped for 60 min and followed by 120 min reperfusion. Prednisolone was administered at 1.0, 3.0, or 10 mg/kg at 30 min before ischemia. In addition to biochemical and microscopic analyses, activation of calpain μ was determined using specific antibodies against the intermediate (activated) form of calpain μ. Degradation of talin was also studied by Western blotting.RESULTS: In the control and prednisolone (1.0 mg/kg) groups, serum aspartate transaminase (AST) and alanine transaminase (ALT) level were elevated, and cell membrane bleb formation was observed after 120 min of reperfusion. Moreover, calpain μ activation and talin degradation were detected. Infusion of prednisolone at 3.0 or 10 mg/kg significantly suppressed serum AST and ALT, and prevented cell membrane bleb formation. At 10 mg/kg, prednisolone markedly suppressed calpain μ activation and talin degradation. CONCLUSION: Prednisolone can suppress ischemia- reperfusion injury of the rat liver. Its cytoprotective effect is closely associated with the suppression of calpain μ activation and talin degradation.

  2. Antioxidant and protective effect of inulin and catechin grafted inulin against CCl4-induced liver injury.

    Science.gov (United States)

    Liu, Jun; Lu, Jian-feng; Wen, Xiao-yuan; Kan, Juan; Jin, Chang-hai

    2015-01-01

    In this study, the antioxidant activity and hepatoprotective effect of inulin and catechin grafted inulin (catechin-g-inulin) against carbon tetrachloride (CCl4)-induced acute liver injury were investigated. Results showed that both inulin and catechin-g-inulin had moderate scavenging activity on superoxide radical, hydroxyl radical and H2O2, as well as lipid peroxidation inhibition effect. The antioxidant activity decreased in the order of Vc > catechin >catechin-g-inulin > inulin. Administration of inulin and catechin-g-inulin could significantly reduce the elevated levels of serum aspartate transaminase, alanine transaminase and alkaline phosphatase as compared to CCl4 treatment group. Moreover, inulin and catechin-g-inulin significantly increased the levels of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione and total antioxidant capacity, whereas markedly decreased the malondialdehyde level when compared with CCl4 treatment group. Notably, catechin-g-inulin showed higher hepatoprotective effect than inulin. In addition, the hepatoprotective effect of catechin-g-inulin was comparable to positive standard of silymarin. Our results suggested that catechin-g-inulin had potent antioxidant activity and potential protective effect against CCl4-induced acute liver injury.

  3. Effects of polysaccharide from fruiting bodies of Agaricus bisporus, Agaricus brasiliensis, and Phellinus linteus on alcoholic liver injury.

    Science.gov (United States)

    Uyanoglu, Mustafa; Canbek, Mediha; van Griensven, Leo J L D; Yamac, Mustafa; Senturk, Hakan; Kartkaya, Kazım; Oglakcı, Aysegul; Turgak, Ozge; Kanbak, Gungor

    2014-06-01

    In the present study, the curative effects of crude polysaccharides (PSs) from mushrooms on the symptoms of alcoholic liver injury were investigated. PSs from Agaricus bisporus, Agaricus brasiliensis, and Phellinus linteus fruiting bodies were administered by gavage at levels of 100 mg per kg body weight per day for 7 d after the onset of the disease. The caspase-3 activity, mitochondrial membrane potential, mitochondrial outer membrane integrity of the liver tissues of sacrificed rats, and the serum alanine aminotransferase (ALT) levels were determined. In addition, light and transmission electron microscope (TEM) studies were performed for histopathological and cytological evaluations on liver sections. PSs from A. brasiliensis decreased ALT level and mitochondrial membrane potential and increased the outer membrane integrity; microscopic examinations also revealed normal hepatocytes and tissue. On the basis of our data, it can be argued that crude PSs from Agaricus brasiliensis have therapeutic potential for alcoholic liver injury.

  4. 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury.

    Science.gov (United States)

    Fullerton, Aaron M; Roth, Robert A; Ganey, Patricia E

    2013-01-15

    Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four. Mice treated with TCDD did not develop liver injury; however, TCDD pretreatment increased liver injury resulting from moderate doses of Con A (4-10 mg/kg). TCDD-pretreated mice had altered plasma concentrations of inflammatory cytokines, including interferon gamma (IFNγ), and TCDD/Con A-induced hepatotoxicity was attenuated in IFNγ knockout mice. At various times after treatment, intrahepatic immune cells were isolated, and expression of cell activation markers as well as cytolytic proteins was determined. TCDD pretreatment increased the proportion of activated natural killer T (NKT) cells and the percent of cells expressing Fas ligand (FasL) after Con A administration. In addition FasL knockout mice and mice treated with CD18 antiserum were both protected from TCDD/Con A-induced hepatotoxicity, suggesting a requirement for direct cell-cell interaction between effector immune cells and parenchymal cell targets in the development of liver injury from TCDD/Con A treatment. In summary, exposure to TCDD increased NKT cell activation and exacerbated immune-mediated liver injury induced by Con A through a mechanism involving IFNγ and FasL expression.

  5. Hepatoprotective effects of flavonoids from shekwasha (Citrus depressa) against D-galactosamine-induced liver injury in rats.

    Science.gov (United States)

    Akachi, Toshiyuki; Shiina, Yasuyuki; Ohishi, Yayoi; Kawaguchi, Takumi; Kawagishi, Hirokazu; Morita, Tatsuya; Mori, Makoto; Sugiyama, Kimio

    2010-01-01

    We attempted to isolate the constituent(s) responsible for the suppressive effect of the juice of shekwasha, a citrus produced in Okinawa Prefecture, on D-galactosamine (GalN)-induced liver injury in rats. Liver injury-suppressive activity, as assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, was found only in the fraction that was extracted with n-hexane when three fractions were added to the diet and fed to rats. Of five compounds isolated from the n-hexane-soluble fraction by silica gel column chromatography, three compounds had liver injury-suppressive effects when five compounds were singly force-fed to rats at a level of 300 mg/kg body wt 4 h before the injection with GalN. The structures of the three active compounds were determined as 3',4',5,6,7,8-hexamethoxyflavanone (citromitin), 4',5,6,7,8-pentamethoxyflavone (tangeretin) and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), which are known flavonoids mainly existing in citrus. Nobiletin, the most important compound in the n-hexane-soluble fraction, also had suppressive effects on liver injuries induced by carbon tetrachloride, acetaminophen and GalN/lipopolysaccharide (LPS) in addition to liver injury induced GalN. Nobiletin suppressed GalN/LPS-induced increases in plasma tumor necrosis factor (TNF)-alpha and nitric oxide (NO) concentrations and hepatic mRNA levels for inducible NO synthase and DNA fragmentation. These results suggest that nobiletin suppressed GalN/LPS-induced liver injury at least by suppressing the production of both TNF-alpha and NO. The results obtained here indicate that the hepatoprotective effect of shekwasha juice is mainly ascribed to several polymethoxy flavonoids included in the juice.

  6. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; Ramachandran, Anup [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Breckenridge, David G.; Liles, John T. [Department of Biology, Gilead Sciences, Inc., Foster City, CA (United States); Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-07-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is

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

    Institute of Scientific and Technical Information of China (English)

    Lei Xiang; Jing-Wang Tan; Li-Jie Huang; Lin Jia; Ya-Qian Liu; Yu-Qiong Zhao; Kai Wang; Jia-Hong Dong

    2012-01-01

    AIM:To study the effect of H2 gas on liver injury in massive hepatectomy using the Intermittent Pringle maneuver in swine.METHODS:Male Bama pigs (n =14) treated with ketamine hydrochloride and Sumianxin Ⅱ as induction drugs followed by inhalation anesthesia with 2% isoflurane,underwent 70% hepatotectomy with loss of bleeding less than 50 mL,and with hepatic pedicle occlusion for 20 min,were divided into two groups:Hydrogen-group (n =7),the pigs with inhalation of 2% hydrogen by the tracheal intubation during major hepatotectomy; Contrast-group (n =7),underwent 70% hepatotectomy without inhalation of hydrogen.Hemodynamic changes and plasma concentrations of alanine aminotransferase (ALT),aspartate aminotransferase (AST),hyaluronic acid (HA),tumor necrosis factor-α (TNF-α),interleukin-6 (IL-6),and malondialdehyde (MDA) in liver tissue were measured at pre-operation,post-hepatotectomy (PH) 1 h and 3 h.The apoptosis and proliferating cell nuclear antigen (PCNA) expression in liver remnant were evaluated at PH 3 h.Then we compared the two groups by these marks to evaluate the effect of the hydrogen in the liver injury during major hepatotectomy with the Pringle Maneuver in the swine.RESULTS:There were no significant differences in body weight,blood loss and removal liver weight between the two groups.There was no significant difference in changes of portal vein pressure between two groups at pre-operation,PH 30 min,but in hydrogen gas treated-group it slightly decrease and lower than its in Contrast-group at PH 3 h,although there were no significant difference (P =0.655).ALT and AST in Hydrogen-group was significantly lower comparing to Contrast-group (P =0.036,P =0.011,vs P =0.032,P =0.013) at PH 1 h and 3 h,although the two groups all increased.The MDA level increased between the two group at PH 1 h and 3 h.In the hydrogen gas treated-group,the MDA level was not significantly significant at pre-operation and significantly low at PH 1 h and 3 h comparing to

  8. Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.

    Directory of Open Access Journals (Sweden)

    Barbara Renga

    Full Text Available BACKGROUND: The farnesoid-x-receptor (FXR is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. PRINCIPAL FINDINGS: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTα, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. CONCLUSIONS: FXR antagonism in vivo

  9. Differences in Liver Injury and Trophoblastic Mitochondrial Damage in Different Preeclampsia-like Mouse Models

    Institute of Scientific and Technical Information of China (English)

    Yi-Wei Han; Zi Yang; Xiao-Yan Ding; Huan Yu

    2015-01-01

    Background:Preeclampsia is a multifactorial disease during pregnancy.Dysregulated lipid metabolism may be related to some preeclampsia.We investigated the relationship between triglycerides (TGs) and liver injury in different preeclampsia-like mouse models and their potential common pathways.Methods:Preeclampsia-like models (Nw-nitro-L-arginine-methyl ester [L-NAME],lipopolysaccharide [LPS],apolipoprotein C-Ⅲ [Apo] transgnic mice + L-NAME,β2 glycoprotein Ⅰ [βGPI]) were used in four experimental groups:L-NAME (LN),LPS,Apo-LN and βGPI,respectively,and controls received saline (LN-C,LPS-C,Apo-C,βGPI-C).The first three models were established in preimplantation (PI),early-,mid-and late-gestation (EG,MG and LG).βGPI and controls were injected before implantation.Mean arterial pressure (MAP),24-hour urine protein,placental and fetal weight,serum TGs,total cholesterol (TC) and pathologic liver and trophocyte changes were assessed.Results:MAP and proteinuria were significantly increased in the experimental groups.Placenta and fetal weight in PI,EP and MP subgroups were significantly lower than LP.Serum TGs significantly increased in most groups but controls.TC was not different between experimental and control groups.Spotty hepatic cell necrosis was observed in PI,EG,MG in LN,Apo-LN and βGPI,but no morphologic changes were observed in the LPS group.Similar trophoblastic mitochondrial damage was observed in every experimental group.Conclusions:Earlier preeclampsia onset causes a higher MAP and urine protein level,and more severe placental and fetal damage.Preeclampsia-like models generated by varied means lead to different changes in lipid metabolism and associated with liver injury.Trophoblastic mitochondrial damage may be the common terminal pathway in different preeclampsia-like models.

  10. The protective effects of dexmedetomidine on liver injury-induced myocardial ischemia reperfusion.

    Science.gov (United States)

    Erer, D; Ozer, A; Arslan, M; Oktar, G L; Iriz, E; Elmas, C; Zor, M H; Tatar, T; Goktas, G

    2014-01-01

    The aim of this study was to evaluate the effect of dexmedetomidine (100 µg/kg-ip) on liver injury-induced myocardial ischemia and reperfusion (IR) in rats. Twenty-four Wistar Albino rats were separated into four groups. There were four experimental groups (Group C (Control; n = 6), Group IR (ischemia-reperfusion, n = 6), Group D (Dexmedetomidine; n = 6) that underwent left thoracotomy and received ip dexmedetomidine without IR administered via 100 µg/kg ip route 30 minutes before ligating the left coronary artery, and Group IR-D (IR-Dexmedetomidine; n = 6). A small plastic snare was threaded through the ligature and placed in contact with the heart. To produce IR, a branch of the left coronary artery was occluded for 30 min followed by two hours of reperfusion. However, after the above procedure, the coronary artery was not occluded or reperfused in the control rats. At the end of the study, liver tissue was obtained for histochemical and immunohistochemical determination.Some part of tissue samples were stained with Masson-trichrome for the evaluation of ultrastructural changes and inducible nitric oxide synthase (iNOS) expression was evaluated in other part of samples for immunohistochemical examination. Histopathological changes were detected in Group IR when compared with Group C. iNOS expression was found to be increased and stronger particularly in the vascular wall, perisinusoidal space and hepatocytes around vena centralis in this group compared to the control group. Perivascular oedema was detected to be decreased in Group IR-D compared to Group IR. It was also observed that the impairment in the radial arrangement of hepatocytes significantly recovered in Group IR-D. The immunoreactivity was found to be significantly decreased in the assessment of iNOS expression in the same group when compared with Group IR. Administration of dexmedetomidine ameliorates liver injury induced by myocardial ischemia and reperfusion (Fig. 8, Ref. 33).

  11. Hepatoprotective Evaluation of Ganoderma lucidum Pharmacopuncture: In vivo Studies of Ethanol-induced Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Sun-Hee Jang

    2014-09-01

    Full Text Available Objectives: Alcohol abuse is a public issue and one of the major causes of liver disease worldwide. This study was aimed at investigating the protective effect of Ganoderma lucidum pharmacopuncture (GLP against hepatotoxicity induced by acute ethanol (EtOH intoxication in rats. Methods: Sprague-Dawley (SD rats were divided into 4 groups of 8 animals each: normal, control, normal saline pharmacopuncture (NP and GLP groups. The control, NP and GLP groups received ethanol orally. The NP and the GLP groups were treated daily with injections of normal saline and Ganoderma lucidum extract, respectively. The control group received no treatment. The rats in all groups, except the normal group, were intoxicated for 6 hours by oral administration of EtOH (6 g/kg BW. The same volume of distilled water was administered to the rats in the normal group. Two local acupoints were used: Qimen (LR14 and Taechung (LR3. A histopathological analysis was performed, and the liver function and the activities of antioxidant enzymes were assessed. Results: GLP treatment reduced the histological changes due to acute liver injury induced by EtOH and significantly reduced the increase in the alanine aminotransferase (ALT enzyme; however, it had an insignificant effect in reducing the increase in aspartate aminotransferase (AST enzyme. It also significantly ameliorated the superoxide dismutase (SOD and the catalase (CAT activities. Conclusion: The present study suggests that GLP treatment is effective in protecting against ethanol-induced acute hepatic injury in SD rats by modulating the activities of ethanol metabolizing enzymes and by attenuating oxidative stress.

  12. Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.

    Science.gov (United States)

    Song, Ming; Song, Zhenyuan; Barve, Shirish; Zhang, Jingwen; Chen, Theresa; Liu, Marcia; Arteel, Gavin E; Brewer, George J; McClain, Craig J

    2008-05-01

    Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.

  13. Chemical composition and hepatotoxic effect of Geranium schiedeanum in a thioacetamide-induced liver injury model

    Directory of Open Access Journals (Sweden)

    Juan Gayosso-De-Lucio

    2014-01-01

    Full Text Available One of the major components of some geraniums is geraniin, described by its discoverer as crystallizable tannin, well known as an excellent antioxidant, and also found in fruits such as pomegranate. Recently, natural antioxidants have attracted great attention from consumers over the world due to their lower toxicity than synthetics. But geraniin is not a stable compound, and also is difficult to obtain, that is why in the present study we obtained acetonylgeraniin from Geranium schideanum (Gs, a stable acetone condensate of geraniin. In the present study the effect of Gs acetone-water extract was studied in reference to postnecrotic liver regeneration induced by thioacetamide (TA in rats. Two months male rats were pretreated with daily dose of Gs extract for 4 days (300 mg/kg and the last day also were intraperitoneally injected with TA (6.6 mmol/kg. Samples of blood were obtained from rats at 0, 24, 48, 72 and 96 h following TA intoxication. The pre-treatment with the crude extract in the model of thioacetamide-induced hepatotoxicity in rats decreased and delayed liver injury by 66% at 24 h. This result suggests that Gs extract may be used as an alternative for reduction of liver damage. On the other hand, acute toxicity study revealed that the LD 50 value of the Gs extract is more than the dose 5000 mg/kg in rats, according to the Lorke method.

  14. Multiple treatment of propolis extract ameliorates carbon tetrachloride induced liver injury in rats.

    Science.gov (United States)

    Bhadauria, Monika; Nirala, Satendra Kumar; Shukla, Sangeeta

    2008-08-01

    Propolis, a resinous wax-like beehive product has been used as a traditional remedy for various diseases due to a variety of biological activities of this folk medicine. In the present investigation, an attempt has been made to validate hepatoprotective activity of ethanolic extract of propolis (50-400mg/kg, p.o.) against carbon tetrachloride (CCl(4,) 0.5 ml/kg, p.o.) induced acute liver injury in rats. Silymarin, a known hepatoprotective drug was used as a positive control. Administration of CCl(4) altered various diagnostically important biochemical variables. Multiple treatment of propolis significantly prevented the release of transaminases, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, urea and uric acid in serum; improved the activity of hepatic microsomal drug metabolizing enzymes, i.e., aniline hydroxylase and amidopyrine-N-demethylase; significantly inhibited lipid peroxidation and markedly enhanced glutathione in liver and kidney as well as brought altered carbohydrate contents (blood sugar and tissue glycogen), protein contents (serum, microsomal and tissue protein) and lipid contents (serum and tissue triglycerides, serum cholesterol, total and esterified cholesterol in tissue) towards control. Propolis treatment also reversed CCl(4) induced severe alterations in histoarchitecture of liver and kidney in a dose dependent manner. Hepatoprotective activity of propolis at doses of 200 and 400 mg/kg was statistically compared to silymarin and found that propolis exhibited better effectiveness than silymarin in certain parameters, concluded its hepatoprotective potential.

  15. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis

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    Nikolaos P. Karidis

    2015-01-01

    Full Text Available Chronic hepatitis C virus (HCV infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even “similar” causes, such as hepatitis B virus- (HBV- related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.

  16. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

    Science.gov (United States)

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP

  17. Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Xiao-Rong Zhou; Zuo-Jiong Gong; Pin Zhang; Xiao-Mei Sun; Shi-Hua Zheng

    2006-01-01

    AIM: To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-KB (NF-кB) and tumor necrosis factor-α (TNF-α)expression in the liver.METHODS: Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT)activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-KB p65, iNOS, eNOS and TNF-αprotein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR).RESULTS: Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-кB p65, iNOS and TNF-α protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-кB, and TNF-α mRNA expression.CONCLUSION: iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-KB and TNF-αexpression. eNOS activity is reduced, but its mRNA expression is not affected.

  18. Comparison Analysis of Dysregulated LncRNA Profile in Mouse Plasma and Liver after Hepatic Ischemia/Reperfusion Injury.

    Science.gov (United States)

    Chen, Zhenzhen; Luo, Yanjin; Yang, Weili; Ding, Liwei; Wang, Junpei; Tu, Jian; Geng, Bin; Cui, Qinghua; Yang, Jichun

    2015-01-01

    Long noncoding RNAs (LncRNAs) have been believed to be the major transcripts in various tissues and organs, and may play important roles in regulation of many biological processes. The current study determined the LncRNA profile in mouse plasma after liver ischemia/reperfusion injury (IRI) using microarray technology. Microarray assays revealed that 64 LncRNAs were upregulated, and 244 LncRNAs were downregulated in the plasma of liver IRI mouse. Among these dysregulated plasma LncRNAs, 59-61% were intergenic, 22-25% were antisense overlap, 8-12% were sense overlap and 6-7% were bidirectional. Ten dysregulated plasma LncRNAs were validated by quantitative PCR assays, confirming the accuracy of microarray analysis result. Comparison analysis between dysregulated plasma and liver LncRNA profile after liver IRI revealed that among the 308 dysregulated plasma LncRNAs, 245 LncRNAs were present in the liver, but remained unchanged. In contrast, among the 98 dysregulated liver LncRNAs after IRI, only 19 were present in the plasma, but remained unchanged. LncRNA AK139328 had been previously reported to be upregulated in the liver after IRI, and silencing of hepatic AK139328 ameliorated liver IRI. Both microarray and RT-PCR analyses failed to detect the presence of AK139328 in mouse plasma. In summary, the current study compared the difference between dysregulated LncRNA profile in mouse plasma and liver after liver IRI, and suggested that a group of dysregulated plasma LncRNAs have the potential of becoming novel biomarkers for evaluation of ischemic liver injury.

  19. PREVENTION AND TREATMENT OF ISCHEMIA-REPERFUSION INJURY IN LIVER TRANSPLANTATION-POSSIBLE WAY TO EXPAND THE DONOR POOL

    Directory of Open Access Journals (Sweden)

    D. L. Tsoy

    2013-01-01

    Full Text Available The shortage of donor organs results in the search for alternative ways to increase the donor pool. One of these is the expansion of marginal donor criteria. The use of liver grafts from donors in this group is associated with a high risk of primary non-functioning graft which lies at the basis of ischemia-reperfusion injury of the liver. In this regard, in this review, we examined the main stages of the pathogenesis of liver disturbances as well as modern methods of prevention and treatment. 

  20. Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.

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    Jody A Rule

    Full Text Available Because acute liver failure (ALF patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD subjects served as controls.Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169. PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001. Subjects with acetaminophen (APAP toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.

  1. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

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    Yiannis N Kallis

    Full Text Available Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1 is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

  2. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice.

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    Rachel P L van Swelm

    Full Text Available Drug-induced liver injury (DILI is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP. Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT values (p<0.0001. Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001, including superoxide dismutase 1 (SOD1, carbonic anhydrase 3 (CA3 and calmodulin (CaM, as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001 in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.

  3. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells.

    Science.gov (United States)

    Chen, Yi-Xing; Zeng, Zhao-Chong; Sun, Jing; Zeng, Hai-Ying; Huang, Yan-; Zhang, Zhen-Yu

    2015-07-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow-derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague-Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  4. Role of Kupffer cells in reperfusion injury in fat-loaded livers from ethanol-treated rats.

    Science.gov (United States)

    Zhong, Z; Connor, H D; Mason, R P; Qu, W; Gao, W; Lemasters, J J; Thurman, R G

    1995-12-01

    Reperfusion injury was studied in blood-free perfused livers from fat-loaded, ethanol-treated rats. Rats were pair-fed a modified Lieber-DeCarli liquid diet containing 36% calories as ethanol or isocaloric maltose-dextrin for 4 to 5 weeks. Reperfusion injury to the liver, which occurs in previously hypoxic regions upon reintroduction of oxygen, was studied in a low-flow, reflow perfusion model. Lactate dehydrogenase in effluent perfusate increased from basal levels of < 1 to 17 IU/g/h in livers from controls, whereas prior alcohol treatment elevated values to 37 IU/g/h. Pretreatment of rats with gadolinium chloride (GdCl3, 20 mg/kg i.v.), a selective Kupffer cell toxicant, minimized lactate dehydrogenase release during reperfusion to 7 to 8 IU/g/h in livers from both groups. Rates of malondialdehyde production were 144 and 166 nmol/g/h during reperfusion in control and alcohol-treated rats, respectively, but values reached only 54 and 79 nmol/g/h after GdCl3 treatment. Interestingly, a typical PBN/carbon-centered free radical adduct signal was detected in bile of livers from ethanol-treated rats, but not in controls or ethanol-treated rats given GdCl3. Portal pressure increased during the reperfusion period in livers from alcohol-treated rats, although not in controls, and GdCl3 reduced it significantly. Taken together, these data indicate that reperfusion injury is greater in fatty livers from alcohol-treated rats in a blood-free model. Inactivation of Kupffer cells minimized reperfusion injury in both control and alcohol-treated rats, most likely by diminishing lipid peroxidation thereby improving hepatic microcirculation.

  5. Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by α-lipoic acid in humans

    Institute of Scientific and Technical Information of China (English)

    Fritz Dünschede; Kirsten Erbes; Achim Kircher; Stefanie Westermann; Joachim Seifert; Arno Schad; Kempski Oliver; Alexandra K Kiemer; Junginger Theodor

    2006-01-01

    AIM:To evaluate the protective effects of preconditioning by α-lipoic acid (LA) in patients undergoing hepatic resection under inflow occlusion of the liver.METHODS:Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCl 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver.RESULTS:Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNELpositive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion.CONCLUSION:This is the first report on the potential for LA reducing ischemia/reperfusion injury (IRI) of the liver in humans who were undergoing liver surgery.Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.

  6. Risk factors for alcohol-related liver injury in the island population of China: A population-based case-control study

    Institute of Scientific and Technical Information of China (English)

    Zhe Shen; You-Ming Li; Chao-Hui Yu; Yi Shen; Lei Xu; Cheng-Fu Xu; Jin-Jin Chen; Hua Ye; Gen-Yun Xu

    2008-01-01

    AIM: To investigate the association of alcohol dose,duration of drinking and obesity with abnormal alcoholrelated liver injury indicators, the prevalence of alcoholrelated liver injury in the island population of China.METHODS: Randomized multistage stratified cluster sampling from the island population of China was used in the population-based case-control study. Then interview,physical examination, laboratory assessments and ultrasonography were done.RESULTS: Daily alcohol intake≥20 g, duration of drinking ≥ 5 years and obesity were closely related to alcohol-related liver injury (P < 0.05). The odds-ratio (OR) (95% CI) was 1.965 (1.122-3.442), 3.412 (1.789-6.507) and 1.887 (1.261-2.824), respectively. The prevalence rate of alcohol-related liver injury in ≥ 20 g daily alcohol intake group and < 20 g daily alcohol intake group was 37.14% and 12.06%, respectively. The prevalence rate of alcohol-related liver injury in ≥ 5 years drinking group and < 5 years drinking group was 34.44% and 8.53%,respectively. No significant dose-response relation was found between daily alcohol intake and abnormal alcohol-related liver injury indicators as well as between duration of drinking and abnormal alcohol-related liver injury indicators. There was no significant difference in the prevalence of alcohol-related liver injury between beer drinking group and yellow rice wine drinking group,hard liquor drinking group, multiple drinking group.CONCLUSION: The risk threshold of daily alcohol intake is 20 g and duration of drinking inducing alcohol-related liver injury 5 years in the island population of China.liver injury induced by obesity should be concerned.(c)2008 WIG. All rights reserved.

  7. IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

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    A. E. Shcherba

    2013-01-01

    Full Text Available Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury

  8. Nuclear factor-κB decoy oligodeoxynucleotides attenuates ischemia/reperfusion injury in rat liver graft

    Institute of Scientific and Technical Information of China (English)

    Ming-Qing Xu; Xiu-Rong Shuai; Mao-Lin Yan; Ming-Man Zhang; Lu-Nan Yan

    2005-01-01

    AIM: To evaluate the protective effect of NF-κB decoy oligodeoxynucleotides (ODNs) on ischemia/reperfusion (I/R) injury in rat liver graft.METHODS: Orthotopic syngeneic rat liver transplantation was performed with 3 h of cold preservation of liver graft in University of Wisconsin solution containing phosphorothioated double-stranded NF-κB decoy ODNs or scrambled ODNs. NF-κB decoy ODNs or scrambled ODNs were injected intravenously into donor and recipient rats 6 and 1 h before operation,respectively. Recipients were killed 0 to 16 h after liver graft reperfusion. NF-κB activity in the liver graft was analyzed by electrophoretic mobility shift assay (EMSA). Hepatic mRNA expression of TNF-α, IFN-γand intercellular adhesion molecule-1 (ICAM-1) were determined by semiquantitative RT-PCR. Serum levels of TNF-α and IFN-γ were measured by enzyme-linked immunosorbent assays (ELISA). Serum level of alanine transaminase (ALT) was measured using a diagnostic kit. Liver graft myeloperoxidase (MPO) content was assessed.RESULTS: NF-κB activation in liver graft was induced in a time-dependent manner, and NF-κB remained activated for 16 h after graft reperfusion. NF-κB activation in liver graft was significant at 2 to 8 h and slightly decreased at 16 h after graft reperfusion. Administration of NF-κB decoy ODNs significantly suppressed NF-κB activation as well as mRNA expression of TNF-α, IFN-γ and ICAM-1 in the liver graft. The hepatic NF-κB DNA binding activity [presented as integral optical density (IOD) value] in the NF-κB decoy ODNs treatment group rat was significantly lower than that of the I/R group rat (2.16±0.78 vs 36.78±6.35 and 3.06±0.84 vs 47.62± 8.71 for IOD value after 4 and 8 h of reperfusion, respectively, P<0.001).The hepatic mRNA expression level of TNF-α, IFN-y and ICAM-1 [presented as percent of β-actin mRNA(%)] in the NF-κBdecoy ODNs treatment group rat was significantly lower than that of the I/R group rat (8.31 ±3.48 vs 46.37±10

  9. Effect of alpha-naphthylisothiocyanate-induced liver injury on intestinal adaptation in a rat model of short bowel syndrome.

    Science.gov (United States)

    Sukhotnik, Igor; Razon, Hila; Pollak, Yulia; Hayari, Lili; Bejar, Jacob; Mogilner, Jorge G; Sylvester, Karl G

    2012-02-01

    Progressive hyperbilirubinemia and end-stage liver failure are among the most serious complications of short bowel syndrome (SBS), representing the principle cause of death in a majority of fatal cases. In the current study, we examined the effects of alpha-naphthylisothiocyanate (ANIT)-induced liver injury on intestinal adaptation in a rat model of SBS. Male rats were divided into four groups: Sham rats underwent bowel transection (n = 8), Sham liver-injury rats underwent bowel transection and IP injection of ANIT (100 mg/kg, n = 8), SBS rats underwent a 75% bowel resection, and SBS-ANIT rats underwent bowel resection and liver injury similar to group sham-ANIT (n = 8). Fourteen days after intervention, liver biopsies and intestinal samples were obtained and evaluated for liver damage and measures of intestinal adaptation. Real time PCR and Western blotting were used to determine the level of bax and bcl-2 mRNA and protein, and p-ERK protein levels. Statistical analysis was performed using the one-way ANOVA test, with p < 0.05 considered statistically significant. All ANIT-treated animals exhibited histological evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas, intense neutrophil infiltration in the liver, increased mitotic activity, Kupfer cells hyperplasia and fatty liver degeneration. ANIT-induced liver damage in bowel resected animals was associated with a significant decrease in all parameters of intestinal adaptation including bowel and mucosal weight in jejunum (twofold decrease) and ileum (twofold decrease), mucosal DNA in jejunum (fourfold decrease), mucosal protein in jejunum (threefold decrease) and ileum (threefold decrease), villus height in jejunum (38%) and ileum (34%), and crypt depth in jejunum (24%) and ileum (30%) compared to SBS animals. Both Sham-ANIT and SBS-ANIT rats demonstrated decreased enterocyte proliferation rates that were accompanied by decreased p-ERK protein

  10. Liver sinusoidai endothelial cell injury by neutrophils in rats with acute obstructive cholangitis

    Institute of Scientific and Technical Information of China (English)

    Jian-Ping Gong; Chuan-Xin Wu; Chang-An Liu; Sheng-Wei Li; Yu-Jun Shi; Xu-Hong Li; Yong Peng

    2002-01-01

    AIM: The objective of this study is to elucidate the potentialrole of poly-morphonuclear neutrophils (PMN) in thedevelopment of such a sinusoidal endothelial cell (SEC)injury during early acute obstructive cholangitis (AOC) inrats.METHODS: Twenty one Wistar rats were divided into threegroups: the AOC group, the bile duct ligated group (BDLgroup), and the sham operation group (SO group ) . Thecommon bile duct (CBD) of rats in AOC group was duallyligated and 0.2 mi of the E. coli O111 B4 (5 × 109 cfu/ml)suspension was injected into the upper segment, in BDLgroup, only the CBD was ligated and in SO group, neitherinjection of E. coil suspension nor CBD ligation was done,but the same operative procedure. Such group consisted ofseven rats, all animals were killed 6 h after the operation.Morphological changes of the liver were observed underlight and electron microscope. Expression of intercellularadhesion molecule-1 (ICAM-1) mRNA in hepatic tissue wasdetermined with reverse transcription polymerase chainreaction ( RT-PCR ). The serum levels of alanineaminotransferase (ALT) were determined with anutoanalygerand cytokine-induced neutrophil chemoattractant (ClNC)was determined by enzyme-linked immunosorbent assay( ELISA).RESULTS: Neutrophils was accumulated in the hepaticsinusoids and sinusoidal endothelial cell injury existed inAOC group. In contrast, in rats of BDL group, all thefeatures of SEC damage were greatly reduced. Expressionof ICAM- 1 mRNA in hepatic tissue in three groups were 7.54±0.82, 2.87 ± 0.34, and 1.01 ± 0.12, respectively. Therewere significant differences among three groups ( P< 0.05).The serum ClNC levels in the three groups were 188 ± 21 ng@L-1 , 94 ± 11 ng@ L-1 , and 57 ± 8 ng@ L-1 , respectively. Therewere also significant differences among the three groups ( P< 0.05). Activity of the senum ALT was 917 ± 167 nkat@ L1 , 901 ±171 nkat@ L-1, and 908 ± 164 nkat@L-1, respectively, ( P> 0.05).CONCLUSION: Hepatic SEC injury occurs earlier

  11. Global MicroRNA Expression Profiling of Mouse Livers following Ischemia-Reperfusion Injury at Different Stages.

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    Weisheng Zheng

    Full Text Available Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.

  12. Effects of polysaccharide from fruiting bodies of Agaricus bisporus, Agaricus brasiliensis, and Phenllinus linteus on alcoholic liver injury

    NARCIS (Netherlands)

    Uyanoglu, M.; Canbek, M.; Griensven, van L.J.L.D.; Yamac, M.; Senturk, H.; Kartkaya, K.; Oglakci, A.; Turgak, O.; Kanbak, G.

    2014-01-01

    In the present study, the curative effects of crude polysaccharides (PSs) from mushrooms on the symptoms of alcoholic liver injury were investigated. PSs from Agaricus bisporus, Agaricus brasiliensis, and Phellinus linteus fruiting bodies were administered by gavage at levels of 100¿mg per kg body w

  13. [Pharmacotherapeutical efficiency of the dry extract "Ce-god-5" in liver injury induced by CCl4 in white rats].

    Science.gov (United States)

    Dashinamzhilov, Zh B; Turtuev, C D

    2014-01-01

    It has been established that the complex plant remedy "Ce-god-5" possesses the marked hepatoprotective effect in liver injury induced by CCl4 in white rats. The ability to inhibit the processes of lipid peroxidation and stimulate antioxidant system of the body is a basic mechanism of hepatoprotective activity of "Ce-god-5".

  14. The risk of acute liver injury among users of antibiotic medications : a comparison of case-only studies

    NARCIS (Netherlands)

    Brauer, Ruth; Ruigómez, Ana; Klungel, Olaf; Reynolds, Robert; Feudjo Tepie, Maurille; Smeeth, Liam; Douglas, Ian

    2016-01-01

    PURPOSE: The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self-controlled case series and case-crossover study and (ii) to compare the results between the case-only studies. METHODS: For the self-controlled

  15. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...... performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 microg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase...... in AFP above 4 microg/L occurred in 158 (79%) of 201 survivors compared with 11 of 33 nonsurvivors (33%; P AFP occurred a mean of 1.0 days (range, -2 to +6 days) after peak ALT in survivors compared with 4.1 days (range, +2 to +7 days) in nonsurvivors (P

  16. Structural characterisation of algae Costaria costata fucoidan and its effects on CCl₄-induced liver injury.

    Science.gov (United States)

    Wang, Qiukuan; Song, Yuefan; He, Yunhai; Ren, Dandan; Kow, Felicia; Qiao, Zhiyong; Liu, Shu; Yu, Xingju

    2014-07-17

    Fucoidan is a well-known natural product that is commonly found in brown algae and shows a variety of activities, including immunomodulation, antioxidation, and the combat of carcinogens. The fucoidan fractions of Costaria costata, a brown algae introduced from Japan and cultured in northern China, were studied. The fucoidan fractions were extracted, separated, and purified using a combinatorial procedure consisting of enzymolysis, ethanol precipitation, and DEAE and size-exclusion chromatographies. The fundamental characteristics of the four enriched fucoidan fractions (F1-F4), such as their sulphate content and monosaccharide composition, were investigated. FTIR and NMR spectroscopy were employed to further elucidate the structural features of the four fractions. It was found that the F1-F4 fractions all showed oxidative activity against hydroxyl radicals. The bioactive effects of the fucoidan fractions on CCl4-induced liver injury suggest their potential use as ingredients for functional foods or pharmaceuticals.

  17. Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice

    Directory of Open Access Journals (Sweden)

    Bei Yang

    2014-01-01

    Full Text Available Perfluorooctanoic acid (PFOA is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day. Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice.

  18. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic.

    Science.gov (United States)

    Moreno, Luís; Sánchez-Delgado, Jordi; Vergara, Mercedes; Casas, Meritxell; Miquel, Mireia; Dalmau, Blai

    2015-12-01

    Ciprofloxacin and amoxicillin/clavulanic are two widely used antibiotics due to their high efficacy and few side effects. While the percentage of hepatotoxicity of these antibiotics is low, their frequent use has led to a progressive increase in the number of cases. Both antibiotics have been associated with a wide variety of hepatotoxic reactions, from a slight rise of transaminases to fulminant hepatitis. Once hepatotoxicity secondary to a drug appears, the first step is to discontinue the drug. Physicians may opt to administer an alternative treatment with a different chemical structure. It should be borne in mind, however, that different chemical structures may also cause recurrent drug-induced liver injuries (DILI). We present the case of a patient who consecutively developed DILI due to ciprofloxacin and amoxicillin/clavulanic.

  19. 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Fullerton, Aaron M., E-mail: fuller22@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Room 215, East Lansing, MI 48824 (United States); Roth, Robert A., E-mail: rothr@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, Food Safety and Toxicology Building, 1129 Farm Lane, Room 221, East Lansing, MI 48824 (United States); Ganey, Patricia E., E-mail: ganey@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, Food Safety and Toxicology Building, 1129 Farm Lane, Room 214, East Lansing, MI 48824 (United States)

    2013-01-15

    Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four. Mice treated with TCDD did not develop liver injury; however, TCDD pretreatment increased liver injury resulting from moderate doses of Con A (4–10 mg/kg). TCDD-pretreated mice had altered plasma concentrations of inflammatory cytokines, including interferon gamma (IFNγ), and TCDD/Con A-induced hepatotoxicity was attenuated in IFNγ knockout mice. At various times after treatment, intrahepatic immune cells were isolated, and expression of cell activation markers as well as cytolytic proteins was determined. TCDD pretreatment increased the proportion of activated natural killer T (NKT) cells and the percent of cells expressing Fas ligand (FasL) after Con A administration. In addition FasL knockout mice and mice treated with CD18 antiserum were both protected from TCDD/Con A-induced hepatotoxicity, suggesting a requirement for direct cell–cell interaction between effector immune cells and parenchymal cell targets in the development of liver injury from TCDD/Con A treatment. In summary, exposure to TCDD increased NKT cell activation and exacerbated immune-mediated liver injury induced by Con A through a mechanism involving IFNγ and FasL expression. -- Highlights: ► TCDD pretreatment sensitizes mice to Con A-induced hepatotoxicity. ► TCDD pretreatment increased concentration of IFNγ in plasma after Con A. ► Con A-induced activation of NKT cells was increased by TCDD pretreatment. ► Fas

  20. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

    2015-03-01

    Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.

  1. Inhibitor of Apoptosis Signal-Regulating Kinase 1 Protects Against Acetaminophen-induced Liver Injury

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    Xie, Yuchao; Ramachandran, Anup; Breckenridge, David G.; Liles, John T.; Lebofsky, Margitta; Farhood, Anwar; Jaeschke, Hartmut

    2015-01-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affected the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. PMID:25818599

  2. Dietary glycine blunts liver injury after bile duct ligation in rats

    Institute of Scientific and Technical Information of China (English)

    Matthias Froh; Juirgen Scholmerich; Ronald G Thurman; Zhi Zhong; Peter Walbrun; Mark Lehnert; Susanne Netter; Reiner Wiest; Lars Conzelmann; Erwin Gaibele; Claus Hellerbrand

    2008-01-01

    AIM: To investigate the effects of (dietary) glycine against oxidant-induced injury caused by bile duct ligation (BDL).METHODS: Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley (SD) rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid (DCA) in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase (LDH) activity was determined in the supernatant of cultivated hepatocytes.RESULTS: Serum alanine transaminase levels increased to about 600 U/L 1 d after BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed.CONCLUSION: These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis.

  3. Dietary glycine blunts liver injury after bile duct ligation in rats

    Science.gov (United States)

    Froh, Matthias; Zhong, Zhi; Walbrun, Peter; Lehnert, Mark; Netter, Susanne; Wiest, Reiner; Conzelmann, Lars; Gäbele, Erwin; Hellerbrand, Claus; Schölmerich, Jürgen; Thurman, Ronald G

    2008-01-01

    AIM: To investigate the effects of (dietary) glycine against oxidant-induced injury caused by bile duct ligation (BDL). METHODS: Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley (SD) rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid (DCA) in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase (LDH) activity was determined in the supernatant of cultivated hepatocytes. RESULTS: Serum alanine transaminase levels increased to about 600 U/L 1 d after BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed. CONCLUSION: These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis. PMID:18932277

  4. Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series

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    Castellote José

    2011-07-01

    Full Text Available Abstract Background Acute liver injury (ALI induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug. The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. Methods Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. Results In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8 and of 10 per million paracetamol users-year (95% CI 4.3-19.4. Conclusions Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

  5. Neonatal androgenization exacerbates alcohol-induced liver injury in adult rats, an effect abrogated by estrogen.

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    Whitney M Ellefson

    Full Text Available Alcoholic liver disease (ALD affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2 and ethanol metabolizing enzymes (cytochrome P450, CYP450 are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl, androgenized females (Andro and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood.

  6. Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

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    Kamran Qureshi

    2014-01-01

    Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

  7. Protective Effects of Salubrinal on Liver Injury in Rat Models of Brain Death

    Institute of Scientific and Technical Information of China (English)

    Tao Wang; Shui-Jun Zhang; Sheng-Li Cao; Wen-Zhi Guo; Bing Yan; Hong-Bo Fang

    2015-01-01

    Background:Previous studies have indicated that endoplasmic reticulum stress participates in and mediates liver injury and apoptosis in brain-dead (BD) rats.In this study,we observed the effect ofsalubrinal (Sal,Sigma,USA) on liver cells in BD rats and explored its relevant mechanisms.Methods:Thirty Sprague-Dawley rats were equally randomized into three groups:BD group,Sal group,and DMSO group.The BD models were established by increasing intracranial pressure in a modified,slow,and intermittent way.In the drug groups,Sal was administered l h before the induction of BD.After modeling was completed,the blood and liver samples were harvested.CHOP and Caspase-12 mRNA expression was detected using quantitative polymerase chain reaction.PKR-like ER kinase (PERK),P-eukaryotic translation initiation factor 2α (eIF2α),eIF2α,CHOP and caspase-12 expression was detected using western blotting (WB).CHOP and caspase-12 distribution and expression in liver tissues were determined using immunohistochemistry (IHC).Alanine aminotransferase and aspartate aminotransferase level were detected using an automatic biochemical analyzer.Hepatic cell apoptosis was detected using TUNEL.The results were analyzed using Quantity-one v4.62 software (Bio-Rad,USA).Results:CHOP and caspase-12 expression and PERK,eIF2α,and P-eIF2α protein expression showed no significant difference between BD group and DMSO group.Compared with BD group,Sal group had a significantly higher P-eIF2C level and a lower P-PERK level 2 h and 6 h after BD (P < 0.05).However,eIF2α expression showed no significant difference (P > 0.05).After the Sal treatment,CHOP and caspase-12 mRNA expression significantly decreased 4 h after BD (P < 0.05).WB and IHC indicated that CHOP and caspase-12 expression also significantly decreased after Sal treatment.Sal was associated with improved liver function and decreased hepatic cell apoptosis.Conclusions:Sal can significantly reduce apoptosis in hepatic cells of BD rats

  8. Serum γ-glutamyltransferase activity as an indicator of chronic liver injury in cattle with no clinical signs

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    C.N. Moreira

    2012-12-01

    Full Text Available This study aimed to determine the power of the serum aspartate aminotransferase (AST and gamma-glutamyltransferasase (GGT activities and of the albumin and cholesterol dosages for detecting hepatic histopathological injuries. A total of 220 healthy male Nelore cattle that had been extensively bred were evaluated. Blood and liver samples were collected on the day of slaughter for biochemical and histopathological tests. The results showed that the sensitivity to AST, GGT, albumin, and cholesterol tests were respectively 22.4%, 22.4%, 36%, and 37.2%. The specificity of AST, GGT, albumin, and cholesterol tests was respectively 78.8%, 90.4%, 75.6%, and 68.3%. In short, the detection of minor liver injuries through biochemical tests is limited; however, the high specificity of the GGT allows its use as an indicator of hepatic chronic injuries in cattle herds.

  9. Evaluating the effects of different fractions obtained from Gundelia tournefortii extract against carbon tetrachloride-induced liver injury in rats

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    Hossein Niknahad

    2016-03-01

    Full Text Available Xenobiotics-induced liver injury is a major challenge for clinicians and pharmaceutical industry. Hence, finding new therapeutic molecules against this complication has clinical value. The current investigation aimed to evaluate the potential protective effects of different fractions obtained from Gundelia tournefortii (GT hydroalcoholic extract in a rat model of acute hepatic injury. Male Sprague-Dawley rats (200 250 g were treated with carbon tetrachloride (CCl4 (1.5 ml/kg, i.p. Then ethanol, water, chloroform, ethyl acetate, and n-Butanol fractions of GT extract were administered. Biochemical and histopathological markers of hepatic injury were assessed, and glutathione (GSH and lipid peroxidation were monitored in liver samples. CCl4 administration caused hepatotoxicity as revealed by an increase in serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH activity, as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in CCl4 treated rats. It was found that the n butanol (200 mg/kg and the ethyl acetate (300 mg/kg fractions of GT extract protected liver against CCL4 induced damage as judged by lower AST, ALT, LDH and lipid peroxidation, prevention of tissue glutathione depletion, and alleviation of histopathological damages of liver in the extract treated animals. As n butanol and the ethyl acetate fractions of GT effectively alleviated the liver injury induced by CCl4 and provided antioxidant properties, we might be able to propose that the hepatoprotective chemicals of GT extract are present in these fractions.

  10. Effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats.

    Science.gov (United States)

    Li, Bin; Zhu, Lijie; Wu, Ting; Zhang, Jiachen; Jiao, Xinyao; Liu, Xiuying; Wang, Yanqun; Meng, Xianjun

    2015-03-01

    Alcohol-induced oxidative stress plays a crucial role in the pathological development of alcoholic liver disease. The aim of this study was to investigate the effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats. We found that the administration of triterpenoid attenuated alcohol-induced oxidative stress in multiple organs including liver. Moreover, the impaired liver function and histological changes resulted from alcohol consumption was improved by triterpenoid treatment. Finally, we found that pretreatment with triterpenoid from Schisandra chinensis to alcohol-fed rats increased the expression level of haem oxygenase-1 (HO-1) while inhibited the induction of cytochrome P-450 2E1 (CYP2E1) in liver microsomes. Further assays revealed that the microsomal activity of HO-1 was accordingly induced whereas CYP2E1 was suppressed in rats received triterpenoid intervention. Our findings suggest that triterpenoid from Schisandra chinensis may protect against alcohol-induced liver injury through ameliorating oxidative stress in rats.

  11. Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress.

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    Lv, Peng; Fan, Li-Juan; Li, Hong-Yun; Meng, Qing-Shun; Liu, Jie

    2015-01-01

    This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-κB p65 (NF-κBp65), tumor necrosis factor α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-κBp65, TNF-α, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats.

  12. Short-term starvation attenuates liver ischemia-reperfusion injury (IRI) by Sirt1-autophagy signaling in mice

    Science.gov (United States)

    Qin, Jianjie; Zhou, Junjin; Dai, Xinzheng; Zhou, Haoming; Pan, Xiongxiong; Wang, Xuehao; Zhang, Feng; Rao, Jianhua; Lu, Ling

    2016-01-01

    Calorie restriction or starvation (fasting) has some beneficial effects in terms of prolonging life and increasing resistance to stress. It has also been shown that calorie restriction has a protective role during ischemia-reperfusion injury (IRI) in several organs, but the underlying mechanism has not been elucidated. In this study we investigated the effects and molecular mechanisms of short-term starvation (STS) on liver IRI in a mouse liver IRI model. We found that STS significantly attenuated liver IRI in this model, as evidenced by inhibition of serum aminotransferase levels, and decreased pathological damage and hepatocellular apoptosis, especially after 2- or 3-day starvation. Furthermore, we found that 2- or 3-day starvation induced expression of hepatocellular autophagy in vivo and in vitro. Further experiments provided support for the notion that STS-induced autophagy played a key role during starvation-regulated protection against liver IRI via autophagy inhibition with 3-methyladenine. Interestingly, the longevity gene Sirt1 was also significantly up-regulated in liver after STS. Importantly, inhibition of Sirt1 by sirtinol abolished STS-induced autophagy and further abrogated STS-mediated protection against liver IRI. In conclusion, our results indicate that STS attenuates liver IRI via the Sirt1-autophagy pathway. Our findings provide a rationale for a novel therapeutic strategy for managing liver IRI. PMID:27648127

  13. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

    Science.gov (United States)

    Fontana, Robert J

    2014-04-01

    Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

  14. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis.

    Science.gov (United States)

    Tag, Carmen G; Sauer-Lehnen, Sibille; Weiskirchen, Sabine; Borkham-Kamphorst, Erawan; Tolba, René H; Tacke, Frank; Weiskirchen, Ralf

    2015-02-10

    In most vertebrates, the liver produces bile that is necessary to emulsify absorbed fats and enable the digestion of lipids in the small intestine as well as to excrete bilirubin and other metabolic products. In the liver, the experimental obstruction of the extrahepatic biliary system initiates a complex cascade of pathological events that leads to cholestasis and inflammation resulting in a strong fibrotic reaction originating from the periportal fields. Therefore, surgical ligation of the common bile duct has become the most commonly used model to induce obstructive cholestatic injury in rodents and to study the molecular and cellular events that underlie these pathophysiological mechanisms induced by inappropriate bile flow. In recent years, different surgical techniques have been described that either allow reconnection or reanastomosis after bile duct ligation (BDL), e.g., partial BDL, or other microsurgical methods for specific research questions. However, the most frequently used model is the complete obstruction of the common bile duct that induces a strong fibrotic response after 21 to 28 days. The mortality rate can be high due to infectious complications or technical inaccuracies. Here we provide a detailed surgical procedure for the BDL model in mice that induce a highly reproducible fibrotic response in accordance to the 3R rule for animal welfare postulated by Russel and Burch in 1959.

  15. Does Citrulline Have Protective Effects on