Home About us Contact
|
Home About us Contact | ||
|
|
||
Liver Sections (liver + section)
Selected AbstractsActivation of hepatic stellate cells after phagocytosis of lymphocytes: A novel pathway of fibrogenesis,HEPATOLOGY, Issue 3 2008Nidal Muhanna Increased CD8-T lymphocytes and reduced natural killer (NK) cells contribute to hepatic fibrosis. We have characterized pathways regulating the interactions of human hepatic stellate cells (HSCs) with specific lymphocyte subsets in vivo and in vitro. Fluorescence-activated cell sorting (FACS) was used to characterize human peripheral blood lymphocytes (PBLs) and intrahepatic lymphocytes (IHLs) obtained from healthy controls and from patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) with advanced fibrosis. Liver sections were analyzed by immunohistochemistry and confocal microscopy. To investigate in vitro interactions, PBLs from healthy controls or patients with HCV cirrhosis were co-cultured with an immortalized human HSC line (LX2 cells) or with primary HSCs. Significant alterations in lymphocyte distribution were identified in IHLs but not PBLs. The hepatic CD4/CD8 ratio and NK cells were significantly reduced in HBV/HCV patients. Expression of alpha-smooth muscle actin and infiltration of CD4, CD8, and NK cells were readily apparent in liver sections from patients with cirrhosis but not in healthy controls. Lymphocytes from each subset were in proximity to HSCs primarily within the periportal regions, and some were directly attached or engulfed. In culture, HSC activation was stimulated by HCV-derived CD8-subsets but attenuated by NK cells. Confocal microscopy identified lymphocyte phagocytosis within HSCs that was completely prevented by blocking intracellular adhesion molecule 1 (ICAM-1) and integrin molecules, or by irradiation of HSCs. LX2 knockdown of either Cdc42 or Rac1 [members of the Rho-guanosine triphosphatase (GTPase) family] prevented both phagocytosis and the activation of HSC by HCV-derived lymphocytes. Conclusion: The CD4/CD8 ratio and NK cells are significantly decreased in livers with advanced human fibrosis. Moreover, disease-associated but not healthy lymphocytes are engulfed by cultured HSCs, which is mediated by the Rac1 and Cdc42 pathways. Ingestion of lymphocytes by HSCs in hepatic fibrosis is a novel and potentially important pathway regulating the impact of lymphocytes on the course of hepatic fibrosis. (HEPATOLOGY 2008.) [source] Susceptibility to experimental biliary atresia linked to different hepatic gene expression profiles in two mouse strainsHEPATOLOGY RESEARCH, Issue 2 2010Johannes Leonhardt Aim:, To compare hepatic gene expression during the development of experimental biliary atresia (BA) in two different mouse strains. Methods:, Balb/c mice and C57Black/6 (Black/6) mice were infected with rhesus rotavirus (RRV) postpartum, clinical signs of BA and survival were noted. Liver sections were assessed for cluster of differentiation antigen (CD) 3, CD4 and CD8 expression, and the hepatic virus load was determined. Second, mice of both strains were sacrificed three days after infection. Isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0. Results:, The incidence of BA was significantly lower in Black/6 mice compared to Balb/c mice (13.5% vs. 67%, P < 0.05). The mean virus titers were higher in mice with BA compared to mice without BA. Different gene profiles three days after virus infection were noted, with differential expression of 201 genes, including those regulating apoptosis, nucleic acid binding, transport function and particularly the immune response (chemokine C-C motif ligand 2, toll-like receptor 3, CD antigen 14, chemokine (C-X-C motif) ligands 10 and 11). This correlated with a significant increase of CD4 positive cells only in Balb/c mice with BA compared to healthy mice (13.5 vs. 5.0; P < 0.05). Black/6 mice did not exhibit any significant increase of CD3 or CD4 leukocytes despite cholestasis. Conclusion:, The different susceptibility to experimental BA was associated with an increase of CD4 T-cells in the liver of Balb/c mice, which is linked to different gene profiles at the onset of bile duct obstruction. [source] Novel fibrinogen mutation ,314Thr,Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemiaLIVER INTERNATIONAL, Issue 10 2010Stephen O. Brennan Abstract Mutation in fibrinogen genes may lead to quantitative or qualitative disorders that result in bleeding, thrombosis or hepatic fibrinogen storage disease. Only three mutations in the fibrinogen , gene have been identified that cause hepatic endoplasmic reticulum storage of mutant fibrinogen. To investigate the possibility of hepatic fibrinogen storage disease in a 4-year-old male with persistently elevated serum aminotransferases and preserved synthetic function except for a prolonged INR. After informed consent, liver and blood samples were obtained. Liver sections were examined by light microscopy, anti-fibrinogen immunolabelling and electron microscopy. Purified fibrinogen was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and reverse phase high performance liquid chromatography; DNA sequencing was performed using a BigDye Terminator (v. 3.1) cycle sequencing kit. Four-year-old male with persistently elevated transaminases with an INR 1.5 but otherwise normal synthetic function. Fibrinogen activity and thrombin clotting time were abnormal at 0.47 g/L and 46 s respectively. Hepatic histological examination revealed portal inflammatory infiltrates with bridging fibrosis. Clumped eosinophilic material was observed in hepatocytes that was immunoreactive to fibrinogen antisera. Ultrastructural examination showed cytoplasmic inclusions arrayed in fingerprint-like patterns. DNA sequence analysis revealed heterozygosity for a novel ,314Thr ,Pro mutation (fibrinogen AI duPont) in the fibrinogen , gene. Protein analyses showed normal patterns of A,, B, and , chains suggesting that the variant , allele was not expressed in plasma fibrinogen. We describe only the fourth mutation to be identified, ,314Thr,Pro (fibrinogen AI duPont), giving rise to hypofibrinogenaemia and hepatic fibrinogen storage disease. [source] Identification and characterization of IgG4-associated autoimmune hepatitisLIVER INTERNATIONAL, Issue 2 2010Hobyung Chung Abstract Background: Autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) share clinical and pathological features such as high serum levels of immunoglobulin (Ig) G and autoantibodies, and lymphoplasmacytic infiltration, suggesting the presence of common immunological abnormalities. However, little is known about the possible involvement of IgG4, a hallmark of AIP, in AIH. Aims: In this study, we examined whether the IgG4 response contributes to the histopathological and clinical findings in AIH. Methods: Liver sections from 26 patients with AIH, 10 patients with primary biliary cirrhosis (PBC), three patients with primary sclerosing cholangitis (PSC) and 20 chronic hepatitis patients with hepatitis C virus (HCV) infection were immunostained for IgG4. We investigated the relationship among the histopathology, the responses to steroid therapy and the IgG4 staining. Results: Nine of the 26 liver specimens from patients with AIH showed positive staining for IgG4 whereas none of the 10 samples from patients with PBC, the three samples from patients with PSC or the 20 samples from patients with HCV hepatitis were positive. Patients with IgG4-positive AIH also showed increased serum levels of IgG. The numbers of T cells, B cells and plasma cells were significantly increased in the livers of patients with IgG4-positive AIH as compared with those patients with IgG4-negative AIH. Patients with IgG4-positive AIH also showed a marked response to prednisolone therapy. Conclusions: AIH may be classified into either an IgG4-associated type or an IgG4 non-associated type with the former showing a marked response to prednisolone treatment. [source] The liver stage of Plasmodium berghei inhibits host cell apoptosisMOLECULAR MICROBIOLOGY, Issue 3 2005Claudia Van De Sand Summary Plasmodium berghei is the causative agent of rodent malaria and is widely used as a model system to study the liver stage of Plasmodium parasites. The entry of P. berghei sporozoites into hepatocytes has extensively been studied, but little is known about parasite,host interaction during later developmental stages of the intracellular parasite. Growth of the parasite far beyond the normal size of the host cell is an important stress factor for the infected cell. Cell stress is known to trigger programmed cell death (apoptosis) and we examined several apoptotic markers in P. berghei -infected cells and compared their level of expression and their distribution to that of non-infected cells. As none of the apoptotic markers investigated were found altered in infected cells, we hypothesized that parasite infection might confer resistance to apoptosis of the host cell. Treatment with peroxide or serum deprivation induced apoptosis in non-infected HepG2 cells, whereas P. berghei -infected cells appeared protected, indicating that the parasite interferes indeed with the apoptotic machinery of the host cell. To prove the physiological relevance of these results, mice were infected with high numbers of P. berghei sporozoites and treated with tumour necrosis factor (TNF)-,/d -galactosamine to induce massive liver apoptosis. Liver sections of these mice, stained for degraded DNA, confirmed that infected cells containing viable parasites were protected from programmed cell death. However, in non-treated control mice as well as in TNF-,-treated mice a small proportion of dead intracellular parasites with degraded DNA were detected. Most hepatocytes containing dead parasites provoked an infiltration of immunocompetent cells, indicating that these cells are no longer protected from cell death. [source] Upregulation of Brain Expression of P-Glycoprotein in MRP2-deficient TR - Rats Resembles Seizure-induced Up-regulation of This Drug Efflux Transporter in Normal RatsEPILEPSIA, Issue 4 2007Katrin Hoffmann Summary:,Purpose: The multidrug resistance protein 2 (MRP2) is a drug efflux transporter that is expressed predominantly at the apical domain of hepatocytes but seems also to be expressed at the apical membrane of brain capillary endothelial cells that form the blood,brain barrier (BBB). MRP2 is absent in the transport-deficient (TR,) Wistar rat mutant, so that this rat strain was very helpful in defining substrates of MRP2 by comparing tissue concentrations or functional activities of compounds in MRP2-deficient rats with those in transport-competent Wistar rats. By using this strategy to study the involvement of MRP2 in brain access of antiepileptic drugs (AEDs), we recently reported that phenytoin is a substrate for MRP2 in the BBB. However, one drawback of such studies in genetically deficient rats is the fact that compensatory changes with upregulation of other transporters can occur. This prompted us to study the brain expression of P-glycoprotein (Pgp), a major drug efflux transporter in many tissues, including the BBB, in TR, rats compared with nonmutant (wild-type) Wistar rats. Methods: The expression of MRP2 and Pgp in brain and liver sections of TR, rats and normal Wistar rats was determined with immunohistochemistry, by using a novel, highly selective monoclonal MRP2 antibody and the monoclonal Pgp antibody C219, respectively. Results: Immunofluorescence staining with the MRP2 antibody was found to label a high number of microvessels throughout the brain in normal Wistar rats, whereas such labeling was absent in TR, rats. TR, rats exhibited a significant up-regulation of Pgp in brain capillary endothelial cells compared with wild-type controls. No such obvious upregulation of Pgp was observed in liver sections. A comparable overexpression of Pgp in the BBB was obtained after pilocarpine-induced seizures in wild-type Wistar rats. Experiments with systemic administration of the Pgp substrate phenobarbital and the selective Pgp inhibitor tariquidar in TR, rats substantiated that Pgp is functional and compensates for the lack of MRP2 in the BBB. Conclusions: The data on TR, rats indicate that Pgp plays an important role in the compensation of MRP2 deficiency in the BBB. Because such a compensatory mechanism most likely occurs to reduce injury to the brain from cytotoxic compounds, the present data substantiate the concept that MRP2 performs a protective role in the BBB. Furthermore, our data suggest that TR, rats are an interesting tool to study consequences of overexpression of Pgp in the BBB on access of drugs in the brain, without the need of inducing seizures or other Pgp-enhancing events for this purpose. [source] A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH)EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2008Jana Pachlopnik Schmid Abstract Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and is a rare and potentially fatal immune disorder associated with hemophagocytic lymphohistiocytosis (HLH). Animal models could provide assistance for better understanding the mechanisms and finding new treatments. Rab27a-deficient (ashen) mice do not spontaneously develop HLH. When injected with lymphocytic choriomeningitis virus (LCMV) strain WE, Rab27a-deficient C57BL/6 mice developed wasting disease, hypothermia, splenomegaly, cytopenia (anemia, neutropenia and thrombocytopenia), hypertriglyceridemia and increased levels of IFN-,, TNF-,, GM-CSF, IL-12, CCL5 and IL-10. Activated macrophages with hemophagocytosis were found in liver sections of these mice. Compared with perforin-deficient mice, LCMV-infected Rab27a-deficient mice showed a substantially better survival rate and slightly higher viral doses were needed to trigger HLH in Rab27a-deficient mice. This study demonstrates that LCMV-infected Rab27a-deficient C57BL/6 mice develop features consistent with HLH and, therefore, represent a murine model of HLH in human Griscelli syndrome type 2. [source] Activation of hepatic stellate cells after phagocytosis of lymphocytes: A novel pathway of fibrogenesis,HEPATOLOGY, Issue 3 2008Nidal Muhanna Increased CD8-T lymphocytes and reduced natural killer (NK) cells contribute to hepatic fibrosis. We have characterized pathways regulating the interactions of human hepatic stellate cells (HSCs) with specific lymphocyte subsets in vivo and in vitro. Fluorescence-activated cell sorting (FACS) was used to characterize human peripheral blood lymphocytes (PBLs) and intrahepatic lymphocytes (IHLs) obtained from healthy controls and from patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) with advanced fibrosis. Liver sections were analyzed by immunohistochemistry and confocal microscopy. To investigate in vitro interactions, PBLs from healthy controls or patients with HCV cirrhosis were co-cultured with an immortalized human HSC line (LX2 cells) or with primary HSCs. Significant alterations in lymphocyte distribution were identified in IHLs but not PBLs. The hepatic CD4/CD8 ratio and NK cells were significantly reduced in HBV/HCV patients. Expression of alpha-smooth muscle actin and infiltration of CD4, CD8, and NK cells were readily apparent in liver sections from patients with cirrhosis but not in healthy controls. Lymphocytes from each subset were in proximity to HSCs primarily within the periportal regions, and some were directly attached or engulfed. In culture, HSC activation was stimulated by HCV-derived CD8-subsets but attenuated by NK cells. Confocal microscopy identified lymphocyte phagocytosis within HSCs that was completely prevented by blocking intracellular adhesion molecule 1 (ICAM-1) and integrin molecules, or by irradiation of HSCs. LX2 knockdown of either Cdc42 or Rac1 [members of the Rho-guanosine triphosphatase (GTPase) family] prevented both phagocytosis and the activation of HSC by HCV-derived lymphocytes. Conclusion: The CD4/CD8 ratio and NK cells are significantly decreased in livers with advanced human fibrosis. Moreover, disease-associated but not healthy lymphocytes are engulfed by cultured HSCs, which is mediated by the Rac1 and Cdc42 pathways. Ingestion of lymphocytes by HSCs in hepatic fibrosis is a novel and potentially important pathway regulating the impact of lymphocytes on the course of hepatic fibrosis. (HEPATOLOGY 2008.) [source] Hepatocarcinogenesis in Female Mice With Mosaic Expression of Connexin32HEPATOLOGY, Issue 3 2000Oliver Moennikes Mice deficient for connexin32 (Cx32), the major gap junction forming protein in liver, are highly susceptible to hepatocarcinogenesis. Because the Cx32 gene is located on the X-chromosome, heterozygous females show mosaicism with respect to Cx32 expression; this enables their use in studying the effect of Cx32-deficiency in a mixed Cx32-plus/Cx32-minus environment in vivo. Female C3H/He mice (Cx32+/+) were crossed with Cx32-deficient C57BL/129Sv males (Cx32Y/- ) to yield F1 females heterozygous with respect to Cx32 (Cx32+/,). Patches of hepatocytes were observed in normal liver that either expressed Cx32 or failed to express the protein. The mean fraction of Cx32-negative tissue in liver was about 60% and did not change significantly with age of mice. Neoplastic liver lesions, induced in weanling mice, were identified in serial liver sections by their deficiency in glucose-6-phosphatase staining. Parallel sections were used for immunohistochemical demonstration of Cx32 protein. Smaller lesions were either homogenously Cx32-negative or showed unchanged to slightly elevated levels of Cx32 protein. There were no major differences in number and size distribution between lesions of these 2 phenotypes. In addition, larger lesions were mostly Cx32-negative but often contained embedded patches of Cx32-positive cells. Staining for the proliferation-associated nuclear antigen Ki-67 did not reveal significant differences between Cx32-negative and Cx32-positive hepatocytes in Cx32-mosaic tumors. This suggests that expression of Cx32 within a subpopulation of tumor cells does not negatively regulate their growth nor does it seem to affect the proliferation of their directly neighboring Cx32-negative counterparts. [source] Murid herpesvirus-4 induces chronic inflammation of intrahepatic bile ducts in mice deficient in gamma-interferon signallingHEPATOLOGY RESEARCH, Issue 2 2009Babunilayam Gangadharan Aim:, Infection of gamma interferon receptor defective mice with murid herpesvirus-4 also known as murine gammaherpesvirus-68 results in multi-organ fibrosis. In this paper we characterise the pathological changes occurring in the liver in this model. Methods:, Standard immunohistochemistry and in situ hybridisation techniques were used to identify the cellular changes and the presence of virus at different times post infection. Results:, In liver sections from infected gamma interferon receptor defective mice sampled on day 16 to at least day 120, 79% showed proliferating intrahepatic bile ducts associated with a chronic mononuclear cell inflammation. Only 8% of wild type mice showed similar lesions. Coincident with the inflammatory response bile duct epithelial cells were positive for arginase 1. Around day 50 post infection onwards focal fibrotic lesions appeared in approximately 30% of gamma interferon receptor defective mice resulting in destruction of intrahepatic bile ducts. In contrast to the chronic persisting inflammatory response the presence of virus infected cells were only observed between day 12,20 post-infection. Conclusion:, Infection of gamma interferon receptor defective mice with a murine gammaherpesvirus initiates a chronic persisting inflammatory response with a pathological profile similar to the human fibrotic liver disorder Primary Sclerosing Cholangitis. [source] Cholangiocyte bile salt transporters in cholesterol gallstone,susceptible and resistant inbred mouse strainsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2008Julia J Liu Abstract Background and Aim:, We investigated the dietary and gender influences on the expression and functionality of cholangiocyte bile salt transporters and development of biliary hyperplasia in cholesterol gallstone-susceptible C57L/J and resistant AKR/J mice. Methods:, C57L and AKR mice were fed chow, a lithogenic diet, or a cholic acid-containing diet for 14 days. Expression of cholangiocyte bile salt transporter proteins ASBT (SLC10A2), ILBP (FABP6), and MRP3 (ABCC3) were studied by Western blot analysis. Taurocholate uptake studies were performed using microperfusion of isolated bile duct units. The pre- and post-perfusion taurocholate concentrations were analyzed by high performance liquid chromatography. Biliary proliferation in liver sections was scored. Results:, The lithogenic diet induced ductular proliferation in C57L mice. On chow, SLC10A2 and ABCC3 were overexpressed in male and female C57L compared to AKR mice. A lithogenic diet reduced the expressions of FABP6 in both male and female C57L mice, SLC10A2 in female C57L mice, and ABCC3 in male C57L mice. These alterations in transporter expressions were not associated with changes in taurocholate uptake. The lithogenic diet induced biliary hyperplasia and reduced bile salt transporter expressions in C57L mice. Conclusions:, Although bile salt uptake was not increased in the bile duct unit, we speculate that the biliary hyperplasia on the lithogenic diet may lead to an increase in intrahepatic bile salt recycling during cholesterol cholelithogenesis. [source] Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in ratsJOURNAL OF PINEAL RESEARCH, Issue 1 2006Min Pan Abstract:, Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Oxidative stress and lipid peroxidation are key pathophysiological mechanisms in NAFLD. We investigate the preventive effects of intraperitoneal administration of melatonin (2.5, 5, 10 mg/kg, daily, respectively) in NAFLD rats induced by high-fat diets for 12 wk. Liver damage was evaluated by serological analysis, serum and hepatic lipid assay as well as hematoxylin,eosin staining in liver sections. Oxidative stress and lipid peroxidation were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver. The results showed that high-fat diet induced oxidative stress with extensive liver steatosis in rats. Melatonin (5 or 10 mg/kg) was effective in reducing hepatic steatosis and inflammation with lowering serum alanine aminotransferase, aspartate aminotransferase, and levels liver total cholesterol and triglycerides in high-fat diet rats. Moreover, melatonin (2.5, 5, 10 mg/kg) increased SOD and GSH-Px activities and the 10 mg/kg dose of melatonin reduced MDA levels in liver. This study shows that melatonin exerts protective effects against fatty liver in rats induced by high-fat diet possibly through its antioxidant actions. [source] Immunohistochemical Characterization of Hepatic Malondialdehyde and 4-Hydroxynonenal Modified Proteins During Early Stages of Ethanol-Induced Liver InjuryALCOHOLISM, Issue 6 2003Brante P. Sampey Background: Chronic ethanol consumption is associated with hepatic lipid peroxidation and the deposition or retention of aldehyde-adducted proteins postulated to be involved in alcohol-induced liver injury. The purpose of this study was to characterize hepatocellular formation of aldehyde-protein adducts during early stages of alcohol-induced liver injury. Methods: Female Sprague Dawley® rats were subjected to the intragastric administration of a low-carbohydrate/high-fat total enteral nutrition diet or a total enteral nutrition diet containing ethanol for a period of 36 days. Indexes of hepatic responses to ethanol were evaluated in terms of changes in plasma alanine aminotransferase activity, hepatic histopathologic analysis, and induction of cytochrome P-4502E1 (CYP2E1). Immunohistochemical methods were used to detect hepatic proteins modified with malondialdehyde (MDA) or 4-hydroxynonenal (4-HNE) for subsequent quantitative image analysis. Results: After 36 days of treatment, rats receiving the alcohol-containing diet displayed hepatic histopathologies characterized by marked micro- and macrosteatosis associated with only minor inflammation and necrosis. Alcohol administration resulted in a 3-fold elevation of plasma alanine aminotransferase activity and 3-fold increases (p < 0.01) in hepatic CYP2E1 apoprotein and activity. Quantitative immunohistochemical analysis revealed significant (p < 0.01) 5-fold increases in MDA- and 4-HNE modified proteins in liver sections prepared from rats treated with alcohol. The MDA- or 4-HNE modified proteins were contained in hepatocytes displaying intact morphology and were colocalized primarily with microvesicular deposits of lipid. Aldehyde-modified proteins were not prevalent in parenchymal or nonparenchymal cells associated with foci of necrosis or inflammation. Conclusions: These results suggest that alcohol-induced lipid peroxidation is an early event during alcohol-mediated liver injury and may be a sensitizing event resulting in the production of bioactive aldehydes that have the potential to initiate or propagate ensuing proinflammatory or profibrogenic cellular events. [source] The protective effects of garlic oil on acute ethanol-induced oxidative stress in the liver of miceJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 13 2008Tao Zeng Abstract BACKGROUND: Alcoholic liver disease is so serious that no effective therapies have been developed up to now. This study was conducted to elucidate the effects of garlic oil (GO) on acute ethanol-induced liver injury. Male Kun-Ming mice were orally administered GO (50, 100 or 200 mg kg,1) for 30 days and then ethanol (4.8 g kg,1). At 16 h after ethanol treatment the mice were sacrificed. Subsequent serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) levels, hepatic malondialdehyde (MDA) and glutathione (GSH) levels and antioxidant enzyme activities were measured. Histopathological examination of mouse liver sections was performed by Sudan III staining. RESULTS: GO pretreatment significantly inhibited acute ethanol-induced increase in ALT, AST, TG and MDA and decrease in GSH in a dose-dependent manner. In the three GO groups the level of GSH increased by 10.3%, 15.8% (P < 0.05) and 25.5% (P < 0.01) respectively compared with that in the ethanol group. The activities of superoxide dismutase, catalase and glutathione reductase were increased markedly in the 200 mg kg,1 GO group (P < 0.01). Histopathological examination showed fewer fat droplets in liver sections of GO-pretreated mice. CONCLUSION: GO may have protective effects against acute ethanol-induced liver injury through restoration of the GSH level and enhancement of the activities of antioxidant enzymes. Copyright © 2008 Society of Chemical Industry [source] Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitisLIVER INTERNATIONAL, Issue 6 2010Lars P. Bechmann Abstract Background & aims: Hepatocyte apoptosis is a key event in non-alcoholic steatohepatitis (NASH). We studied the effect of obesity on free fatty acid (FFA) levels, fatty acid transport proteins (FATPs) and on extrinsic and intrinsic activation of apoptosis in the liver. Methods: Liver biopsies were harvested from 52 morbidly obese patients [body mass index (BMI): 53.82±1.41; age: 45±10.50; 15 males/37 females] undergoing bariatric surgery, and were scored for NASH, evaluated for fibrosis, and investigated for intrahepatic expression of FATPs, death receptors and cytosolic apoptosis-related molecules. Findings were correlated with serum FFA levels and the degrees of intrahepatic (terminal dUTP nick end labelling) and systemic (M30) apoptosis. Results: In patients' liver sections, FATPs as well as select parameters of extrinsic and intrinsic apoptosis were found to be upregulated (CD36/FAT: × 11.56; FATP-5: × 1.33; CD95/Fas: × 3.18; NOXA: × 2.79). These findings correlated with significantly elevated serum FFAs (control: 14.72±2.32 mg/dl vs. patients: 23.03±1.24 mg/dl) and M30 levels (control: 83.12±7.46 U/L vs. patients: 212.61±22.16 U/L). We found correlations between FATPs and apoptosis mediators as well as with histological criteria of NASH and fibrosis. Conclusions: Increased FFA and FATPs are associated with extrinsically and intrinsically induced apoptosis, liver damage and fibrosis in obese patients. Thus, FATPs may offer an interesting new approach to understand and potentially intervene NASH pathogenesis. [source] Regulation of cholangiocyte proliferationLIVER INTERNATIONAL, Issue 2 2001Gene LeSage Abstract: Intrahepatic bile duct epithelial cells (i.e., cholangiocytes) are the target cells of chronic cholestatic liver diseases (i.e., cholangiopathies), which makes these cells of great interest to clinical hepatologists. This review will focus on "typical" cholangiocyte proliferation, whereas "atypical" (extension of cholangiocyte proliferation into parenchyma), and premalignant "oval" cell proliferation are reviewed elsewhere. The bile duct ligated (BDL) rat model, where most of the known mechanisms of cholangiocyte proliferation have been illustrated, was the first and remains the prototype animal model for "typical" cholangiocyte proliferation. Following a short overview of cholangiocyte functions, we briefly discuss the: (i) in vivo models [i.e., BDL (Fig. 1 and 4), chronic ,-naphthylisothiocyanate (ANIT) or bile acid feeding (Fig. 2), acute carbon tetrachloride (CCl4) feeding and partial hepatectomy; and (ii) in vitro experimental tools [e.g., purified cholangiocytes and isolated intrahepatic bile duct units (IBDU)] that are key to the understanding of the mechanisms of "typical" cholangiocyte growth. In the second part of the review, we discuss a number of potential factors or conditions [e.g., gastrointestinal hormones, nerves, estrogens, blood supply, and growth factors] as well as the intracellular mechanisms [e.g., adenosine 3,,5,-monophosphate (cAMP), and protein kinase C (PKC)] that may regulate "typical" cholangiocyte hyperplasia. Figure 1. Measurement of the number of intrahepatic bile ducts by histochemistry for ,-GT[a specific cholangiocyte marker (1, 3, 27)] in liver sections from normal rats [left] and rats that (immediately following bile duct ligation (BDL)) were infused by osmotic minipumps with 0.2% bovine serum albumin (BSA, control) [middle] or gastrin (2.5 nmol/kg/h) in 0.2% BSA [right] for 1 week. Following BDL [middle], there was a marked increase in the number of ducts as compared to normal rats [left]. Chronic gastrin infusion [right] markedly decreased the number of intrahepatic bile ducts as compared to BSA-treated BDL rats [middle]. Orig. magn., ×125. Reproduced with permission from reference (17). Figure 4. In situ immunohistochemistry for CK-19 [a cholangiocyte-specific marker (3)] in frozen liver sections n=6) from BDL [a] and BDL+vagotomy [b] rats. Note that vagotomy induced a marked decrease in the number of ducts as compared with BDL control rats. Orig. magn., ×125. Reproduced with permission from reference (11). Figure 2. In situ immunohistochemistry for cellular nuclear antigen (PCNA) in liver sections from normal rats [left] and normal rats fed 1% TC [middle] or 1% TLC [right] for 1 week. Chronic feeding of TC [middle] and TLC [right] induced a significant increase in the number of PCNA-positive cholangiocytes as compared with liver sections from normal rats [left]. Reproduced with permission from reference (7). [source] Identification of proteins to predict the molecular basis for the observed gender susceptibility in a rat model of alcoholic steatohepatitis by 2-D gel proteomicsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 20 2008Atrayee Banerjee Abstract Females are reported to be highly susceptible to alcoholic steatohepatitis (ASH) compared to the males. Although a variety of mechanisms have been proposed to explain this higher sensitivity of females, the precise mechanism is not well understood. The objective of this study was to identify changes in global protein expression in liver tissues of male and female rats with pathologically evident ASH by 2-DE (dimensional electrophoresis). ASH was induced in the SD (Sprague-Dawley) rats by feeding ethanol (EtOH) containing Lieber-DeCarli diet for 6,wk followed by a single injection of lipopolysaccharide (LPS, 10,mg/kg, i.p.). Higher liver injury in females in the ASH group as compared to the males was confirmed by HE stained liver sections. As identified by 2-DE, 22 protein-spots were differentially expressed in the females in the ASH group as compared to the males. Following identification of these proteins by MALDI-MS, they were mainly categorized into metabolism and oxidative stress-related proteins. The expression pattern of a few of these oxidative stress-related proteins like Ferritin Heavy chain (Ferritin-H chain), ER stress protein 60 (ER 60) and Heat-shock protein-60 (HSP 60) were verified by Western blotting. To conclude, the current study has identified a set of proteins that highlights potential novel mechanisms associated with higher liver injury noted in the female rat ASH model. [source] Dialysis Reduces Portal Pressure in Patients With Chronic Hepatitis CARTIFICIAL ORGANS, Issue 7 2010Sandeep Khurana Abstract The purpose of this study was to characterize changes in hepatic venous pressures in patients with chronic hepatitis C. The histology and laboratory data from patients with chronic hepatitis C who underwent a transjugular liver biopsy (TJLB) and hepatic venous pressure gradient measurement were analyzed. Portal hypertension was defined as hepatic venous pressure gradient ,6 mm Hg. A single pathologist masked to hepatic venous pressure gradient scored liver sections for inflammation and fibrosis. The patients with high-grade inflammation (relative risk [RR] 2.82, P = 0.027, multivariate analysis) and late-stage fibrosis (RR 2.81, P = 0.022) were more likely to have a hepatic venous pressure gradient ,6 mm Hg, while the patients on dialysis (RR 0.32, P = 0.01) were less likely to have a hepatic venous pressure gradient ,6 mm Hg. The patients on dialysis (n = 58) had an elevated serum blood urea nitrogen and creatinine when compared with those who were not (n = 75) (47.6 ± 3.3 and 7.98 ± 0.4 vs. 25.9 ± 2.0 and 1.66 ± 0.22 mg/dL, respectively; P < 0.001). While the hepatic venous pressure gradient increased with the rising levels of liver fibrosis in the latter group (P < 0.01), it did not change in the patients on dialysis (P = 0.41). The median hepatic venous pressure gradient was especially low in late-stage fibrosis patients on dialysis when compared with the latter group (5 vs. 10 mm Hg, P = 0.017). In patients on dialysis, serum transaminases were low across all levels of fibrosis. Twenty-three of the 92 patients with early fibrosis had a hepatic venous pressure gradient ,6 mm Hg. In patients with chronic hepatitis C, concomitant TJLB and hepatic venous pressure gradient measurement identify those who have early fibrosis and portal hypertension. Long-term hemodialysis may reduce portal pressure in these patients. [source] Effects of Embelin on Lipid Peroxidation and Free Radical Scavenging Activity against Liver Damage in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Dharmendra Singh Carbon tetrachloride (CCl4) treatment to rats has been more susceptible to peroxidative damage through production of reactive metabolites, namely trichloromethyl-free radicals (CCl?3 and/or CCl3OO?) as measured by thiobarbituric acid reactive species. After the induction of liver damage by CCl4 intoxication to rats, the concentration of lipid peroxidation was significantly (P , 0.001) higher in liver and serum, along with concomitant decrease in the levels of antioxidants and cytochrome P450 enzyme in liver as compared to vehicle controls. The activities of marker enzymes , transaminases (AST, ALT), alkaline phosphatase (ALP), ,-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) , along with the total bilirubin and total protein levels were altered significantly (P , 0.001) in the serum of CCl4 -treated rats. When these rats received embelin orally (25 mg/kg) from day 1 to day 15, peroxidative damage was minimal in both liver and serum along with effectively inducing the antioxidant potential in CCl4 -treated rats. The biochemical results were compared with the standard drug silymarin , a combination of flavonolignans of Silybum marianum and histology of liver sections. In conclusion, this study suggests that embelin acts as a natural antioxidant against hepatotoxicity induced in rats. [source] | ||||||||||||||||