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Sample records for a-induced hepatitis model

  1. Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A-induced hepatitis.

    PubMed

    Nakano, Toshiaki; Goto, Shigeru; Lai, Chia-Yun; Hsu, Li-Wen; Takaoka, Yuki; Kawamoto, Seiji; Chiang, Kuei-Chen; Shimada, Yayoi; Ohmori, Naoya; Goto, Takeshi; Sato, Shuji; Ono, Kazuhisa; Cheng, Yu-Fan; Chen, Chao-Long

    2010-04-01

    We previously demonstrated the immunosuppressive activity of anti-histone H1 autoantibody induced in experimental and clinical liver allograft tolerance. This study aimed to explore the immunological aspects of anti-histone H1 autoantibody in liver injury induced by concanavalin A (Con A). To establish a Con A-hepatitis model, 20 mg/kg Con A was intravenously injected into rats, after which liver function and histopathological analyses were performed. In this model, anti-histone H1 autoantibody was transiently induced in the sera during the natural recovery stage, 3-7 days after Con A injection. To evaluate the therapeutic significance of anti-histone H1 autoantibody, a polyclonal antibody against histone H1 was intraperitoneally injected immediately after Con A injection. We found that injection of anti-histone H1 antibody could reduce Con A-induced liver damage. Further mechanical analyses revealed that anti-histone H1 antibody altered the intracellular activation of mitogen-activated protein kinase, nuclear factor-kappaB and calcineurin via T-cell receptor signalling, suggesting that anti-histone H1 antibody may protect the liver from Con A-induced injury by inhibiting activation of effector T cells. These findings suggest that anti-histone H1 autoantibody may be a natural immune regulatory factor that protects inflamed livers suffering from autoimmune hepatitis and may lead to T-cell unresponsiveness through the selective regulation of mitogen-activated protein kinase/nuclear factor-kappaB and calcineurin signalling.

  2. Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein.

    PubMed

    Fu, Qiuxia; Yan, Shaoduo; Wang, Licui; Duan, Xiangguo; Wang, Lei; Wang, Yue; Wu, Tao; Wang, Xiaohui; An, Jie; Zhang, Yulong; Zhou, Qianqian; Zhan, Linsheng

    2016-08-04

    The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and φC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered. Next, we investigated whether the reduction in NK cells within HCV mouse livers might elicit an effect on immune-mediated liver injury. HCV mice were subjected to acute liver injury models upon ConA administration. We observed that HCV mice developed more severe ConA-induced immune-mediated hepatitis, which was dependent on the accumulated intrahepatic NK cells. Our results indicated that after the administration of ConA, NK cells not only mediated liver injury through the production of immunoregulatory cytokines (IFN-γ, TNF-α and perforin) with direct antiviral activity, but they also killed target cells directly through the TRAIL/DR5 and NKG2D/NKG2D ligand signaling pathway in HCV mice. Our findings suggest a critical role for NK cells in oversensitive liver injury during chronic HCV infection.

  3. Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells.

    PubMed

    Siegmund, Sören V; Schlosser, Monika; Schildberg, Frank A; Seki, Ekihiro; De Minicis, Samuele; Uchinami, Hiroshi; Kuntzen, Christian; Knolle, Percy A; Strassburg, Christian P; Schwabe, Robert F

    2016-01-01

    Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.

  4. Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells

    PubMed Central

    Siegmund, Sören V.; Schlosser, Monika; Schildberg, Frank A.; Seki, Ekihiro; De Minicis, Samuele; Uchinami, Hiroshi; Kuntzen, Christian; Knolle, Percy A.; Strassburg, Christian P.; Schwabe, Robert F.

    2016-01-01

    Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs. PMID:26937641

  5. Atg7 Knockdown Augments Concanavalin A-Induced Acute Hepatitis through an ROS-Mediated p38/MAPK Pathway

    PubMed Central

    Li, Xuefeng; Xie, Qing; Wu, Min

    2016-01-01

    Concanavalin A (ConA), a T-cell mitogen that induces acute autoimmune hepatitis, is widely used to model pathophysiological processes of human acute autoimmune liver disease. Although autophagy has been extensively studied in the past decade, little is known about its molecular mechanism underlying the regulation of ConA-induced acute hepatitis. In this study, we used a Cre-conditional atg7 KO mouse to investigate the effects of Atg7-associated autophagy on ConA-induced murine hepatitis. Our results demonstrated that atg7 deficiency in mice enhanced macrophage activation and increased pro-inflammatory cytokines upon ConA stimulation. Atg7 silencing resulted in accumulation of dysfunctional mitochondria, disruption of reactive oxygen species (ROS) degradation, and increase in pro-inflammatory cytokines in Raw264.7 cells. p38/MAPK and NF-κB levels were increased upon ConA induction due to Atg7 deficiency. Blocking ROS production inhibited ConA-induced p38/IκB phosphorylation and subsequent intracellular inflammatory responses. Hence, this study demonstrated that atg7 knockout in mice or Atg7 knockdown in cell culture augmented ConA-induced acute hepatitis and related cellular malfunction, indicating protective effects of Atg7 on regulating mitochondrial ROS via a p38/MAPK-mediated pathway. Collectively, our findings reveal that autophagy may attenuate macrophage-mediated inflammatory response to ConA and may be the potential therapeutic targets for acute liver injury. PMID:26939081

  6. CRISPR/Cas9 Technology Targeting Fas Gene Protects Mice From Concanavalin-A Induced Fulminant Hepatic Failure.

    PubMed

    Liang, Wei-Cheng; Liang, Pu-Ping; Wong, Cheuk-Wa; Ng, Tzi-Bun; Huang, Jun-Jiu; Zhang, Jin-Fang; Waye, Mary Miu-Yee; Fu, Wei-Ming

    2017-03-01

    Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively. The in vivo delivery of CRISPR/Cas9 could maintain liver homeostasis and protect hepatocytes from Fas-mediated cell apoptosis in the fulminant hepatic failure model. Our study indicates the clinical potential of developing the CRISPR/Cas9 system as a novel therapeutic strategy to rescue Concanavalin-A-induced fulminant hepatic failure in the mouse model. J. Cell. Biochem. 118: 530-536, 2017. © 2016 Wiley Periodicals, Inc.

  7. Protective effect of galangin in Concanavalin A-induced hepatitis in mice.

    PubMed

    Luo, Qingqiong; Zhu, Liping; Ding, Jieying; Zhuang, Xing; Xu, Lili; Chen, Fuxiang

    2015-01-01

    Galangin is an active pharmacological ingredient from propolis and Alpinia officinarum Hance, and has been reported to have anti-inflammatory and antioxidative properties. The present study aims to reveal the effect of galangin on Concanavalin A (ConA)-induced hepatitis (CIH), a well-established animal model of immune-mediated liver injury, and to clarify the related mechanism. C57BL/6 mice were pretreated with galangin followed by ConA challenge. Results indicated that galangin inhibited ConA-induced liver damage. Mice pretreated with galangin showed more reduction of liver damage when compared with control mice pretreated with vehicle solution. In galangin-pretreated mice with induced CIH, increases in serum levels of several inflammatory cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-12 were dramatically attenuated, and chemokines and adhesion molecules like interferon inducible protein-10, macrophage inflammatory protein-1α, and inter-cellular adhesion molecule-1 messenger RNA expressions in liver were decreased. Moreover, CIH mice pretreated with galangin showed less leukocyte infiltration and T-cell activation in the liver. Further, the mechanism of the anti-inflammatory effects of galangin may be attributed to its modulation of crucial inflammatory signaling pathways, including nuclear factor kappa B and interferon-gamma/signal transducer and activator of transcription 1. Collectively, these findings suggest the preventive and therapeutic potential of galangin in immune-mediated liver injury in vivo.

  8. Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy.

    PubMed

    Zhang, Ya-Min; Liu, Zi-Rong; Cui, Zi-Lin; Yang, Chao; Yang, Long; Li, Yang; Shen, Zhong-Yang

    2016-02-14

    To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. Mice were injected intravenously with ConA at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.

  9. Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy

    PubMed Central

    Zhang, Ya-Min; Liu, Zi-Rong; Cui, Zi-Lin; Yang, Chao; Yang, Long; Li, Yang; Shen, Zhong-Yang

    2016-01-01

    AIM: To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. METHODS: Mice were injected intravenously with ConA at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. RESULTS: IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. CONCLUSION: In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy. PMID:26877612

  10. Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation

    PubMed Central

    Lee, D H; Son, D J; Park, M H; Yoon, D Y; Han, S B; Hong, J T

    2016-01-01

    Concanavalin A (Con A)-induced hepatitis model is well-established experimental T cell-mediated liver disease. Reactive oxygen species (ROS) is associated with T-cell activation and proliferation, but continued ROS exposure induces T-cell hyporesponsiveness. Because glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme and is involved in T-cell development, we investigated the role of Gpx1 during Con A-induced liver injury in Gpx1 knockout (KO) mice. Male wild-type (WT) mice and Gpx1 KO mice were intravenously injected with Con A (10 mg/kg), and then killed after 8 h after Con A injection. Serum levels of aspartate transaminase and alanine transaminase were measured to assess hepatic injury. To identify that Gpx1 affects T cell-mediated inflammation, we pretreated Gpx1 inhibitor to Human Jurkat T cells then treated Con A. Con A-induced massive liver damage in WT mice but its damage was attenuated in Gpx1 KO mice. Con A-induced Th1 cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-2 were also decreased in the liver and spleen of Gpx1 KO mice compared with WT mice. In Jurkat T cells, Con A-induced mRNA levels of IL-2, IFN-γ and TNF-α were downregulated by pretreatment of Gpx inhibitor, mercaptosuccinic acid. We also observed that Gpx1 KO mice showed increasing oxidative stress in the liver and spleen compared with WT mice. These results suggest that Gpx1 deficiency attenuates Con A-induced liver injury by induction of T-cell hyporesponsiveness through chronic ROS exposure. PMID:27124582

  11. Coronin 1 is dispensable for leukocyte recruitment and liver injury in concanavalin A-induced hepatitis.

    PubMed

    Siegmund, Kerstin; Lee, Woo-Yong; Tchang, Vincent S; Stiess, Michael; Terracciano, Luigi; Kubes, Paul; Pieters, Jean

    2013-06-01

    Coronin 1, a member of the evolutionary conserved coronin protein family, is highly expressed in all leukocytes. In mice and human, genetic inactivation of coronin 1 results in immuno-deficiencies that are linked to a strong reduction of naïve T cell numbers in peripheral organs, while memory/effector T cells, B cells, monocytes and neutrophils are less or not at all affected. Whether or not coronin 1 is important for leukocyte functions such as migration and phagocytosis has been a matter of debate. The current work addresses coronin 1-dependent leukocyte function by analyzing the response of coronin 1-deficient mice in a model of concanavalin A (Con A)-induced liver injury. Histological evaluation and determination of serum liver enzyme levels showed that coronin 1-deficient mice develop signs of acute hepatitis similar to Con A-treated wild type mice despite a reduced activation of T cells in the absence of coronin 1. Furthermore, analysis by intravital microscopy following Con A stimulation revealed that Gr-1+ neutrophils and CD4+ T cell adhesion in the post-sinusoidal venules increased in wild type as well as in coronin 1-deficient mice. These results suggest that coronin 1, while important for naïve T cell survival, is dispensable for other leukocyte function under inflammatory conditions in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Modeling Hepatitis C treatment policy.

    SciTech Connect

    Kuypers, Marshall A.; Lambert, Gregory Joseph; Moore, Thomas W.; Glass, Robert John,; Finley, Patrick D.; Ross, David; Chartier, Maggie

    2013-09-01

    Chronic infection with Hepatitis C virus (HCV) results in cirrhosis, liver cancer and death. As the nations largest provider of care for HCV, US Veterans Health Administration (VHA) invests extensive resources in the diagnosis and treatment of the disease. This report documents modeling and analysis of HCV treatment dynamics performed for the VHA aimed at improving service delivery efficiency. System dynamics modeling of disease treatment demonstrated the benefits of early detection and the role of comorbidities in disease progress and patient mortality. Preliminary modeling showed that adherence to rigorous treatment protocols is a primary determinant of treatment success. In depth meta-analysis revealed correlations of adherence and various psycho-social factors. This initial meta-analysis indicates areas where substantial improvement in patient outcomes can potentially result from VA programs which incorporate these factors into their design.

  13. Animal models of hepatitis A and E.

    PubMed

    Purcell, R H; Emerson, S U

    2001-01-01

    Several useful animal models for both hepatitis A and E have been identified, characterized, and refined. At present, all of the best models utilize nonhuman primates: chimpanzees, tamarin species, and owl monkeys for hepatitis A; and macaque species, chimpanzees, and owl monkeys for hepatitis E. Pigs may prove useful for some studies of hepatitis E, and it is hoped that serological evidence of widespread infection of rats with an HEV-like agent may lead to the development of an animal model based on laboratory rats. As has been the case for each of the hepatitis viruses as they have been discovered, the development of useful and reproducible animal model systems has been critical for moving the field forward as expeditiously as possible.

  14. Sophocarpine Protects Mice from ConA-Induced Hepatitis via Inhibition of the IFN-Gamma/STAT1 Pathway

    PubMed Central

    Sang, Xiu-Xiu; Wang, Rui-Lin; Zhang, Cong-En; Liu, Shi-Jing; Shen, Hong-Hui; Guo, Yu-Ming; Zhang, Ya-Ming; Niu, Ming; Wang, Jia-Bo; Bai, Zhao-Fang; Xiao, Xiao-He

    2017-01-01

    Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg-1 of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN-γ/STAT1 signaling pathway. PMID:28377718

  15. Sophocarpine Protects Mice from ConA-Induced Hepatitis via Inhibition of the IFN-Gamma/STAT1 Pathway.

    PubMed

    Sang, Xiu-Xiu; Wang, Rui-Lin; Zhang, Cong-En; Liu, Shi-Jing; Shen, Hong-Hui; Guo, Yu-Ming; Zhang, Ya-Ming; Niu, Ming; Wang, Jia-Bo; Bai, Zhao-Fang; Xiao, Xiao-He

    2017-01-01

    Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg(-1) of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN-γ/STAT1 signaling pathway.

  16. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.

    PubMed

    Kaneko, Y; Harada, M; Kawano, T; Yamashita, M; Shibata, Y; Gejyo, F; Nakayama, T; Taniguchi, M

    2000-01-03

    The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A-induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Valpha14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A-activated Valpha14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Valpha14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Valpha14 NKT cells. Moreover, Valpha14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin-granzyme B and FasL appear to be effector molecules in Con A-induced Valpha14 NKT cell-mediated hepatocyte injury.

  17. Salidroside attenuates concanavalin A-induced hepatitis via modulating cytokines secretion and lymphocyte migration in mice.

    PubMed

    Hu, Baoji; Zou, Yun; Liu, Shanshan; Wang, Jun; Zhu, Jiali; Li, Jinbao; Bo, Lulong; Deng, Xiaoming

    2014-01-01

    Salidroside, isolated from the medicinal plant Rhodiola, was reported to serve as an "adaptogen." This study was designed to explore the protective effect of salidroside on concanavalin A- (Con A-) induced hepatitis in mice and investigate potential mechanisms. C57BL/6 mice were randomly divided into control group, Con A group, and salidroside group. Salidroside (50 mg/kg) was injected intravenously followed by Con A administration. The levels of ALT, AST, inflammatory cytokines and CXCL-10 were examined. The pathological damage of livers was assessed, the amounts of phosphorylated IκBα and p65 were measured, and the numbers of CD4(+) and CD8(+) T lymphocytes in the blood, spleen and infiltrated in the liver were calculated. Our results showed that salidroside pretreatment reduced the levels of ALT, AST dramatically and suppressed the secretion of proinflammatory cytokines through downregulating the activity of NF-κB partly. Salidroside altered the distribution of CD4(+) and CD8(+) T lymphocyte in the liver and spleen through regulating CXCL-10 and decreased the severity of liver injuries. In conclusion, these results confirm the efficacy of salidroside in the prevention of immune mediated hepatitis in mice.

  18. Salidroside Attenuates Concanavalin A-Induced Hepatitis via Modulating Cytokines Secretion and Lymphocyte Migration in Mice

    PubMed Central

    Zou, Yun; Liu, Shanshan; Wang, Jun; Zhu, Jiali; Li, Jinbao

    2014-01-01

    Salidroside, isolated from the medicinal plant Rhodiola, was reported to serve as an “adaptogen.” This study was designed to explore the protective effect of salidroside on concanavalin A- (Con A-) induced hepatitis in mice and investigate potential mechanisms. C57BL/6 mice were randomly divided into control group, Con A group, and salidroside group. Salidroside (50 mg/kg) was injected intravenously followed by Con A administration. The levels of ALT, AST, inflammatory cytokines and CXCL-10 were examined. The pathological damage of livers was assessed, the amounts of phosphorylated IκBα and p65 were measured, and the numbers of CD4+ and CD8+ T lymphocytes in the blood, spleen and infiltrated in the liver were calculated. Our results showed that salidroside pretreatment reduced the levels of ALT, AST dramatically and suppressed the secretion of proinflammatory cytokines through downregulating the activity of NF-κB partly. Salidroside altered the distribution of CD4+ and CD8+ T lymphocyte in the liver and spleen through regulating CXCL-10 and decreased the severity of liver injuries. In conclusion, these results confirm the efficacy of salidroside in the prevention of immune mediated hepatitis in mice. PMID:24808635

  19. Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells

    PubMed Central

    2014-01-01

    Background Activin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation. Results Using the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model. Conclusion Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells. PMID:24628936

  20. Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A-induced hepatitis by inhibiting BNIP3

    PubMed Central

    Li, Sainan; Xia, Yujing; Chen, Kan; Li, Jingjing; Liu, Tong; Wang, Fan; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2016-01-01

    Background Epigallocatechin-3-gallate (EGCG) is the most effective compound in green tea, and possesses a wide range of beneficial effects, including anti-inflammatory, antioxidant, antiobesity, and anticancer effects. In this study, we investigated the protective effects of EGCG in concanavalin A (ConA)-induced hepatitis in mice and explored the possible mechanisms involved in these effects. Methods Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and EGCG (10 or 30 mg/kg) was administered orally twice daily for 10 days before ConA injection. Serum liver enzymes, proinflammatory cytokines, and other marker proteins were determined 2, 8, and 24 hours after the ConA administration. Results BNIP3 mediated cell apoptosis and autophagy in ConA-induced hepatitis. EGCG decreased the immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-α, IL-6, IFN-γ, and IL-1β. EGCG also exhibited an antiapoptotic and antiautophagic effect by inhibiting BNIP3 via the IL-6/JAKs/STAT3 pathway. Conclusion EGCG attenuated liver injury in ConA-induced hepatitis by downregulating IL-6/JAKs/STAT3/BNIP3-mediated apoptosis and autophagy. PMID:26929598

  1. Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis.

    PubMed

    Chen, Yu-Fon; Wang, Sheng-Hung; Chang, Sue-Joan; Shiau, Ai-Li; Her, Lu-Shiun; Shieh, Gia-Shing; Chen, Chin-Fu; Chang, Chao-Ching; Su, Yu-Chu; Wu, Chao-Liang; Wu, Tian-Shung

    2014-09-15

    Fruiting bodies of Taiwanofungus camphoratus have been widely used as an antidote for food poisoning and considered to be a precious folk medicine for anti-inflammation and hepatoprotection. Zhankuic acid A (ZAA) is its major pharmacologically active compound. Janus kinase 2 (JAK2), whose activation is involved in cytokine signaling, plays critical roles in the development and biology of the hematopoietic system. JAK2 has been implicated as a therapeutic target in inflammatory diseases. The HotLig modeling approach was used to generate the binding model for ZAA with JAK2, showing that ZAA could bind to the ATP-binding pocket of JAK2 exclusively via the H-bond. The interaction between ZAA and JAK2 was verified by antibody competition assay. Binding of ZAA to JAK2 reduced antibody recognition of native JAK2. The expressions of phosphorylated JAK2 and STATs were analyzed by immuno-blotting. ZAA reduced the phosphorylation and downstream signaling of JAK2, and inhibited the interferon (IFN)-γ/signal transducer and activator of transcription (STAT) 1/interferon regulatory factor (IRF)-1 pathway. The protective effect of ZAA on liver injury was evaluated in mice by Con-A-induced acute hepatitis. Pre-treatment with ZAA also significantly ameliorated acute liver injury in mice. Therefore, ZAA can inhibit JAK2 phosphorylation and protect against liver injury during acute hepatitis in mice. In this study, we present data that ZAA exerts anti-inflammatory effects through the JAK2 signaling pathway. As such, ZAA may be a potential therapeutic agent for the treatment of inflammatory diseases.

  2. Forced expression of Hnf4a induces hepatic gene activation through directed differentiation.

    PubMed

    Yahoo, Neda; Pournasr, Behshad; Rostamzadeh, Jalal; Fathi, Fardin

    2016-08-05

    Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. γδ T cells are indispensable for interleukin-23-mediated protection against Concanavalin A-induced hepatitis in hepatitis B virus transgenic mice.

    PubMed

    Meng, Ziyu; Wang, Jingya; Yuan, Yifang; Cao, Guangchao; Fan, Shuobing; Gao, Chao; Wang, Li; Li, Zheng; Wu, Xiaoli; Wu, Zhenzhou; Zhao, Liqing; Yin, Zhinan

    2017-05-01

    Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between γδ T cells and liver damage in patients with hepatitis B virus (HBV). However, whether γδ T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation-induced hepatitis is unknown. In this study, using HBV transgenic (HBs-Tg) and HBs-Tg T-cell receptor-δ-deficient (TCR-δ(-/-) ) mice, we found that mice genetically deficient in γδ T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon-γ (IFN-γ) levels and more extensive necrosis. γδ T-cell deficiency resulted in elevated IFN-γ in CD4(+) T cells but not in natural killer or natural killer T cells. The depletion of CD4(+) T cells and neutralization of IFN-γ reduced liver damage in HBs-Tg and HBs-Tg-TCR-δ(-/-) mice to a similar extent. Further investigation revealed that HBs-Tg mice showed an enhanced interleukin-17 (IL-17) signature. The administration of exogenous IL-23 enhanced IL-17A production from Vγ4 γδ T cells and ameliorated liver damage in HBs-Tg mice, but not in HBs-Tg-TCR-δ(-/-) mice. In summary, our results demonstrated that γδ T cells played a protective role in restraining Con A-induced hepatitis by inhibiting IFN-γ production from CD4(+) T cells and are indispensable for IL-23-mediated protection against Con A-induced hepatitis in HBs-Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation-induced liver damage.

  4. Hepatitis

    MedlinePlus

    ... CPR: A Real Lifesaver Kids Talk About: Coaches Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... have liver damage because of it. What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  5. A rat model for hepatitis E virus

    PubMed Central

    Mishra, Niraj; Verbeken, Erik; Ramaekers, Kaat; Dallmeier, Kai

    2016-01-01

    ABSTRACT Hepatitis E virus (HEV) is one of the prime causes of acute viral hepatitis, and chronic hepatitis E is increasingly recognized as an important problem in the transplant setting. Nevertheless, the fundamental understanding of the biology of HEV replication is limited and there are few therapeutic options. The development of such therapies is partially hindered by the lack of a robust and convenient animal model. We propose the infection of athymic nude rats with the rat HEV strain LA-B350 as such a model. A cDNA clone, pLA-B350, was constructed and the infectivity of its capped RNA transcripts was confirmed in vitro and in vivo. Furthermore, a subgenomic replicon, pLA-B350/luc, was constructed and validated for in vitro antiviral studies. Interestingly, rat HEV proved to be less sensitive to the antiviral activity of α-interferon, ribavirin and mycophenolic acid than genotype 3 HEV (a strain that infects humans). As a proof-of-concept, part of the C-terminal polymerase sequence of pLA-B350/luc was swapped with its genotype 3 HEV counterpart: the resulting chimeric replicon replicated with comparable efficiency as the wild-type construct, confirming that LA-B350 strain is amenable to humanization (replacement of certain sequences or motifs by their counterparts from human HEV strains). Finally, ribavirin effectively inhibited LA-B350 replication in athymic nude rats, confirming the suitability of the rat model for antiviral studies. PMID:27483350

  6. Establishment of a hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol.

    PubMed

    Wang, Lei; He, Fu-Liang; Liu, Fu-Quan; Yue, Zhen-Dong; Zhao, Hong-Wei

    2015-08-28

    To determine the feasibility and safety of establishing a porcine hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol. Twenty-one healthy Guizhou miniature pigs were randomly divided into three experimental groups and three control groups. The pigs in the three experimental groups were subjected to hepatic arterial perfusion with 7, 12 and 17 mL of 80% alcohol, respectively, while those in the three control groups underwent hepatic arterial perfusion with 7, 12 and 17 mL of saline, respectively. Hepatic arteriography and direct portal phlebography were performed on all animals before and after perfusion, and the portal venous pressure and diameter were measured before perfusion, immediately after perfusion, and at 2, 4 and 6 wk after perfusion. The following procedures were performed at different time points: routine blood sampling, blood biochemistry, blood coagulation and blood ammonia tests before surgery, and at 2, 4 and 6 wk after surgery; hepatic biopsy before surgery, within 6 h after surgery, and at 1, 2, 3, 4 and 5 wk after surgery; abdominal enhanced computed tomography examination before surgery and at 6 wk after surgery; autopsy and multi-point sampling of various liver lobes for histological examination at 6 wk after surgery. In experimental group 1, different degrees of hepatic fibrosis were observed, and one pig developed hepatic cirrhosis. In experimental group 2, there were cases of hepatic cirrhosis, different degrees of increased portal venous pressure, and intrahepatic portal venous bypass, but neither extrahepatic portal-systemic bypass circulation nor death occurred. In experimental group 3, two animals died and three animals developed hepatic cirrhosis, and different degrees of increased portal venous pressure and intrahepatic portal venous bypass were also observed, but there was no extrahepatic portal-systemic bypass circulation. It is feasible to establish an animal model of hepatic cirrhosis and

  7. Murine Bioluminescent Hepatic Tumour Model

    PubMed Central

    Rajendran, Simon; Salwa, Slawomir; Gao, Xuefeng; Tabirca, Sabin; O'Hanlon, Deirdre; O'Sullivan, Gerald C.; Tangney, Mark

    2010-01-01

    This video describes the establishment of liver metastases in a mouse model that can be subsequently analysed by bioluminescent imaging. Tumour cells are administered specifically to the liver to induce a localised liver tumour, via mobilisation of the spleen and splitting into two, leaving intact the vascular pedicle for each half of the spleen. Lewis lung carcinoma cells that constitutively express the firefly luciferase gene (luc1) are inoculated into one hemi-spleen which is then resected 10 minutes later. The other hemi-spleen is left intact and returned to the abdomen. Liver tumour growth can be monitored by bioluminescence imaging using the IVIS whole body imaging system. Quantitative imaging of tumour growth using IVIS provides precise quantitation of viable tumour cells. Tumour cell death and necrosis due to drug treatment is indicated early by a reduction in the bioluminescent signal. This mouse model allows for investigating the mechanisms underlying metastatic tumour-cell survival and growth and can be used for the evaluation of therapeutics of liver metastasis. PMID:20689502

  8. Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

    PubMed Central

    Bruck, R; Shirin, H; Hershkoviz, R; Lider, O; Kenet, G; Aeed, H; Matas, Z; Zaidel, L; Halpern, Z

    1997-01-01

    BACKGROUND/AIMS: It has been shown that synthetic non-peptidic analogues of Arg-Gly-Asp, a major cell adhesive ligand of extracellular matrix, prevented an increase in serum aminotransferase activity, as a manifestation of concanavalin A induced liver damage in mice. This study examined the effects of an Arg-Gly-Asp mimetic on liver histology and cytokine release in response to concanavalin A administration, and the efficacy of soluble receptor of tumour necrosis factor (TNF) alpha in preventing hepatitis in this model of liver injury. METHODS: Mice were pretreated with either the Arg-Gly-Asp mimetic SF-6,5 or recombinant soluble receptor of TNF alpha before their inoculation with 10 mg/kg concanavalin A. Liver enzymes, histology, and the serum values of TNF alpha and interleukin (IL)6 were examined. RESULTS: The histopathological damage in the liver, and the concanavalin A induced release of TNF alpha and IL6 were significantly inhibited by the synthetic Arg-Gly-Asp mimetic (p < 0.001). Liver injury, manifested by the increase in serum aminotransferase and cytokines, as well as by histological manifestations of hepatic damage, was effectively prevented by pretreatment of the mice with the soluble TNF receptor (p < 0.001). CONCLUSIONS: This study confirms the efficacy of a synthetic Arg-Gly-Asp mimetic and soluble TNF receptor in the prevention of immune mediated liver damage in mice. Images PMID:9155591

  9. Experimental models for hepatitis C viral infection.

    PubMed

    Boonstra, Andre; van der Laan, Luc J W; Vanwolleghem, Thomas; Janssen, Harry L A

    2009-11-01

    Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C.

  10. Hepatitis

    MedlinePlus

    ... clotting problems or chronic liver disease. previous continue Hepatitis B and Hepatitis C Although hep A is a ... does — through direct contact with infected body fluids. Hepatitis B and C are even more easily passed in ...

  11. Hepatitis

    MedlinePlus

    ... A if they've been vaccinated against it. Hepatitis B Hepatitis B is a more serious infection. It may lead ... of which cause severe illness and even death. Hepatitis B virus (HBV) is transmitted from person to person ...

  12. Hepatitis

    MedlinePlus

    ... a problem with the liver itself What Is Hepatitis A? Hepatitis A virus (HAV) is contagious, usually spreading to others ... objects contaminated by feces (poop) containing HAV. The hepatitis A vaccine has helped to make the infection rare ...

  13. Mathematical modelling of hepatic lipid metabolism.

    PubMed

    Pratt, Adrian C; Wattis, Jonathan A D; Salter, Andrew M

    2015-04-01

    The aim of this paper is to develop a mathematical model capable of simulating the metabolic response to a variety of mixed meals in fed and fasted conditions with particular emphasis placed on the hepatic triglyceride element of the model. Model validation is carried out using experimental data for the ingestion of three mixed composition meals over a 24-h period. Comparison with experimental data suggests the model predicts key plasma lipids accurately given a prescribed insulin profile. One counter-intuitive observation to arise from simulations is that liver triglyceride initially decreases when a high fat meal is ingested, a phenomenon potentially explained by the carbohydrate portion of the meal raising plasma insulin. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Theoretical Modeling for Hepatic Microwave Ablation

    PubMed Central

    Prakash, Punit

    2010-01-01

    Thermal tissue ablation is an interventional procedure increasingly being used for treatment of diverse medical conditions. Microwave ablation is emerging as an attractive modality for thermal therapy of large soft tissue targets in short periods of time, making it particularly suitable for ablation of hepatic and other tumors. Theoretical models of the ablation process are a powerful tool for predicting the temperature profile in tissue and resultant tissue damage created by ablation devices. These models play an important role in the design and optimization of devices for microwave tissue ablation. Furthermore, they are a useful tool for exploring and planning treatment delivery strategies. This review describes the status of theoretical models developed for microwave tissue ablation. It also reviews current challenges, research trends and progress towards development of accurate models for high temperature microwave tissue ablation. PMID:20309393

  15. Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice.

    PubMed

    Zhou, Yong-Qin; Weng, Xiu-Fang; Dou, Rui; Tan, Xiao-Sheng; Zhang, Tian-Tian; Fang, Jin-Bo; Wu, Xiong-Wen

    2017-02-01

    Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg·kg(-1)·d(-1), ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg·kg(-1)·d(-1)) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg·kg(-1)·d(-1)) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

  16. Immune mechanisms of Concanavalin A model of autoimmune hepatitis

    PubMed Central

    Wang, Hai-Xia; Liu, Man; Weng, Shun-Yan; Li, Jing-Jing; Xie, Chao; He, Hong-Lin; Guan, Wen; Yuan, Yun-Sheng; Gao, Jin

    2012-01-01

    As a chronic inflammatory disease of the liver, the pa-thogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated, with prognosis and diagnosis remaining unsatisfied. Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation. It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure. The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice, which closely mimics the pathogenesis mechanisms and pathological changes of patients, and is regarded as the best experimental model for AIH research so far. In this paper we elucidated the pathogenic mechanisms of AIH and the evolution of relative animal models. We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels. Finally, we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development. PMID:22253517

  17. Establishment of a hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol

    PubMed Central

    Wang, Lei; He, Fu-Liang; Liu, Fu-Quan; Yue, Zhen-Dong; Zhao, Hong-Wei

    2015-01-01

    AIM: To determine the feasibility and safety of establishing a porcine hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol. METHODS: Twenty-one healthy Guizhou miniature pigs were randomly divided into three experimental groups and three control groups. The pigs in the three experimental groups were subjected to hepatic arterial perfusion with 7, 12 and 17 mL of 80% alcohol, respectively, while those in the three control groups underwent hepatic arterial perfusion with 7, 12 and 17 mL of saline, respectively. Hepatic arteriography and direct portal phlebography were performed on all animals before and after perfusion, and the portal venous pressure and diameter were measured before perfusion, immediately after perfusion, and at 2, 4 and 6 wk after perfusion. The following procedures were performed at different time points: routine blood sampling, blood biochemistry, blood coagulation and blood ammonia tests before surgery, and at 2, 4 and 6 wk after surgery; hepatic biopsy before surgery, within 6 h after surgery, and at 1, 2, 3, 4 and 5 wk after surgery; abdominal enhanced computed tomography examination before surgery and at 6 wk after surgery; autopsy and multi-point sampling of various liver lobes for histological examination at 6 wk after surgery. RESULTS: In experimental group 1, different degrees of hepatic fibrosis were observed, and one pig developed hepatic cirrhosis. In experimental group 2, there were cases of hepatic cirrhosis, different degrees of increased portal venous pressure, and intrahepatic portal venous bypass, but neither extrahepatic portal-systemic bypass circulation nor death occurred. In experimental group 3, two animals died and three animals developed hepatic cirrhosis, and different degrees of increased portal venous pressure and intrahepatic portal venous bypass were also observed, but there was no extrahepatic portal-systemic bypass circulation. CONCLUSION: It is feasible to establish an

  18. Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

    PubMed Central

    Zhou, Yong-qin; Weng, Xiu-fang; Dou, Rui; Tan, Xiao-sheng; Zhang, Tian-tian; Fang, Jin-bo; Wu, Xiong-wen

    2017-01-01

    Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg·kg−1·d−1, ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg·kg−1·d−1) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg·kg−1·d−1) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases. PMID:27796295

  19. Animal model for study of human hepatitis viruses.

    PubMed

    Chayama, Kazuaki; Hayes, C Nelson; Hiraga, Nobuhiko; Abe, Hiromi; Tsuge, Masataka; Imamura, Michio

    2011-01-01

    Human hepatitis B virus (HBV) and hepatitis C virus (HCV) infect only chimpanzees and humans. Analysis of both viruses has long been hampered by the absence of a small animal model. The recent development of human hepatocyte chimeric mice has enabled us to carry out studies on viral replication and cellular changes induced by replication of human hepatitis viruses. Various therapeutic agents have also been tested using this model. In the present review, we summarize published studies using chimeric mice and discuss the merits and shortcomings of this model.

  20. A Dog Model for Acetaminophen-Induced Fulminant Hepatic Failure

    PubMed Central

    FRANCAVILLA, A.; MAKOWKA, L.; POLIMENO, L.; BARONE, M.; DEMETRIS, J.; PRELICH, J.; Van THIEL, D. H.; STARZL, T. E.

    2010-01-01

    The development of a large animal model of fulminant hepatic failure produced with acetaminophen that should be useful in the development and evaluation of potential medical therapies for the important clinical problem of fulminant hepatic failure is described. Acetaminophen in dimethyl sulfoxide (600 mg/ml) given as three subcutaneous injections, with the first dose (750 mg/kg body wt) being given at noon, the second dose (200 mg/kg body wt) being given 9 h later, and the third dose (200 mg/kg body wt) being given 24 h after the initial dose consistently produces fulminant hepatic failure in dogs. The dimethyl sulfoxide vehicle, injected intramuscularly, does not influence either animal survival or hepatic function in control-treated dogs. No deaths occur within the first 36 h. By 72 h after initial drug administration, the mortality is 90%. Histopathological and biochemical investigations demonstrate a high degree of hepatocellular necrosis in nonsurviving animals without appreciable damage to the kidneys, lungs, or heart. The drug schedule and preparation outlined avoids the administration of large volumes of vehicle and results in prolonged high levels of acetaminophen in the blood sufficient to induce severe hepatic injury. Ranitidine (120 mg/kg body wt i.m.) given 30 min before each acetaminophen dose significantly reduces the mortality and hepatic necrosis produced using this model. This model satisfies all criteria established by Miller et al. for the production of a suitable large animal model of fulminant acute hepatic failure. PMID:2910762

  1. The Chimpanzee Model for Hepatitis B Virus Infection

    PubMed Central

    Wieland, Stefan F.

    2015-01-01

    Even before the discovery of hepatitis B virus (HBV), it was known that chimpanzees (Pan troglodytes) are susceptible to human hepatitis viruses. The chimpanzee is the only primate animal model for HBV infections. Much like HBV-infected human patients, chimpanzees can develop acute and chronic HBV infections and consequent hepatitis. Chimpanzees also develop a cellular immune response similar to that observed in humans. For these reasons, the chimpanzee has proven to be an invaluable model for investigations on HBV-driven disease pathogenesis and also the testing of novel antiviral therapies and prophylactic approaches. PMID:26033082

  2. Humanized chimeric mouse models of hepatitis B virus infection.

    PubMed

    Sun, Suwan; Li, Jun

    2017-06-01

    Hepatitis B virus (HBV) infection is associated with an increased risk of hepatic cirrhosis, hepatocellular carcinoma, fulminant hepatitis and end-stage hepatic failure. Despite the availability of anti-HBV therapies, HBV infection remains a major global public health problem. Developing an ideal animal model of HBV infection to clarify the details of the HBV replication process, the viral life cycle, the resulting immunoresponse and the precise pathogenesis of HBV is difficult because HBV has an extremely narrow host range and almost exclusively infects humans. In this review, we summarize and evaluate animal models available for studying HBV infection, especially focusing on humanized chimeric mouse models, and we discuss future development trends regarding immunocompetent humanized mouse models that can delineate the natural history and immunopathophysiology of HBV infection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  3. National treatment programme of hepatitis C in Egypt: Hepatitis C virus model of care.

    PubMed

    El-Akel, W; El-Sayed, M H; El Kassas, M; El-Serafy, M; Khairy, M; Elsaeed, K; Kabil, K; Hassany, M; Shawky, A; Yosry, A; Shaker, M K; ElShazly, Y; Waked, I; Esmat, G; Doss, W

    2017-02-01

    Hepatitis C virus (HCV) infection is a major health problem in Egypt as the nation bears the highest prevalence rate worldwide. This necessitated establishing a novel model of care (MOC) to contain the epidemic, deliver patient care and ensure global treatment access. In this review, we describe the process of development of the Egyptian model and future strategies for sustainability. Although the magnitude of the HCV problem was known for many years, the HCV MOC only came into being in 2006 with the establishment of the National Committee for Control of Viral Hepatitis (NCCVH) to set up and implement a national control strategy for the disease and other causes of viral hepatitis. The strategy outlines best practices for patient care delivery by applying a set of service principles through identified clinical streams and patient flow continuums. The Egyptian national viral hepatitis treatment programme is considered one of the most successful and effective public health programmes. To date, more than one million patients were evaluated and more than 850 000 received treatment under the umbrella of the programme since 2006. The NCCVH has been successful in establishing a strong infrastructure for controlling viral hepatitis in Egypt. It established a nationwide network of digitally connected viral hepatitis-specialized treatment centres covering the country map to enhance treatment access. Practice guidelines suiting local circumstances were issued and regularly updated and are applied in all affiliated centres. This review illustrates the model and the successful Egyptian experience. It sets an exemplar for states, organizations and policy-makers setting up programmes for care and management of people with hepatitis C.

  4. Protective Effects of Astaxanthin on ConA-Induced Autoimmune Hepatitis by the JNK/p-JNK Pathway-Mediated Inhibition of Autophagy and Apoptosis

    PubMed Central

    Liu, Tong; Wang, Junshan; Dai, Weiqi; Wang, Fan; Zheng, Yuanyuan; Chen, Kan; Li, Sainan; Abudumijiti, Huerxidan; Zhou, Zheng; Wang, Jianrong; Lu, Wenxia; Zhu, Rong; Yang, Jing; Zhang, Huawei; Yin, Qin; Wang, Chengfen; Zhou, Yuqing; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2015-01-01

    Objective Astaxanthin, a potent antioxidant, exhibits a wide range of biological activities, including antioxidant, atherosclerosis and antitumor activities. However, its effect on concanavalin A (ConA)-induced autoimmune hepatitis remains unclear. The aim of this study was to investigate the protective effects of astaxanthin on ConA-induced hepatitis in mice, and to elucidate the mechanisms of regulation. Materials and Methods Autoimmune hepatitis was induced in in Balb/C mice using ConA (25 mg/kg), and astaxanthin was orally administered daily at two doses (20 mg/kg and 40 mg/kg) for 14 days before ConA injection. Levels of serum liver enzymes and the histopathology of inflammatory cytokines and other maker proteins were determined at three time points (2, 8 and 24 h). Primary hepatocytes were pretreated with astaxanthin (80 μM) in vitro 24 h before stimulation with TNF-α (10 ng/ml). The apoptosis rate and related protein expression were determined 24 h after the administration of TNF-α. Results Astaxanthin attenuated serum liver enzymes and pathological damage by reducing the release of inflammatory factors. It performed anti-apoptotic effects via the descending phosphorylation of Bcl-2 through the down-regulation of the JNK/p-JNK pathway. Conclusion This research firstly expounded that astaxanthin reduced immune liver injury in ConA-induced autoimmune hepatitis. The mode of action appears to be downregulation of JNK/p-JNK-mediated apoptosis and autophagy. PMID:25761053

  5. Hepatitis

    MedlinePlus

    ... low because of routine testing of donated blood. Sexual transmission and transmission among family members through close contact ... associated with drinking contaminated water. Hepatitis Viruses ... B Blood, needles, sexual 10% of older children develop chronic infection. 90% ...

  6. MicroRNA let-7a ameliorates con A-induced hepatitis by inhibiting IL-6-dependent Th17 cell differentiation.

    PubMed

    Zhang, Yingying; Wang, Xiangmin; Zhong, Min; Zhang, Mengying; Suo, Qifeng; Lv, Kun

    2013-04-01

    In this study we explored the effects of microRNA let-7a on Con A-induced hepatitis and its possible mechanisms involved. We demonstrated that IL-6 and IL-17 expression were significantly upregulated in the liver following Con A treatment and IL-6 level was correlated with the IL-17 expression. To explore whether let-7a may have therapeutic effect on Con A-induced hepatitis, mice was infected with a lentiviral vector containing the let-7a sequence 7 days before Con A treatment. Significantly reduced Th17 cells and remarkably increased regulatory T cells frequency in the liver tissue were found as compared to control mice. It was accompanied by a significant decreased level of inflammatory cytokines as TNF-α, IL-6 and IFN-γ in the serum, and an decreased level of Th17 lineage-specific genes such as Il17a, Il17f, Il21 and Il23r. let-7a was further found to inhibit Th17 differentiation by downregulating IL-6 secretion. It may represent as a novel therapeutic strategy in treating immune-mediated inflammatory hepatitis.

  7. Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway.

    PubMed

    Li, Xi; Liu, Hong-chun; Yao, Qun-yan; Xu, Bei-li; Zhang, Shun-cai; Tu, Chuan-tao

    2016-02-01

    The dietary flavonoid quercetin has hepatoprotective effects. We analyzed the effects of quercetin on concanavalin A (ConA)-induced hepatitis in mice and its underlying molecular mechanisms of action. Mice were administered quercetin (50 mg/kg body weight, i.p.) or vehicle 30 min before intravenous administration of ConA. Quercetin pretreatment significantly reduced the ConA-induced elevations in plasma aminotransferase concentrations and liver necrosis, as well as reducing serum concentrations of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interferon-γ, and interleukin-4. Quercetin pretreatment also reduced expression of high-mobility group box 1 protein (HMGB1) and toll-like receptor (TLR)-2 and TLR-4 messenger RNA (mRNA) and protein in liver tissues. Quercetin pretreatment significantly inhibited degradation of inhibitory kappa B alpha and modulated ConA-induced nuclear translocation in the liver of nuclear factor kappa B (NF-κB) p65. These results demonstrate that quercetin protects against ConA-mediated hepatitis in mice by attenuating the HMGB1-TLRs-NF-κB signaling pathway.

  8. Methane-rich saline protects against concanavalin A-induced autoimmune hepatitis in mice through anti-inflammatory and anti-oxidative pathways.

    PubMed

    He, Rong; Wang, Liping; Zhu, Jiali; Fei, Miaomiao; Bao, Suhong; Meng, Yan; Wang, Yuanyuan; Li, Jinbao; Deng, Xiaoming

    2016-01-29

    Methane is a common gas which has been reported to play a protective role in organ injury and presents an anti-inflammatory property. However, its effects on Concanavalin A (Con A)-induced autoimmune hepatitis (AIH) remain unknown. Thus, the aim of this study was to investigate the effects of methane on Con A-induced autoimmune hepatitis in mice and its underlying mechanism. Autoimmune hepatitis was induced by Con A (15 mg/kg) in healthy C57BL/6 mice and methane-rich saline (MS) (20 ml/kg) was intraperitoneally injected 30 min after the challenge with Con A. We found that methane treatment significantly reduced the elevated serum aminotransferase levels and ameliorated liver pathological damage. Furthermore, methane treatment obviously suppressed the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and increased anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, we found that the levels of malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were highly increased while the activities of superoxide dismutase (SOD) and catalase (CAT) were decreased in liver with the injection of Con A, which was reversed by methane. Also, the data demonstrated that the phosphorylated IκB, NF-κB and P38 MAPK in liver were significantly down-regulated by methane. These results suggested that methane protected liver against Con A-induced injury through anti-inflammatory and anti-oxidative pathways.

  9. Development of a Murine Model of Blunt Hepatic Trauma

    PubMed Central

    Nemzek-Hamlin, Jean A; Hwang, Haejin; Hampel, Joseph A; Yu, Bi; Raghavendran, Krishnan

    2013-01-01

    Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses. We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine–xylazine–buprenorphine and placed in left lateral recumbency. A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. An impact velocity of 6 m/s and a piston depth of 12 mm produced a consistent pattern of hepatic injury with low mortality. All mice that recovered from anesthesia survived without complication for the length of the study. Mice were euthanized at various time points (n = 5 per group) until 7 d after injury for gross examination and collection of blood and peritoneal lavage fluids. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI. At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 2 h after trauma, there were significant increases in plasma IL10 as well as peritoneal lavage fluid IL6 and CXCL1/KC; however, these levels decreased within 24 h. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size. In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response. PMID:24210016

  10. A Macaca mulatta model of fulminant hepatic failure

    PubMed Central

    Zhou, Ping; Xia, Jie; Guo, Gang; Huang, Zi-Xing; Lu, Qiang; Li, Li; Li, Hong-Xia; Shi, Yu-Jun; Bu, Hong

    2012-01-01

    AIM: To establish an appropriate primate model of fulminant hepatic failure (FHF). METHODS: We have, for the first time, established a large animal model of FHF in Macaca mulatta by intraperitoneal infusion of amatoxin and endotoxin. Clinical features, biochemical indexes, histopathology and iconography were examined to dynamically investigate the progress and outcome of the animal model. RESULTS: Our results showed that the enzymes and serum bilirubin were markedly increased and the enzyme-bilirubin segregation emerged 36 h after toxin administration. Coagulation activity was significantly decreased. Gradually deteriorated parenchymal abnormality was detected by magnetic resonance imaging (MRI) and ultrasonography at 48 h. The liver biopsy showed marked hepatocyte steatosis and massive parenchymal necrosis at 36 h and 49 h, respectively. The autopsy showed typical yellow atrophy of the liver. Hepatic encephalopathy of the models was also confirmed by hepatic coma, MRI and pathological changes of cerebral edema. The lethal effects of the extrahepatic organ dysfunction were ruled out by their biochemical indices, imaging and histopathology. CONCLUSION: We have established an appropriate large primate model of FHF, which is closely similar to clinic cases, and can be used for investigation of the mechanism of FHF and for evaluation of potential medical therapies. PMID:22346249

  11. Methionine deficiency and hepatic injury in a dietary steatohepatitis model.

    PubMed

    Oz, Helieh S; Chen, Theresa S; Neuman, Manuela

    2008-03-01

    Methionine (Meth) is an essential amino acid involved in DNA methylation and glutathione biosynthesis. We examined the effect of Meth on the development of steatohepatitis. Rats were fed (five weeks) amino acid-based Meth-choline-sufficient (A-MCS) or total deficient (MCD) diets and gavaged daily (two weeks) with vehicle (B-vehicle/MCD), or Meth replacement (C-Meth/MCD). To assess the effect of short-term deficiency, after three weeks one MCS group was fed a deficient diet (D-MCS/MCD). Animals fed the deficient diet for two weeks lost (29%) weight and after five weeks weighed one third as much as those on the sufficient diet, and also developed anemia (P < 0.01). Hepatic transaminases progressively increased from two to five weeks (P < 0.01), leading to severe hepatic pathology. Meth administration normalized hematocrit, improved weight (P < 0.05), and suppressed abnormal enzymes activities (P < 0.01). Meth administration improved blood and hepatic glutathione (GSH), S-adenosylmethionine (SAMe), and hepatic lesions (P < 0.01). The deficient diet significantly upregulated proinflammatory and fibrotic genes, which was ameliorated by Meth administration. These data support a pivotal role for methionine in the pathogenesis of the dietary model of Meth-choline-deficient (MCD) steatohepatitis (NASH).

  12. Associative learning deficit in two experimental models of hepatic encephalopathy.

    PubMed

    Méndez, Marta; Méndez-López, Magdalena; López, Laudino; Aller, María Angeles; Arias, Jaime; Arias, Jorge L

    2009-03-17

    People with hepatic insufficiency can develop hepatic encephalopathy (HE), a complex neuropsychological syndrome covering a wide range of neurological and cognitive and motor alterations. The cognitive deficits include disturbances in intellectual functions such as memory and learning. In spite of its high prevalence in western societies, the causes of HE have not yet been clearly established. For this reason, experimental models of HE are used to study this condition. In this work, two experimental models were used, one Type B HE (portacaval shunt) and the other Type C HE (cirrhosis by intoxication with thioacetamide), to evaluate its effect on two tasks of associative learning: two-way active avoidance and step-through passive avoidance. The results show an impediment both in acquisition and retention of active avoidance in both models of HE. However, in passive avoidance, only the rats with portacaval shunt presented a memory deficit for the aversive event. In our opinion, these results can be explained by alterations in the neurotransmission system presented by animals with hepatic insufficiency, which are mainly caused by a rise in cerebral histamine and a dysfunction of the glutamatergic system.

  13. Naturally occurring animal models of human hepatitis E virus infection.

    PubMed

    Yugo, Danielle M; Cossaboom, Caitlin M; Meng, Xiang-Jin

    2014-01-01

    Hepatitis E virus (HEV) is a single-stranded, positive-sense RNA virus in the family Hepeviridae. Hepatitis E caused by HEV is a clinically important global disease. There are currently four well-characterized genotypes of HEV in mammalian species, although numerous novel strains of HEV likely belonging to either new genotypes or species have recently been identified from several other animal species. HEV genotypes 1 and 2 are limited to infection in humans, whereas genotypes 3 and 4 infect an expanding host range of animal species and are zoonotic to humans. Historical animal models include various species of nonhuman primates, which have been indispensable for the discovery of human HEV and for understanding its pathogenesis and course of infection. With the genetic identification and characterization of animal strains of HEV, a number of naturally occurring animal models such as swine, chicken, and rabbit have recently been developed for various aspects of HEV research, including vaccine trials, pathogenicity, cross-species infection, mechanism of virus replication, and molecular biology studies. Unfortunately, the current available animal models for HEV are still inadequate for certain aspects of HEV research. For instance, an animal model is still lacking to study the underlying mechanism of severe and fulminant hepatitis E during pregnancy. Also, an animal model that can mimic chronic HEV infection is critically needed to study the mechanism leading to chronicity in immunocompromised individuals. Genetic identification of additional novel animal strains of HEV may lead to the development of better naturally occurring animal models for HEV. This article reviews the current understanding of animal models of HEV infection in both natural and experimental infection settings and identifies key research needs and limitations. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For

  14. Lombok Hepatitis B Model Immunization Project: toward universal infant hepatitis B immunization in Indonesia.

    PubMed

    Ruff, T A; Gertig, D M; Otto, B F; Gust, I D; Sutanto, A; Soewarso, T I; Kandun, N; Marschner, I C; Maynard, J E

    1995-02-01

    The Lombok Hepatitis B (HB) Model Immunization Project was the first mass infant HB immunization project in Indonesia. Key aspects were the procurement of low-cost HB vaccine, integration into routine infant immunization services, and delivery of the first dose in the home within 1 week of birth. The project achieved > 90% coverage with 3 doses of vaccine. The prevalence of HB surface antigen was 1.4% in infants who received 3 doses (with the first dose within 7 days of birth) and 3.0% in those who received the first dose > 7 days after birth, compared with a baseline prevalence of 6.2% (P < .001 in each case). Most vaccine failures occurred in children born to HBe antigen-positive mothers. Antibody prevalence and titers did not correlate with protection. HB vaccine can be successfully integrated into the Expanded Programme on Immunization (EPI), strengthening the EPI and significantly reducing chronic HB infection.

  15. Advancement in the development of models for hepatitis C research.

    PubMed

    Carcamo, Wendy C; Nguyen, Cuong Q

    2012-01-01

    Hepatitis C virus (HCV) is a pandemic disease affecting an estimated 180 million individuals worldwide and infecting each year another ~3-4 million people making HCV a global public health issue. HCV is the main cause for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV-related chronic liver disease is a leading cause of liver transplantation. Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment. Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans. For decades, the chimpanzee model has been the only and instrumental primate for studying HCV infection; however, availability, economic, and ethical issues make the chimpanzee an unsuitable animal model today. Thus, significant research has been devoted to explore different models that are suitable in studying the biology of the virus and application in the clinical research for developing efficient and tolerable treatments for patients. This review focuses on experimental models that have been developed to date and their findings related to HCV.

  16. Hepatitis C Virus Experimental Model Systems and Antiviral drug Research*

    PubMed Central

    Uprichard, Susan L.

    2010-01-01

    An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics. PMID:20960298

  17. Chinese medicinal herbs in treating model rats with hepatic fibrosis.

    PubMed

    Zhou, Yun-Xiao; Chen, Jiu; Li, Jian-Ping; Wang, Yan-Li; Jin, Xiao-Dong

    2009-12-30

    The objective of this study was to examine the effects of Chinese medicine formula-Yu Zhang Dan (YZD, composed of Herba Lysimachiae, Rhizoma Polygoni Cuspidati, Radix Curcumae) on the model rats with hepatic fibrosis. Forty male Sprague-Dawley (SD) rats were used in the present study, and they were separated randomly into 4 groups: a normal control group (Group A, n=5), a model control (Group B, n=15), a high dose of YZD (Group C, n=10), and a low dose of YZD (Group D, n=10). Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl(4)). The variation of the serum alanine transaminase (ALT), aspartate aminotransferase (AST), hyaluronate acid (HA), laminin (LN), type • • procollagen peptide (P• •NP), L-Glutathione (GSH) was respectively measured with radioimmunoassay (RIA) and detection of transforming growth factor-beta 1 (TGF-β1) and smooth muscle alpha actin (α-SMA) was conducted with immunohistochemistry. The ALT, AST HA, LN and PIII NP levels in the serum of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the ALT, AST HA, LN and PIII NP levels of the model rats (P<0.05). The TGF-β1 and α-SMA levels of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the TGF-β1 levels of the model rats (P<0.05) , and only the high dose of YZD significantly decreased the α-SMA levels of the model rats (P<0.05). The expression of TGF-β1 and α-SMA in the liver tissues of the rats were in the cytoplasm of the cells. It may be through decreasing the ALT, AST, HA, LN and PIII NP levels in the serum of the model rats and decreasing the expression of TGF-β1 and α-SMA in the liver tissues of the model rats that YZD significantly relieved the hepatic fibrosis.

  18. Modeling the hepatitis A epidemiological transition in Thailand.

    PubMed

    Van Effelterre, Thierry; Marano, Cinzia; Jacobsen, Kathryn H

    2016-01-20

    In most low- and middle-income countries, hepatitis A virus (HAV) is shifting or expected to shift from high endemicity to intermediate or low endemicity. A decreased risk of HAV infection will cause an increase in the average age at infection and will therefore increase the proportion of infections that results in severe disease. Mathematical models can provide insights into the factors contributing to this epidemiological transition. An MSLIR compartmental dynamic transmission model stratified by age and setting (rural and urban) was developed and calibrated with demographic, environmental, and epidemiological data from Thailand. HAV transmission was modeled as a function of urbanization and access to clean drinking water. The model was used to project various epidemiological measures. The age at midpoint of population immunity remains considerably younger in rural areas than in urban areas. The mean age of symptomatic hepatitis A infection in Thailand has shifted from childhood toward early adulthood in rural areas and is transitioning from early adulthood toward middle adulthood in urban areas. The model showed a significant decrease in incidence rates of total and symptomatic infections in rural and urban settings in Thailand over the past several decades as water access has increased, although the overall incidence rate of symptomatic HAV is projected to slightly increase in the coming decades. Modeling the relationship between water, urbanization, and HAV endemicity is a novel approach in the estimation of HAV epidemiological trends and future projections. This approach provides insights about the shifting HAV epidemiology and could be used to evaluate the public health impact of vaccination and other interventions in a diversity of settings. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Modeling the hepatitis A epidemiological transition in Brazil and Mexico

    PubMed Central

    Van Effelterre, Thierry; Guignard, Adrienne; Marano, Cinzia; Rojas, Rosalba; Jacobsen, Kathryn H.

    2017-01-01

    ABSTRACT Background: Many low- to middle-income countries have completed or are in the process of transitioning from high or intermediate to low endemicity for hepatitis A virus (HAV). Because the risk of severe hepatitis A disease increases with age at infection, decreased incidence that leaves older children and adults susceptible to HAV infection may actually increase the population-level burden of disease from HAV. Mathematical models can be helpful for projecting future epidemiological profiles for HAV. Methods: An age-specific deterministic, dynamic compartmental transmission model with stratification by setting (rural versus urban) was calibrated with country-specific data on demography, urbanization, and seroprevalence of anti-HAV antibodies. HAV transmission was modeled as a function of setting-specific access to safe water. The model was then used to project various HAV-related epidemiological outcomes in Brazil and in Mexico from 1950 to 2050. Results: The projected epidemiological outcomes were qualitatively similar in the 2 countries. The age at the midpoint of population immunity (AMPI) increased considerably and the mean age of symptomatic HAV cases shifted from childhood to early adulthood. The projected overall incidence rate of HAV infections decreased by about two thirds as safe water access improved. However, the incidence rate of symptomatic HAV infections remained roughly the same over the projection period. The incidence rates of HAV infections (all and symptomatic alone) were projected to become similar in rural and urban settings in the next decades. Conclusion: This model featuring population age structure, urbanization and access to safe water as key contributors to the epidemiological transition for HAV was previously validated with data from Thailand and fits equally well with data from Latin American countries. Assuming no introduction of a vaccination program over the projection period, both Brazil and Mexico were projected to

  20. Model-based optimal planning of hepatic radiofrequency ablation.

    PubMed

    Chen, Qiyong; Müftü, Sinan; Meral, Faik Can; Tuncali, Kemal; Akçakaya, Murat

    2016-07-19

    This article presents a model-based pre-treatment optimal planning framework for hepatic tumour radiofrequency (RF) ablation. Conventional hepatic radiofrequency (RF) ablation methods rely on pre-specified input voltage and treatment length based on the tumour size. Using these experimentally obtained pre-specified treatment parameters in RF ablation is not optimal to achieve the expected level of cell death and usually results in more healthy tissue damage than desired. In this study we present a pre-treatment planning framework that provides tools to control the levels of both the healthy tissue preservation and tumour cell death. Over the geometry of tumour and surrounding tissue, we formulate the RF ablation planning as a constrained optimization problem. With specific constraints over the temperature profile (TP) in pre-determined areas of the target geometry, we consider two different cost functions based on the history of the TP and Arrhenius index (AI) of the target location, respectively. We optimally compute the input voltage variation to minimize the damage to the healthy tissue while ensuring a complete cell death in the tumour and immediate area covering the tumour. As an example, we use a simulation of a 1D symmetric target geometry mimicking the application of single electrode RF probe. Results demonstrate that compared to the conventional methods both cost functions improve the healthy tissue preservation.

  1. Evaluation of two experimental models of hepatic encephalopathy in rats.

    PubMed

    García-Moreno, L M; Conejo, N M; González-Pardo, H; Aller, M A; Nava, M P; Arias, J; Arias, J L

    2005-01-01

    The serious neuropsychological repercussions of hepatic encephalopathy have led to the creation of several experimental models in order to better understand the pathogenesis of the disease. In the present investigation, two possible causes of hepatic encephalopathy, cholestasis and portal hypertension, were chosen to study the behavioral impairments caused by the disease using an object recognition task. This working memory test is based on a paradigm of spontaneous delayed non-matching to sample and was performed 60 days after surgery. Male Wistar rats (225-250 g) were divided into three groups: two experimental groups, microsurgical cholestasis (N = 20) and extrahepatic portal hypertension (N = 20), and a control group (N = 20). A mild alteration of the recognition memory occurred in rats with cholestasis compared to control rats and portal hypertensive rats. The latter group showed the poorest performance on the basis of the behavioral indexes tested. In particular, only the control group spent significantly more time exploring novel objects compared to familiar ones (P < 0.001). In addition, the portal hypertension group spent the shortest time exploring both the novel and familiar objects (P < 0.001). These results suggest that the existence of portosystemic collateral circulation per se may be responsible for subclinical encephalopathy.

  2. A Thermodynamic Model for Genome Packaging in Hepatitis B Virus.

    PubMed

    Kim, Jehoon; Wu, Jianzhong

    2015-10-20

    Understanding the fundamentals of genome packaging in viral capsids is important for finding effective antiviral strategies and for utilizing benign viral particles for gene therapy. While the structure of encapsidated genomic materials has been routinely characterized with experimental techniques such as cryo-electron microscopy and x-ray diffraction, much less is known about the molecular driving forces underlying genome assembly in an intracellular environment and its in vivo interactions with the capsid proteins. Here we study the thermodynamic basis of the pregenomic RNA encapsidation in human Hepatitis B virus in vivo using a coarse-grained molecular model that captures the essential components of nonspecific intermolecular interactions. The thermodynamic model is used to examine how the electrostatic interaction between the packaged RNA and the highly charged C-terminal domains (CTD) of capsid proteins regulate the nucleocapsid formation. The theoretical model predicts optimal RNA content in Hepatitis B virus nucleocapsids with different CTD lengths in good agreement with mutagenesis measurements, confirming the predominant role of electrostatic interactions and molecular excluded-volume effects in genome packaging. We find that the amount of encapsidated RNA is not linearly correlated with the net charge of CTD tails as suggested by earlier theoretical studies. Our thermodynamic analysis of the nucleocapsid structure and stability indicates that ∼10% of the CTD residues are free from complexation with RNA, resulting in partially exposed CTD tails. The thermodynamic model also predicts the free energy of complex formation between macromolecules, which corroborates experimental results for the impact of CTD truncation on the nucleocapsid stability.

  3. Transmission model of hepatitis B virus with the migration effect.

    PubMed

    Khan, Muhammad Altaf; Islam, Saeed; Arif, Muhammad; ul Haq, Zahoor

    2013-01-01

    Hepatitis B is a globally infectious disease. Mathematical modeling of HBV transmission is an interesting research area. In this paper, we present characteristics of HBV virus transmission in the form of a mathematical model. We analyzed the effect of immigrants in the model to study the effect of immigrants for the host population. We added the following flow parameters: "the transmission between migrated and exposed class" and "the transmission between migrated and acute class." With these new features, we obtained a compartment model of six differential equations. First, we find the basic threshold quantity Ro and then find the local asymptotic stability of disease-free equilibrium and endemic equilibrium. Furthermore, we find the global stability of the disease-free and endemic equilibria. Previous similar publications have not added the kind of information about the numerical results of the model. In our case, from numerical simulation, a detailed discussion of the parameters and their numerical results is presented. We claim that with these assumptions and by adding the migrated class, the model informs policy for governments, to be aware of the immigrants and subject them to tests about the disease status. Immigrants for short visits and students should be subjected to tests to reduce the number of immigrants with disease.

  4. Mapping Metabolic Brain Activity in Three Models of Hepatic Encephalopathy

    PubMed Central

    Méndez, Marta; Fidalgo, Camino; Aller, María Ángeles; Arias, Jaime; Arias, Jorge L.

    2013-01-01

    Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups. PMID:23573412

  5. Empirical fitness models for hepatitis C virus immunogen design

    NASA Astrophysics Data System (ADS)

    Hart, Gregory R.; Ferguson, Andrew L.

    2015-12-01

    Hepatitis C virus (HCV) afflicts 170 million people worldwide, 2%-3% of the global population, and kills 350 000 each year. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic in the developing world where expensive drug therapies are not available. Despite 20 years of research, the high mutability of the virus and lack of knowledge of what constitutes effective immune responses have impeded development of an effective vaccine. Coupling data mining of sequence databases with spin glass models from statistical physics, we have developed a computational approach to translate clinical sequence databases into empirical fitness landscapes quantifying the replicative capacity of the virus as a function of its amino acid sequence. These landscapes explicitly connect viral genotype to phenotypic fitness, and reveal vulnerable immunological targets within the viral proteome that can be exploited to rationally design vaccine immunogens. We have recovered the empirical fitness landscape for the HCV RNA-dependent RNA polymerase (protein NS5B) responsible for viral genome replication, and validated the predictions of our model by demonstrating excellent accord with experimental measurements and clinical observations. We have used our landscapes to perform exhaustive in silico screening of 16.8 million T-cell immunogen candidates to identify 86 optimal formulations. By reducing the search space of immunogen candidates by over five orders of magnitude, our approach can offer valuable savings in time, expense, and labor for experimental vaccine development and accelerate the search for a HCV vaccine. Abbreviations: HCV—hepatitis C virus, HLA—human leukocyte antigen, CTL—cytotoxic T lymphocyte, NS5B—nonstructural protein 5B, MSA—multiple sequence alignment, PEG-IFN—pegylated interferon.

  6. Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4(+) T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling.

    PubMed

    Zhang, Hongjun; Ju, Baoling; Zhang, Xiaoli; Zhu, Yanfei; Nie, Ying; Xu, Yuanhong; Lei, Qiuxia

    2016-12-29

    Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4(+) T cells preferred to polarizing towards CD4(+) T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell-mediated fibrosis.

  7. Novel robust hepatitis C virus mouse efficacy model.

    PubMed

    Zhu, Qing; Oei, Yoko; Mendel, Dirk B; Garrett, Evelyn N; Patawaran, Montesa B; Hollenbach, Paul W; Aukerman, Sharon L; Weiner, Amy J

    2006-10-01

    The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.

  8. Novel Robust Hepatitis C Virus Mouse Efficacy Model

    PubMed Central

    Zhu, Qing; Oei, Yoko; Mendel, Dirk B.; Garrett, Evelyn N.; Patawaran, Montesa B.; Hollenbach, Paul W.; Aukerman, Sharon L.; Weiner, Amy J.

    2006-01-01

    The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-α) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-α combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts. PMID:17005803

  9. Modelling hepatic osteodystrophy in Abcb4 deficient mice

    PubMed Central

    Hochrath, Katrin; Ehnert, Sabrina; Ackert-Bicknell, Cheryl L.; Lau, Yvonne; Schmid, Andrea; Krawczyk, Marcin; Hengstler, Jan G.; Dunn, Jordanne; Hiththetiya, Kanishka; Rathkolb, Birgit; Micklich, Kateryna; Hans, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valérie; Wolf, Eckhard; de Angelis, Martin Hrabĕ; Dooley, Steven; Paigen, Beverly; Wildemann, Britt

    2014-01-01

    Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4−/−), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4−/− mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4−/− mice. Vitamin D dietary intervention was only partially able to restore the bone phenotypes of Abcb4−/− animals. We conclude that the Abcb4−/− mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions. PMID:23545228

  10. Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Magen, I; Poutahidis, T; Vorobiav, L; Zolotarev, O; Ilan, Y; Mechoulam, R; Berry, EM

    2009-01-01

    Background and purpose: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy. Experimental approach: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB1, CB2 and TRPV1 receptor agonist); HU308 (CB2 receptor agonist), SR141716A (CB1 receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB2 receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively. Results: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin. Conclusions: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value. PMID:19764982

  11. Restorative effects of hydroxysafflor yellow A on hepatic function in an experimental regression model of hepatic fibrosis induced by carbon tetrachloride

    PubMed Central

    Li, Yanuo; Shi, Yan; Sun, Yan; Liu, Luying; Bai, Xianyong; Wang, Dong; Li, Hongxing

    2016-01-01

    Hepatic fibrosis is a reversible pathological process, in which fibrotic tissue is excessively deposited in the liver during the repair process that follows hepatic injury. Early prevention or treatment of hepatic fibrosis has great significance on the treatment of chronic hepatic diseases. Hydroxysafflor yellow A (HSYA) is a water-soluble monomer extracted from safflower, which serves numerous pharmacological roles. However, it remains to be elucidated how HSYA regulates hepatic fibrogenesis. The aim of the present study was to reveal the possible mechanisms underlying the effects of HSYA on the prevention and treatment of hepatic fibrosis. A rat model of hepatic fibrosis was established in the present study, and the rats were administered various doses of HSYA. The effects of HSYA on pathological alterations of the liver tissue in rats with hepatic fibrosis were observed using hematoxylin-eosin staining and Masson staining. In order to explore the anti-hepatic fibrosis effects and underlying mechanisms of HSYA, serum levels, and hepatic function and hepatic fibrosis indices were evaluated. The results demonstrated that HSYA can improve the general condition of rats with hepatic fibrosis and relieve cellular swelling of the liver, fatty degeneration, necrosis, inflammatory cell infiltration and fibroplastic proliferation. Subsequent to administration of HSYA, globulin was increased during hepatic fibrosis caused by tetrachloromethane. However, total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase and levels of hyaluronic acid, laminin, procollagen III N-terminal peptide, collagen type IV and hydroxyproline were significantly reduced. The results additionally demonstrated that HSYA could enhance superoxide dismutase activity and reduce malondialdehyde levels, inhibiting lipid peroxidation caused by free radicals. PMID:27909717

  12. Modelling the hepatitis B vaccination programme in prisons.

    PubMed

    Sutton, A J; Gay, N J; Edmunds, W J; Andrews, N J; Hope, V D; Gilbert, R L; Piper, M; Gill, O N

    2006-04-01

    A vaccination programme offering hepatitis B (HBV) vaccine at reception into prison has been introduced into selected prisons in England and Wales. Over the coming years it is anticipated this vaccination programme will be extended. A model has been developed to assess the potential impact of the programme on the vaccination coverage of prisoners, ex-prisoners, and injecting drug users (IDUs). Under a range of coverage scenarios, the model predicts the change over time in the vaccination status of new entrants to prison, current prisoners and IDUs in the community. The model predicts that at baseline in 2012 57% of the IDU population will be vaccinated with up to 72% being vaccinated depending on the vaccination scenario implemented. These results are sensitive to the size of the IDU population in England and Wales and the average time served by an IDU during each prison visit. IDUs that do not receive HBV vaccine in the community are at increased risk from HBV infection. The HBV vaccination programme in prisons is an effective way of vaccinating this hard-to-reach population although vaccination coverage on prison reception must be increased to achieve this.

  13. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

    2011-01-01

    BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

  14. Establishment of mice model with human viral hepatitis B

    PubMed Central

    Gao, Li-Fen; Sun, Wen-Sheng; Ma, Chun-Hong; Liu, Su-Xia; Wang, Xiao-Yan; Zhang, Li-Ning; Cao, Ying-Lin; Zhu, Fa-Liang; Liu, Yu-Gang

    2004-01-01

    AIM: To establish a mice model of hepatitis B by using HBV-transgenic mice, and to transfer HBV-specific cytotoxic T lymphocytes (CTL) induced from syngeneic BALB/c mice immunized by a eukaryotic expression vector containing HBV complete genome DNA. METHODS: HBV DNA was obtained from digested pBR322-2HBV and ligated with the vector pcDNA3. Recombinant pcDNA3-HBV was identified by restriction endonuclease assay and transfected into human hepatoma cell line HepG2 with lipofectin. ELISA was used to detect the expression of HBsAg in culture supernatant, and RT-PCR to determine the existence of HBV PreS1 mRNA. BALB/c mice were immunized with pcDNA3-HBV or pcDNA3 by intramuscular injection. ELISA was used to detect the expression of HBsAb in serum. MTT assay was used to measure non-specific or specific proliferation ability and specific killing activity of spleen lymphocytes. Lymphocytes from immunized mice were transferred into HBV-transgenic mice (2.5 × 107 per mouse). Forty-eight hours later, the level of serum protein and transaminase was detected with biochemical method, liver and kidney were sectioned and stained by HE to observe the pathological changes. RESULTS: By enzyme digestion with Eco RI, Xho I and Hind III, the recombinant pcDNA3-HBV was verified to contain a single copy of HBV genome, which was inserted in the positive direction. HepG2 cells transfected with the recombinant could stably express PreS1 mRNA and HBsAg. After immunized by pcDNA3-HBV for 4 weeks, HBsAb was detected in the serum of BALB/c mice. The potential of spleen lymphocytes for both non-specific and specific proliferation and the specific killing activity against target cells were enhanced. The transgenic mice in model group had no significant changes in the level of serum protein but had an obvious increase of ALT and AST. The liver had obvious pathological changes, while the kidney had no evident damage. CONCLUSION: A eukaryotic expression vector pcDNA3-HBV containing HBV complete

  15. A noninvasive diagnostic model to assess nonalcoholic hepatic steatosis in patients with chronic hepatitis B

    PubMed Central

    Ou, Hongjie; Cai, Shaohang; Liu, Ying; Xia, Muye; Peng, Jie

    2016-01-01

    Objective: The objective of this study was to develop a noninvasive diagnostic test for nonalcoholic hepatic steatosis in patients with chronic hepatitis B (CHB) by using routinely available clinical markers. Methods: A retrospective study of patients with CHB, with or without hepatic steatosis (fatty change) who were diagnosed with controlled attenuation parameter (CAP) measured by transient elastography were included. Patient information was analyzed on lifestyle; laboratory tests, including serum lipid levels; blood pressure; blood uric acid; and medical history of type 2 diabetes mellitus (T2DM). Results: A total of 1312 patients were included in the study; 618 patients had confirmed hepatic steatosis. The CAP levels were significantly correlated with patient height (p < 0.001), weight (p < 0.001), waistline measurement (p < 0.001), hipline measurement (p < 0.001), and diastolic blood pressure (DBP) (p < 0.001). Multivariate logistic regression analysis resulted in the development of an equation for the diagnostic of simple steatosis: the fatty liver (FL) test. The area under the receiver operating characteristic (AUROC) curve of the FL test was 0.79 (p < 0.001) in the training group and 0.82 in the validation group. When the FL test was >−0.425, the sensitivity, specificity, positive likelihood ratio (LR) and negative LR were 74.72%, 72.12%, 2.68, and 0.35 respectively. The average FL test result was −0.54 ± 1.26 in patients with CHB without hypertension, and 0.42 ± 1.35, 1.12 ± 1.65, and 1.98 ± 1.22 in patients with hypertension grade 1, 2, and 3, respectively (p < 0.001). Conclusion: This study has demonstrated a noninvasive test for hepatic steatosis in patients with CHB. PMID:28203279

  16. Experimental models of hepatitis B and C — new insights and progress

    PubMed Central

    Thomas, Emmanuel; Liang, T. Jake

    2017-01-01

    Viral hepatitis is a major cause of morbidity and mortality, affecting hundreds of millions of people worldwide. Hepatitis-causing viruses initiate disease by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma. Consequently, intense research efforts have been focusing on increasing our understanding of hepatitis virus biology and on improving antiviral therapy and vaccination strategies. Although valuable information on viral hepatitis emerged from careful epidemiological studies on sporadic outbreaks in humans, experimental models using cell culture, rodent and non-human primates were essential in advancing the field. Through the use of these experimental models, improvement in both the treatment and prevention of viral hepatitis has progressed rapidly; however, agents of viral hepatitis are still among the most common pathogens infecting humans. In this Review, we describe the important part that these experimental models have played in the study of viral hepatitis and led to monumental advances in our understanding and treatment of these pathogens. Ongoing developments in experimental models are also described. PMID:27075261

  17. Exposure to Fine Airborne Particulate Matters Induces Hepatic Fibrosis in Murine Models

    PubMed Central

    Zheng, Ze; Zhang, Xuebao; Wang, Jiemei; Dandeka, Aditya; Kim, Hyunbae; Qiu, Yining; Xu, Xiaohua; Cui, Yuqi; Wang, Aixia; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong

    2016-01-01

    Background Hepatic fibrosis, featured by accumulation of excessive extracellular matrix in liver tissues, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM2.5) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM2.5 exposure on hepatic fibrogenesis. Methods Both inhalation exposure of mice and in vitro exposure of specialized cells to PM2.5 were performed to elucidate the effect of PM2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM2.5 exposure promotes hepatic fibrosis. Results Inhalation exposure to concentrated ambient PM2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM2.5 led to activation of the transforming growth factor β (TGFβ)-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ (PPARγ), and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM2.5-induced liver fibrogenesis. Conclusions Exposure to PM2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM2.5 exposure on promoting hepatic fibrosis. PMID:26220751

  18. Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models.

    PubMed

    Zheng, Ze; Zhang, Xuebao; Wang, Jiemei; Dandekar, Aditya; Kim, Hyunbae; Qiu, Yining; Xu, Xiaohua; Cui, Yuqi; Wang, Aixia; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong

    2015-12-01

    Hepatic fibrosis, featured by the accumulation of excessive extracellular matrix in liver tissue, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM2.5) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM2.5 exposure on hepatic fibrogenesis. Both inhalation exposure of mice and in vitro exposure of specialized cells to PM2.5 were performed to elucidate the effect of PM2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM2.5 exposure promotes hepatic fibrosis. Inhalation exposure to concentrated ambient PM2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM2.5 led to activation of the transforming growth factor β-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ, and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM2.5-induced liver fibrogenesis. Exposure to PM2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM2.5 exposure on promoting hepatic fibrosis. Copyright © 2015. Published by Elsevier B.V.

  19. Alcohol induced hepatic degeneration in a hepatitis C virus core protein transgenic mouse model.

    PubMed

    Noh, Dong-Hyung; Lee, Eun-Joo; Kim, Ah-Young; Lee, Eun-Mi; Min, Chang-Woo; Kang, Kyung-Ku; Lee, Myeong-Mi; Kim, Sang-Hyeob; Sung, Soo-Eun; Hwang, Meeyul; Yu, Dae-Yeul; Jeong, Kyu-Shik

    2014-03-07

    Hepatitis C virus (HCV) has become a major public health issue. It is prevalent in most countries. HCV infection frequently begins without clinical symptoms, before progressing to persistent viremia, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the majority of patients (70% to 80%). Alcohol is an independent cofactor that accelerates the development of HCC in chronic hepatitis C patients. The purpose of the current study was to evaluate ethanol-induced hepatic changes in HCV core-Tg mice and mutant core Tg mice. Wild type (NTG), core wild-Tg mice (TG-K), mutant core 116-Tg mice (TG-116) and mutant core 99-Tg mice (TG-99) were used in this investigation. All groups were given drinking water with 10% ethanol and 5% sucrose for 13 weeks. To observe liver morphological changes, we performed histopathological and immunohistochemical examinations. Histopathologically, NTG, TG-K and TG-116 mice showed moderate centrilobular necrosis, while severe centrilobular necrosis and hepatocyte dissociation were observed in TG-99 mice with increasing lymphocyte infiltration and piecemeal necrosis. In all groups, a small amount of collagen fiber was found, principally in portal areas. None of the mice were found to have myofibroblasts based on immunohistochemical staining specific for α-SMA. CYP2E1-positive cells were clearly detected in the centrilobular area in all groups. In the TG-99 mice, we also observed cells positive for CK8/18, TGF-β1 and phosphorylated (p)-Smad2/3 and p21 around the necrotic hepatocytes in the centrilobular area (p < 0.01). Based on our data, alcohol intake induced piecemeal necrosis and hepatocyte dissociation in the TG-99 mice. These phenomena involved activation of the TGF-β1/p-Smad2/3/p21 signaling pathway in hepatocytes. Data from this study will be useful for elucidating the association between alcohol intake and HCV infection.

  20. The Impact of Acute Matriptase Inhibition in Hepatic Inflammatory Models

    PubMed Central

    Szombath, Gergely; Rokonál, Patrik; Mátis, Gábor; Neogrády, Zsuzsanna

    2016-01-01

    Purpose. Dysfunction of matriptase-2 can be involved in iron regulatory disorder via downregulation of hepcidin expression. In the present study, we investigated the effects of 3-amidinophenylalanine-derived matriptase inhibitors on porcine hepatic inflammatory cell models. Methods. Hepatocyte-Kupffer cell cocultures (ratio of 2 : 1 and 6 : 1) were treated with four structurally related matriptase inhibitors at 50 μM. Cell cytotoxicity and relative expressions of IL-6 and IL-8 and the levels of hepcidin were determined by MTS and porcine-specific ELISA. The extracellular H2O2 contents were analyzed by Amplex Red method. Results. Matriptase inhibitors at 50 µM for 24 h did not increase cell death rate. The elevated ROS production observed after short-term application of inhibitor MI-441 could be correlated with lowered hepcidin expression. MI-460 could significantly enhance hepcidin levels in the supernatants of cocultures (by 62.21 ± 26.8% in hepatocyte-Kupffer cell, 2 : 1, and by 42.6 ± 14.3% in hepatocyte-Kupffer cell, 6 : 1, cocultures, resp.). No significant changes were found in IL-6 and IL-8 levels in cocultures exposed to matriptase inhibitors. Conclusions. Based on in vitro findings, administration of MI-460 via modulation of hepcidin expression without cytotoxic and oxidative stress inducing properties might be a reliable alternative to treat iron overload in human and veterinary clinical practice. PMID:27642598

  1. Economic model of observation versus immediate resection of hepatic adenomas.

    PubMed

    Vanounou, Tsafrir; Groeschl, Ryan T; Geller, David A; Marsh, J Wallis; Gamblin, T Clark

    2012-09-15

    For small asymptomatic hepatic adenomas (HA), available data are insufficient to establish the superiority of either observation or surgery. We sought to investigate the cost-effectiveness of two initial management strategies. We performed a comparative analysis of two theoretical cohorts of 100 patients with small (<5 cm), asymptomatic HA. Discounted cash flow (DCF) models compared the net present value (NPV) of both treatment options at year 10 under three distinct progression rate scenarios. A break-even (BE) analysis was used to determine the BE point at which the NPV for observation and immediate surgery intersect. The NPV for immediate surgery was $1,733,955. The NPV for observation varied between $2,065,315-$2,745,631 for computed tomography (CT), $2,264,575-$2,929,541 for magnetic resonance imaging (MRI), and $802,837-$1,580,413 for ultrasound (US). The BE point was between 6 and 8 years for CT and 5-7 years for MRI. The BE point for US was not reached except in the highest progression rate scenario (12 years). This study highlights the importance of the underlying progression rate and the cost of imaging when following patients with asymptomatic HA. Overall, US surveillance is the most cost-efficient approach to observing small asymptomatic HA. If cross-sectional imaging is utilized, then immediate surgery is the most cost-effective decision at 5-8 years. Copyright © 2012 Wiley Periodicals, Inc.

  2. The tree shrews: useful animal models for the viral hepatitis and hepatocellular carcinoma.

    PubMed

    Yang, Er-Bin; Cao, Ji; Su, Jian-Jia; Chow, Pierce

    2005-01-01

    Hepatitis B virus (HBV)-induced hepatitis and hepatocellular carcinoma (HCC) are major diseases worldwide. HBV infection and chemical carcinogens such as aflatoxin B1 are known to be two key factors in the development of HCC. Animal models for hepatitis and HCC are very useful in the in vivo studies of mechanism involved in the development and prevention of these diseases and the pre-clinical research of drugs for the treatment of these diseases. Now, several animals, such as woodchucks, ground squirrels, chimpanzees, ducks and tree shrews, have been used to establish hepatitis and HCC models. HCC occurs in some woodchucks and ground squirrels that are infected with their own hepatitis viruses and exposed to carcinogens. Chimpanzees and ducks can be infected with human and duck hepatitis B viruses, respectively, but HCC is rarely observed in these animals. The tree shrews are non-rodent, small animals and close to primates in evolution. This review focuses on the establishment of human HBV-induced hepatitis and human HBV-associated HCC in tree shrews and their applications in the study of HCC development.

  3. Antenna design for microwave hepatic ablation using an axisymmetric electromagnetic model.

    PubMed

    Bertram, John M; Yang, Deshan; Converse, Mark C; Webster, John G; Mahvi, David M

    2006-02-27

    An axisymmetric finite element method (FEM) model was employed to demonstrate important techniques used in the design of antennas for hepatic microwave ablation (MWA). To effectively treat deep-seated hepatic tumors, these antennas should produce a highly localized specific absorption rate (SAR) pattern and be efficient radiators at approved generator frequencies. As an example, a double slot choked antenna for hepatic MWA was designed and implemented using FEMLABtrade mark 3.0. This paper emphasizes the importance of factors that can affect simulation accuracy, which include boundary conditions, the dielectric properties of liver tissue, and mesh resolution.

  4. Antenna design for microwave hepatic ablation using an axisymmetric electromagnetic model

    PubMed Central

    Bertram, John M; Yang, Deshan; Converse, Mark C; Webster, John G; Mahvi, David M

    2006-01-01

    Background An axisymmetric finite element method (FEM) model was employed to demonstrate important techniques used in the design of antennas for hepatic microwave ablation (MWA). To effectively treat deep-seated hepatic tumors, these antennas should produce a highly localized specific absorption rate (SAR) pattern and be efficient radiators at approved generator frequencies. Methods and results As an example, a double slot choked antenna for hepatic MWA was designed and implemented using FEMLAB™ 3.0. Discussion This paper emphasizes the importance of factors that can affect simulation accuracy, which include boundary conditions, the dielectric properties of liver tissue, and mesh resolution. PMID:16504153

  5. Diurnal locomotor activity and oxidative metabolism of the suprachiasmatic nucleus in two models of hepatic insufficiency.

    PubMed

    Lopez, Laudino; Cimadevilla, Jose M; Aller, Maria A; Arias, Jaime; Nava, M Paz; Arias, Jorge L

    2003-08-15

    Subjects with hepatic cirrhosis develop alterations of several rhythmic behavioural and biochemical patterns. Since most cirrhotic patients combine portal hypertension and hepatic impairment, our work aims to assess the extent to which rhythmical changes can be due to hepatic insufficiency or portal hypertension. This was done using two experimental models in rats, portacaval shunt model (PC) and portal hypertension by a triple stenosing ligature of the portal vein (PH). We assess diurnal locomotor activity and determine the oxidative metabolism of the suprachiasmatic nucleus (SCN) by histochemical determination of cytochrome oxidase (COX). The results show that animals with PC have altered diurnal locomotor rhythm compared to control and PH rats (p<0.001). They also present lower COX activity in the SCN (p<0.05). We conclude that rhythmic alterations are due to hepatic insufficiency and not to portal hypertension.

  6. Dysplastic Hepatocytes Develop Nuclear Inclusions in a Mouse Model of Viral Hepatitis

    PubMed Central

    Thakur, Priyanka; Lamoke, Folami; Chaffin, Joanna M.; Bartoli, Manuela; Lee, Jeffrey R.; Duncan, Michael B.

    2014-01-01

    Viral hepatitis resulting in chronic liver disease is an important clinical challenge and insight into the cellular processes that drive pathogenesis will be critical in order to develop new diagnostic and therapeutic options. Nuclear inclusions in viral and non-viral hepatitis are well documented and have diagnostic significance in some disease contexts. However, the origins and functional consequences of these nuclear inclusions remain elusive. To date the clinical observation of nuclear inclusions in viral and non-viral hepatitis has not been explored at depth in murine models of liver disease. Herein, we report that in a transgenic model of hepatitis B surface antigen mediated hepatitis, murine hepatocytes exhibit nuclear inclusions. Cells bearing nuclear inclusions were more likely to express markers of cell proliferation. We also established a correlation between these inclusions and oxidative stress. N-acetyl cysteine treatment effectively reduced oxidative stress levels, relieved endoplasmic reticulum (ER) stress, and the number of nuclear inclusions we observed in the transgenic mice. Our results suggest that the presence of nuclear inclusions in hepatocytes correlates with oxidative stress and cellular proliferation in a model of antigen mediated hepatitis. PMID:24932583

  7. Protective effect of ellagic acid on concanavalin A-induced hepatitis via toll-like receptor and mitogen-activated protein kinase/nuclear factor κB signaling pathways.

    PubMed

    Lee, Jae Hong; Won, Jong Hoon; Choi, Jong Min; Cha, Hye Hyeon; Jang, Yeo Jin; Park, Seohyeon; Kim, Han Gyeol; Kim, Hyung Chul; Kim, Dae Kyong

    2014-10-15

    Ellagic acid (EA) is present in certain fruits and nuts, including raspberries, pomegranates, and walnuts, and has anti-inflammatory and antioxidant properties. The aims of this study were to examine the protective effect of EA on concanavalin A (Con A)-induced hepatitis and to elucidate its underlying molecular mechanisms in mice. Mice were orally administered EA at different doses before the intravenous delivery of Con A; the different experimental groups were as follows: (i) vehicle control, (ii) Con A alone without EA, (iii) EA at 50 mg/kg, (iv) EA at 100 mg/kg, and (v) EA at 200 mg/kg. We found that EA pretreatment significantly reduced the levels of plasma aminotransferase and liver necrosis in Con A-induced hepatitis. Also, EA significantly decreased the expression levels of the toll-like receptor 2 (TLR2) and TLR4 mRNA and protein in liver tissues. Further, EA decreased the phosphorylation of JNK, ERK1/2, and p38. EA-treated groups showed suppressions of nuclear factor κB (NF-κB) and IκB-α degradation levels in liver tissues. In addition, EA pretreatment decreased the expression of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β). These results suggest that EA protects against T-cell-mediated hepatitis through TLR and mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways.

  8. Physiologically based modeling of hepatic and gastrointestinal biotransformation in fish

    EPA Science Inventory

    In fish, as in mammals, the liver generally viewed as the principal site of chemical biotransformation. For waterborne exposures, such as those conducted in support of standardized BCF testing, the effects of hepatic metabolism on chemical accumulation can be simulated using rela...

  9. Physiologically based modeling of hepatic and gastrointestinal biotransformation in fish

    EPA Science Inventory

    In fish, as in mammals, the liver generally viewed as the principal site of chemical biotransformation. For waterborne exposures, such as those conducted in support of standardized BCF testing, the effects of hepatic metabolism on chemical accumulation can be simulated using rela...

  10. Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

    PubMed Central

    van Gorp, Patrick J.; Jeurissen, Mike L. J.; Houben, Tom; Walenbergh, Sofie M. A.; Debets, Jacques; Oligschlaeger, Yvonne; Gijbels, Marion J. J.; Neumann, Dietbert; Shiri-Sverdlov, Ronit

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)—a serum protein mainly secreted by liver—was shown to inhibit oxidized low-density lipoprotein (OxLDL)/lipopolysaccharides (LPS)-induced inflammation in mouse macrophages. Additionally, MSP could reduce palmitic acid (PA)-induced lipid accumulation and lipogenesis in the HepG2 cell line. Altogether, these data suggest MSP as a suppressor for metabolic inflammation. However, so far the potential of MSP to be used as a treatment for NASH was not investigated. We hypothesized that MSP reduces lipid accumulation and hepatic inflammation. To investigate the effects of MSP in the early stage of NASH, low-density lipoprotein receptor (Ldlr-/-) mice were fed either a regular chow or a high fat, high cholesterol (HFC) diet for 7 days. Recombinant MSP or saline (control) was administrated to the mice by utilizing subcutaneously-implanted osmotic mini-pumps for the last 4 days. As expected, mice fed an HFC diet showed increased plasma and hepatic lipid accumulation, as well as enhanced hepatic inflammation, compared with chow-fed controls. Upon MSP administration, the rise in cholesterol and triglyceride levels after an HFC diet remained unaltered. Surprisingly, while hepatic macrophage and neutrophil infiltration was similar between the groups, MSP-treated mice showed increased gene expression of pro-inflammatory and pro-apoptotic mediators in the liver, compared with saline-treated controls. Contrary to our expectations, MSP did not ameliorate NASH. Observed changes in inflammatory gene expression suggest that further research is needed to clarify the long-term effects of MSP. PMID:27685150

  11. Bisphenol a induces steatosis in HepaRG cells using a model of perinatal exposure.

    PubMed

    Bucher, Simon; Jalili, Pégah; Le Guillou, Dounia; Begriche, Karima; Rondel, Karine; Martinais, Sophie; Zalko, Daniel; Corlu, Anne; Robin, Marie-Anne; Fromenty, Bernard

    2017-03-01

    Human exposure to bisphenol A (BPA) could favor obesity and related metabolic disorders such as hepatic steatosis. Investigations in rodents have shown that these deleterious effects are observed not only when BPA is administered during the adult life but also with different protocols of perinatal exposure. Whether perinatal BPA exposure could pose a risk in human is currently unknown, and thus appropriate in vitro models could be important to tackle this major issue. Accordingly, we determined whether long-term BPA treatment could induce steatosis in human HepaRG cells by using a protocol mimicking perinatal exposure. To this end, the kinetics of expression of seven proteins differentially expressed during liver development was determined during a 4-week period of cell culture required for proliferation and differentiation. By analogy with data reported in rodents and humans, our results indicated that the period of cell culture around day 15 and day 18 after seeding could be considered as the "natal" period. Consequently, HepaRG cells were treated for 3 weeks with BPA (from 0.2 to 2000 nM), with a treatment starting during the proliferating period. BPA was able to induce steatosis with a nonmonotonic dose response profile, with significant effects on neutral lipids and triglycerides observed for the 2 nM concentration. However, the expression of many enzymes involved in lipid and carbohydrate homeostasis was unchanged in exposed HepaRG cells. The expression of other potential BPA targets and enzymes involved in BPA biotransformation was also determined, giving answers as well as new questions regarding the mechanisms of action of BPA. Hence, HepaRG cells provide a valuable model that can prove useful for the toxicological assessment of endocrine disruptors on hepatic metabolisms, in particular in the developing liver. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1024-1036, 2017. © 2016 Wiley Periodicals, Inc.

  12. Randomized, Controlled Comparison of Advanced Hemostatic Pads in Hepatic Surgical Models

    PubMed Central

    Lewis, Kevin M.

    2014-01-01

    Blood loss during hepatic surgery leads to poor patient outcomes. This study investigates the hemostatic efficacy of a novel sealing hemostatic pad (polyethylene glycol-coated collagen, PCC) and a fibrin sealant pad (fibrin-thrombin coated collagen, FTC) in a leporine hepatic segmentectomy and a porcine hepatic abrasion model. A segmentectomy was used to compare hemostatic success and hematoma incidence in 20 rabbits (10/group). Hepatic abrasions were used to compare hemostatic success up to 10 min after application in six pigs (42 lesions/group). In the segmentectomy model, PCC achieved 100% hemostatic success within 2 min (95% CI: 72.3% to 100%) and FTC achieved 80% hemostatic success within 3 min (49.0% to 94.3%). PCC had lower hematoma incidence at 15 min (0.0 versus 11.1%) and 24 h (20.0 versus 66.7%). In the abrasion model, PCC provided superior hemostatic success at 3 (odds ratio: 24.8, 95% CI: 8.86 to 69.2, P < 0.001), 5 (66.3, 28.5 to 153.9, P < 0.001), 7 (177.5, 64.4 to 489.1, P < 0.001), and 10 min (777.6, 148.2 to 4078, P < 0.001) leading to statistically significant less blood loss. The novel sealing hemostat provides faster and more sustained hemostasis than a fibrin sealant pad in a leporine hepatic segmentectomy and a porcine hepatic abrasion model of hepatic surgery. PMID:24729905

  13. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification

    PubMed Central

    Allen, Richard J; Musante, Cynthia J

    2017-01-01

    Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing ‘transfer function’. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole. PMID:28469410

  14. An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers

    EPA Science Inventory

    The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a t...

  15. An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers

    EPA Science Inventory

    The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a t...

  16. Acetylcholinesterase activity in an experimental rat model of Type C hepatic encephalopathy.

    PubMed

    Méndez, Marta; Méndez-López, Magdalena; López, Laudino; Aller, María A; Arias, Jaime; Arias, Jorge L

    2011-05-01

    Patients with liver malfunction often suffer from hepatic encephalopathy, a neurological complication which can affect attention and cognition. Diverse experimental models have been used to study brain alterations that may be responsible for hepatic encephalopathy symptoms. The aim of the study was to determine whether cognitive impairment found in cirrhosis could be due to disturbance of acetylcholinesterase activity. Acetylcholinesterase activity was assessed in the brains of Wistar rats with thioacetamide-induced cirrhosis. The cirrhotic group displayed up-regulation of acetylcholinesterase levels in the entorrhinal cortex, anterodorsal and anteroventral thalamus and accumbens, whereas down-regulation was found in the CA1, CA3 and dentate gyrus of the hippocampus. Our results indicate that the experimental model of hepatic encephalopathy by chronic administration of thioacetamide presents alterations of acetylcholinesterase activity in brain limbic system regions, which play a role in attention and memory.

  17. Bile duct warmer in hepatic cryosurgery--a pig liver model.

    PubMed

    Seifert, J K; Dutkowski, P; Junginger, T; Morris, D L

    1997-11-01

    Freezing of the common bile duct resulted in injury, stenosis, or perforation of the bile duct in a dog model. Biliary cutaneous fistulas and bile leaks are reported as complications of hepatic cryosurgery in man. In an ex vivo pig liver model we compared freezing close to the bile duct with and without warming the bile duct with warmed saline solution via an inserted catheter ("bile duct warmer"). The recorded temperatures at the outer wall of the bile duct were -50 degrees C after 10 min of freezing without and 5. 8 degrees C with the use of the warmer (P < 0.001, two-way ANOVA). The bile duct warmer system may be a simple and inexpensive device in reducing perioperative morbidity after hepatic cryosurgery of hepatic liver lesions close to a bile duct.

  18. Integrated internist - addiction medicine - hepatology model for hepatitis C management for individuals on methadone maintenance.

    PubMed

    Martinez, A D; Dimova, R; Marks, K M; Beeder, A B; Zeremski, M; Kreek, M J; Talal, A H

    2012-01-01

    Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co-localized care model in which an internist-addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti-HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6-22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty-four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices.

  19. Computational classification models for predicting the interaction of compounds with hepatic organic ion importers.

    PubMed

    You, Hwan; Lee, Kyungro; Lee, Sangwon; Hwang, Sung Bo; Kim, Kwang-Yon; Cho, Kwang-Hwi; No, Kyoung Tai

    2015-10-01

    Hepatic transporters, a major determinant of pharmacokinetics, have been used to profile drug properties like efficacy. Among hepatic transporters, importers alter the concentration of the drug by facilitating the transport of a drug into a cell. Despite vast pharmacokinetic studies, the interacting mechanisms of the importers with its substrates or inhibitors are not well understood. Hence, we developed compound binary classification models of whether a compound is binder or nonbinder to a hepatic transporter with experimental data of 284 compounds for four representative hepatic importers, OATP1B1, OATP1B3, OAT2, and OCT1. Support Vector Machine (SVM) along with Genetic Algorithm (GA) was used to construct the classification models of binder versus nonbinder for each target importer. To construct the models, we prepared two data sets, a training data set from Fujitsu database (284 compounds) and an external validation data set from ChEMBL database (1738 compounds). Since an experimental classification criterion between binder and nonbinder has some ambiguity, there is an intrinsic limitation to expect high predictability of the binary classification models developed with the experimental data. The predictability of the classification models calculated with external validation sets were obtained as 77.72%, 84.31%, 84.21%, and 76.38 for OATP1B1, OATP1B3, OAT2, and OCT1, respectively.

  20. Implementation of the ECHO(®) telementoring model for the treatment of patients with hepatitis C.

    PubMed

    Marciano, Sebastián; Haddad, Leila; Plazzotta, Fernando; Mauro, Ezequiel; Terraza, Sergio; Arora, Sanjeev; Thornton, Karla; Ríos, Beatriz; García Dans, Carlos; Ratusnu, Natalia; Calanni, Liliana; Allevato, José; Sirotinsky, María Ester; Pedrosa, Marcos; Gadano, Adrián

    2017-04-01

    We aimed to implement the Extension for Community Healthcare Outcomes (ECHO) telementoring model for hepatitis C and to evaluate its outcomes in the health providers. Following the ECHO model, an hepatitis C teleECHO clinic was established at the Hospital Italiano in Argentina. The teleECHO clinic provides support and training to physicians from Patagonia who treat patients with hepatitis C. In order to evaluate the teleECHO clinic outcomes, physicians completed a survey focused on skills and competence in hepatitis C before and after 6 months of participating in the project. The survey consisted of 10 questions, which participants rated from 1 to 7 (1 no ability; 7 highest ability). To analyze the difference before and after participation in the project, Wilcoxon signed-rank test was used. During the first 6 months of implementation of the model, a total of 14 physicians from 12 sites in Patagonia agreed to participate in the survey. The median age of the participants was 42 years. Participants' primary specialties were Hepatology (55%), Infectious Diseases (25%), General Practice (10%), and other (10%). A significant improvement was observed in all the evaluated fields after 6 month of the participation in the teleECHO clinic, namely fibrosis staging, determining appropriate candidates for treatment, and selecting appropriate HCV treatment. In addition, their general interest in hepatitis C increased. We successfully replicated and implemented the first teleECHO clinic in Argentina. Physicians improved their ability to provide best practice care for patients with Hepatitis C. J. Med. Virol. 89:660-664, 2017. © 2016 Wiley Periodicals, Inc.

  1. Flow cytometric quantification of T cell proliferation and division kinetics in woodchuck model of hepatitis B.

    PubMed

    Gujar, Shashi A; Michalak, Tomasz I

    2005-01-01

    Woodchucks infected with woodchuck hepatitis virus (WHV) represent the closest natural animal model to study the immunopathogenesis of liver injury caused by essentially noncytopathic, highly human specific hepatitis B virus (HBV). The importance of antiviral T cell response in induction of hepatitis and in control of HBV replication has been demonstrated. However, the understanding of how these responses contribute to the development of different immunomorphological forms of liver disease and their outcomes remain elusive. In this study, we established and standardized a flow cytometry assay using peripheral blood mononuclear cells labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) to assess WHV-specific and mitogen-driven T lymphocyte proliferative responses in woodchucks. The assay is of significantly greater sensitivity than the adenine incorporation assay currently used when applied to measure either WHV-specific T cell responses in acute (P < 0.001) and chronic (P < 0.03) viral hepatitis or those induced by mitogens in both healthy and WHV-infected animals. It also provides a new type of information, not previously available, characterizing the strength of woodchuck T cell proliferative reactivity by measuring cell division rates. The study shows that woodchuck PBMC labeled with CFSE exhibit light scatter and fluorescence profiles compatible to those of human PBMC, allowing quantitation and deconvolution of the flow cytometric data by applying the existing analytical softwares. The availability of this novel assay should facilitate a more precise and comprehensive evaluation of hepadnavirus-specific and generalized T cell responses in experimental WHV hepatitis.

  2. Comparative Testing of Hemostatic Dressing in a Large Animal Model (Sus Scorofa) with Severe hepatic Injuries

    DTIC Science & Technology

    2013-12-02

    hemostatic dressings in a large animal model (Sus scrofa ) with severe hepatic injuries PRINCIPAL INVESTIGATOR (PI) / TRAINING COORDINATOR (TC): Capt...to Date Sus scrofa 36 18 18 Note. Many fewer animals than approved were used because one of the original treatment groups (Lypressin- soaked gauze

  3. Viral hepatitis: A new HCV cell culture model for the next clinical challenges.

    PubMed

    Colpitts, Che C; Baumert, Thomas F

    2015-11-01

    Despite advances in hepatitis C treatment, substantial clinical hurdles remain to achieve universal cure and global control of infection. Saeed et al. identified SEC14L2 as a host factor permitting replication of clinical HCV isolates in cell culture, providing a novel system to model infection of patient-derived viruses.

  4. Dynamical modeling of liver Aquaporin-9 expression and glycerol permeability in hepatic glucose metabolism.

    PubMed

    Gena, Patrizia; Buono, Nicoletta Del; D'Abbicco, Marcello; Mastrodonato, Maria; Berardi, Marco; Svelto, Maria; Lopez, Luciano; Calamita, Giuseppe

    2017-01-01

    Liver is crucial in the homeostasis of glycerol, an important metabolic intermediate. Plasma glycerol is imported by hepatocytes mainly through Aquaporin-9 (AQP9), an aquaglyceroporin channel negatively regulated by insulin in rodents. AQP9 is of critical importance in glycerol metabolism since hepatic glycerol utilization is rate-limited at the hepatocyte membrane permeation step. Glycerol kinase catalyzes the initial step for the conversion of the imported glycerol into glycerol-3-phosphate, a major substrate for de novo synthesis of glucose (gluconeogenesis) and/or triacyglycerols (lipogenesis). A model addressing the glucose-insulin system to describe the hepatic glycerol import and metabolism and the correlation with the glucose homeostasis is lacking so far. Here we consider a system of first-order ordinary differential equations delineating the relevance of hepatocyte AQP9 in liver glycerol permeability. Assuming the hepatic glycerol permeability as depending on the protein levels of AQP9, a mathematical function is designed describing the time course of the involvement of AQP9 in mouse hepatic glycerol metabolism in different nutritional states. The resulting theoretical relationship is derived fitting experimental data obtained with murine models at the fed, fasted or re-fed condition. While providing useful insights into the dynamics of liver AQP9 involvement in male rodent glycerol homeostasis our model may be adapted to the human liver serving as an important module of a whole body-model of the glucose metabolism both in health and metabolic diseases.

  5. Comparisons of forecasting for hepatitis in Guangxi Province, China by using three neural networks models.

    PubMed

    Gan, Ruijing; Chen, Ni; Huang, Daizheng

    2016-01-01

    This study compares and evaluates the prediction of hepatitis in Guangxi Province, China by using back propagation neural networks based genetic algorithm (BPNN-GA), generalized regression neural networks (GRNN), and wavelet neural networks (WNN). In order to compare the results of forecasting, the data obtained from 2004 to 2013 and 2014 were used as modeling and forecasting samples, respectively. The results show that when the small data set of hepatitis has seasonal fluctuation, the prediction result by BPNN-GA will be better than the two other methods. The WNN method is suitable for predicting the large data set of hepatitis that has seasonal fluctuation and the same for the GRNN method when the data increases steadily.

  6. Comparisons of forecasting for hepatitis in Guangxi Province, China by using three neural networks models

    PubMed Central

    Gan, Ruijing; Chen, Ni

    2016-01-01

    This study compares and evaluates the prediction of hepatitis in Guangxi Province, China by using back propagation neural networks based genetic algorithm (BPNN-GA), generalized regression neural networks (GRNN), and wavelet neural networks (WNN). In order to compare the results of forecasting, the data obtained from 2004 to 2013 and 2014 were used as modeling and forecasting samples, respectively. The results show that when the small data set of hepatitis has seasonal fluctuation, the prediction result by BPNN-GA will be better than the two other methods. The WNN method is suitable for predicting the large data set of hepatitis that has seasonal fluctuation and the same for the GRNN method when the data increases steadily. PMID:27843718

  7. Mathematical Modeling of Transmission Dynamics and Optimal Control of Vaccination and Treatment for Hepatitis B Virus

    PubMed Central

    Kamyad, Ali Vahidian; Heydari, Ali Akbar; Heydari, Aghileh

    2014-01-01

    Hepatitis B virus (HBV) infection is a worldwide public health problem. In this paper, we study the dynamics of hepatitis B virus (HBV) infection which can be controlled by vaccination as well as treatment. Initially we consider constant controls for both vaccination and treatment. In the constant controls case, by determining the basic reproduction number, we study the existence and stability of the disease-free and endemic steady-state solutions of the model. Next, we take the controls as time and formulate the appropriate optimal control problem and obtain the optimal control strategy to minimize both the number of infectious humans and the associated costs. Finally at the end numerical simulation results show that optimal combination of vaccination and treatment is the most effective way to control hepatitis B virus infection. PMID:24812572

  8. Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression.

    PubMed

    Dou, Lin; Wang, Shuyue; Sun, Libo; Huang, Xiuqing; Zhang, Yang; Shen, Tao; Guo, Jun; Man, Yong; Tang, Weiqing; Li, Jian

    2017-01-01

    Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. © 2017 The Author(s). Published by S. Karger AG, Basel.

  9. In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosmiasis

    PubMed Central

    Laprie, Caroline; Dessein, Helia; Bernard, Monique; Dessein, Alain; Viola, Angèle

    2015-01-01

    Background Schistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis. Methodology/Principal Findings CBA/J mice were imaged at 11.75T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato- and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T2 values below 14 ms, these lesions were characterized by a T2 greater than 16 ms. The area fraction of increased T2 correlated (rS = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers. Conclusions/Significance Our multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore

  10. Application of the Extended Health Control Belief Model to Predict Hepatitis A and B Vaccinations.

    PubMed

    Reynolds, Grace L; Nguyen, Hannah H; Singh-Carlson, Savitri; Fisher, Dennis G; Odell, Anne; Xandre, Pamela

    2016-09-01

    Adult vaccination compliance rates vary according to sample and type of vaccine administered (influenza, pneumococcal). This study looked at vaccination of a community sample of low-income, minority adults. Nurses offered free vaccination for hepatitis A and B in the form of the combined Twinrix vaccine to adults on a walk-in basis. In addition to dosing information, participants completed the Risk Behavior Assessment, the Coping Strategies Indicator and the Cardiovascular Risk Assessment. Skaff's extended Health Belief Model was used as the theoretical framework. Count regression was used to model receipt of one, two, or three doses. The majority of participants were male with a mean age of 40 years. The distribution of doses was: 173 individuals (27.6%) received one dose only, 261 (41.7%) received two doses, and 191 (30.5%) received three doses of vaccine. The multivariate count regression model including being male, having previously been told by a health care provider that one has syphilis, having severe negative emotions, and perceived social support were associated with participants' receiving fewer doses of hepatitis vaccine. A greater problem-solving score was associated with a higher number of vaccine doses received. Despite free vaccinations offered in an easily accessible community setting, the majority of participants failed to complete the hepatitis vaccine series. More effort is needed to get adult men to participate in hepatitis vaccination clinics. Additional research is necessary to understand barriers other than cost to adults receiving vaccination. © 2016 Wiley Periodicals, Inc.

  11. Hepatic iron deposition does not predict extrahepatic iron loading in mouse models of hereditary hemochromatosis.

    PubMed

    Subramaniam, V Nathan; McDonald, Cameron J; Ostini, Lesa; Lusby, Patricia E; Wockner, Leesa F; Ramm, Grant A; Wallace, Daniel F

    2012-10-01

    Hereditary hemochromatosis is characterized by tissue iron loading and associated organ damage. However, the phenotype can be highly variable. The relationship between iron loading of different organs and the temporal nature of its deposition is still not well understood. We examined the progression of tissue iron loading in three mouse models to advance our understanding of the natural history of iron deposition in hereditary hemochromatosis. Wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice were analyzed at 3, 5, 10, 26, and 52 weeks, respectively. Hepatic, splenic, cardiac, and pancreatic iron concentrations were determined. Expression of both iron-regulatory and fibrosis genes was determined by quantitative real-time PCR in livers and hearts of 52-week-old mice. In all models, hepatic iron increased rapidly, plateauing before 10 weeks at different levels, depending on the genotype. Iron deposition in the pancreas and heart occurred after maximal iron loading of the liver was reached and was most marked in the Hfe(-/-)/Tfr2(-/-) mice. Although a significant positive correlation was identified between pancreatic and cardiac iron in all models at 52 weeks, there was no correlation between hepatic and either pancreatic or cardiac iron. There is variability in the timing and extent of tissue iron loading within a genotype, suggesting that hepatic iron levels in hereditary hemochromatosis may not accurately predict the iron content of other organs. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. The Current State of Knowledge of Hepatic Ischemia-Reperfusion Injury Based on Its Study in Experimental Models

    PubMed Central

    Mendes-Braz, M.; Elias-Miró, M.; Jiménez-Castro, M. B.; Casillas-Ramírez, A.; Ramalho, F. S.; Peralta, C.

    2012-01-01

    The present review focuses on the numerous experimental models used to study the complexity of hepatic ischemia/reperfusion (I/R) injury. Although experimental models of hepatic I/R injury represent a compromise between the clinical reality and experimental simplification, the clinical transfer of experimental results is problematic because of anatomical and physiological differences and the inevitable simplification of experimental work. In this review, the strengths and limitations of the various models of hepatic I/R are discussed. Several strategies to protect the liver from I/R injury have been developed in animal models and, some of these, might find their way into clinical practice. We also attempt to highlight the fact that the mechanisms responsible for hepatic I/R injury depend on the experimental model used, and therefore the therapeutic strategies also differ according to the model used. Thus, the choice of model must therefore be adapted to the clinical question being answered. PMID:22649277

  13. Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis

    PubMed Central

    Gilbert, Kathleen M.; Reisfeld, Brad; Zurlinden, Todd; Kreps, Meagan N.; Erickson, Stephen W.; Blossom, Sarah J.

    2014-01-01

    Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+ mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+ mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation. PMID:25026505

  14. Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis.

    PubMed

    Gilbert, Kathleen M; Reisfeld, Brad; Zurlinden, Todd J; Kreps, Meagan N; Erickson, Stephen W; Blossom, Sarah J

    2014-09-15

    Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation.

  15. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

    PubMed

    Christen, Urs; Hintermann, Edith

    2016-12-01

    Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.

  16. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

    PubMed Central

    Christen, Urs; Hintermann, Edith

    2016-01-01

    Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models. PMID:27916939

  17. Recombinant cccDNA of hepatitis B virus induces long-term viral persistence with chronic hepatitis in a mouse model.

    PubMed

    Li, Gaiyun; Zhu, Yuanfei; Shao, Dianhui; Chang, Hao; Zhang, Xiaoming; Zhou, Dongming; Gao, Yueqiu; Lan, Ke; Deng, Qiang

    2017-07-27

    Covalently closed circular (ccc) DNA of hepatitis B virus (HBV) is critical for viral persistence in vivo. We recently reported a technique involving recombinant (r) cccDNA of HBV by site-specific DNA recombination. Using hydrodynamic injection, rcccDNA induces a temporarily prolonged HBV anigenemia in immunocompetent mice, similar to acute resolving HBV infection. In this study, we simulated the pathophysiological impact of chronic hepatitis by which to reproduce (r)cccDNA persistence in mouse models. We showed that rcccDNA achieved long-lasting persistence in the presence of a compromised immune response or when transcriptional activity was repressed. To closely mimic chronic hepatitis, we used a replication-defective recombinant adenoviral (Ad) vector to deliver rcccDNA to the liver, which led to prominent HBV persistence throughout the experiment duration (>62 weeks) in Alb-Cre transgenic mice. A sustained necroinflammatory response and fibrosis were identified in mouse livers, with dysplastic lesions commonly seen during the late stage of viral persistence, analogous to the progressive pathology of clinical chronic hepatitis. (r)cccDNA was intrinsically stable in vivo, enabling long-term persistence in the context of chronic hepatitis. Viral persistence, in turn, may promote progression of chronic liver disease. Our study also presented a valuable surrogate model of HBV cccDNA persistence in mice that could greatly advance our understanding of the pathogenesis of chronic hepatitis B. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  18. Computer Modeling of Yttrium-90-Microsphere Transport in the Hepatic Arterial Tree to Improve Clinical Outcomes

    SciTech Connect

    Kennedy, Andrew S.; Kleinstreuer, Clement; Basciano, Christopher A.; Dezarn, William A.

    2010-02-01

    Purpose: Radioembolization (RE) via yttrium-90 ({sup 90}Y) microspheres is an effective and safe treatment for unresectable liver malignancies. However, no data are available regarding the impact of local blood flow dynamics on {sup 90}Y-microsphere transport and distribution in the human hepatic arterial system. Methods and Materials: A three-dimensional (3-D) computer model was developed to analyze and simulate blood-microsphere flow dynamics in the hepatic arterial system with tumor. Supplemental geometric and flow data sets from patients undergoing RE were also available to validate the accuracy of the computer simulation model. Specifically, vessel diameters, curvatures, and branching patterns, as well as blood flow velocities/pressures and microsphere characteristics (i.e., diameter and specific gravity), were measured. Three-dimensional computer-aided design software was used to create the vessel geometries. Initial trials, with 10,000 noninteracting microspheres released into the hepatic artery, used resin spheres 32-{mu}m in diameter with a density twice that of blood. Results: Simulations of blood flow subject to different branch-outlet pressures as well as blood-microsphere transport were successfully carried out, allowing testing of two types of microsphere release distributions in the inlet plane of the main hepatic artery. If the inlet distribution of microspheres was uniform (evenly spaced particles), a greater percentage would exit into the vessel branch feeding the tumor. Conversely, a parabolic inlet distribution of microspheres (more particles around the vessel center) showed a high percentage of microspheres exiting the branch vessel leading to the normal liver. Conclusions: Computer simulations of both blood flow patterns and microsphere dynamics have the potential to provide valuable insight on how to optimize {sup 90}Y-microsphere implantation into hepatic tumors while sparing normal tissue.

  19. Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease.

    PubMed

    Sauer, Vanessa; Siaj, Ramsi; Stöppeler, Sandra; Bahde, Ralf; Spiegel, Hans-Ullrich; Köhler, Gabriele; Zibert, Andree; Schmidt, Hartmut H J

    2012-02-01

    The outcome of consecutive hepatocyte transplants was explored in a rat model of Wilson's disease before the onset of fulminant hepatitis without preconditioning regimens. Rats received a high-copper diet in order to induce a rapid induction of liver failure. Sham-operated rats (15/15) developed jaundice and fulminant hepatitis, and they died within 4 weeks of first transplantation. Despite the continuation of a high dietary copper challenge, long-term survival was observed for a notable proportion of the transplanted animals (7/18). All survivors displayed normalized levels of hepatitis-associated serum markers and ceruloplasmin oxidase activity by posttransplant days 50 and 98, respectively. The liver copper concentrations, the liver histology, and the expression of marker genes were significantly restored within 4 months of transplantation in comparison with the control group. The high expression of a copper transporter gene (ATPase Cu++ transporting beta polypeptide) in the livers of the survivors indicated a high rate of repopulation by donor hepatocytes. Our data suggest that repeated cell transplantation can overcome the limitations of a single therapy session in rats with severe hepatic disease by functionally restoring the host liver without preconditioning.

  20. Isoflurane and Sevoflurane Induce Severe Hepatic Insulin Resistance in a Canine Model

    PubMed Central

    Kim, Stella P.; Broussard, Josiane L.

    2016-01-01

    Introduction Anesthesia induces insulin resistance, which may contribute to elevated blood glucose and adverse post-operative outcomes in critically ill patients, and impair glycemic control in surgical patients with diabetes. However, little is known about the mechanisms by which anesthesia impairs insulin sensitivity. Here we investigate the effects of anesthesia on insulin sensitivity in metabolic tissues. Methods Hyperinsulinemic-euglycemic clamps were performed in 32 lean (control diet; n = 16 conscious versus n = 16 anesthetized) and 24 fat-fed (6 weeks fat-feeding; n = 16 conscious versus n = 8 anesthetized) adult male mongrel dogs in conjunction with tracer methodology to differentiate hepatic versus peripheral insulin sensitivity. Propofol was administered as an intravenous bolus (3mg/kg) to initiate anesthesia, which was then maintained with inhaled sevoflurane or isoflurane (2–3%) for the duration of the procedure. Results Anesthesia reduced peripheral insulin sensitivity by approximately 50% in both lean and fat-fed animals as compared to conscious animals, and insulin action at the liver was almost completely suppressed during anesthesia such that hepatic insulin sensitivity was decreased by 75.5% and; 116.2% in lean and fat-fed groups, respectively. Conclusion Inhaled anesthesia induces severe hepatic insulin resistance in a canine model. Countermeasures that preserve hepatic insulin sensitivity may represent a therapeutic target that could improve surgical outcomes in both diabetic and healthy patients. PMID:27802272

  1. Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis.

    PubMed

    Kruitwagen, Hedwig S; Oosterhoff, Loes A; Vernooij, Ingrid G W H; Schrall, Ingrid M; van Wolferen, Monique E; Bannink, Farah; Roesch, Camille; van Uden, Lisa; Molenaar, Martijn R; Helms, J Bernd; Grinwis, Guy C M; Verstegen, Monique M A; van der Laan, Luc J W; Huch, Meritxell; Geijsen, Niels; Vries, Robert G; Clevers, Hans; Rothuizen, Jan; Schotanus, Baukje A; Penning, Louis C; Spee, Bart

    2017-04-11

    Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  2. [Mathematical models in epidemiology: Study on viral hepatitis in Italy (author's transl)].

    PubMed

    Jovine, R; Ghezzo, F; Orecchio, F

    1979-01-01

    In this paper a mathematical approach to the epidemics is proposed. The method is based upon a model able to describe any time-depending phenomena using the following elements: "class", "transition" and "related probability". The solution of the differential equations describing the model are obtained: first, by numerical techniques; second, by a Montecarlo simulation method. Deterministic and stochastic solutions which have been obtained, by applying the model to the study of viral hepatitis in Italy during 1960--1970, have been compared each other, to improve the model itself.

  3. Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis

    SciTech Connect

    Gilbert, Kathleen M.; Reisfeld, Brad; Zurlinden, Todd J.; Kreps, Meagan N.; Erickson, Stephen W.; Blossom, Sarah J.

    2014-09-15

    Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL +/+ mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL +/+ mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation. - Highlights: • We developed a toxicodynamic model to study effects of trichloroethylene on liver. • We examined protective as well as pro-inflammatory events in the liver. • Trichloroethylene inhibits IL-6 production by macrophages. • Trichloroethylene

  4. Hepatitis A

    MedlinePlus

    Hepatitis A Hepatitis A Hepatitis A is a contagious viral infection that can easily affect children and adults. It is one of the most common types of hepatitis virus. Often when you hear about hepatitis A ...

  5. Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

    PubMed Central

    Lee, Hye Won; Ahn, Sang Hoon

    2016-01-01

    Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B (CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-naïve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM (Individual Prediction Model), CU-HCC (Chinese University-HCC), GAG-HCC (Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC (Nomogram-HCC), REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM (Liver Stiffness Measurement)-based model, LSM-HCC, and mREACH-B (modified REACH-B). PMID:27729738

  6. Modeling the Health and Economic Burden of Hepatitis C Virus in Switzerland

    PubMed Central

    Müllhaupt, Beat; Bruggmann, Philip; Bihl, Florian; Blach, Sarah; Lavanchy, Daniel; Razavi, Homie; Semela, David; Negro, Francesco

    2015-01-01

    Background Chronic hepatitis C virus infection is a major cause of liver disease in Switzerland and carries a significant cost burden. Currently, only conservative strategies are in place to mitigate the burden of hepatitis C in Switzerland. This study expands on previously described modeling efforts to explore the impact of: no treatment, and treatment to reduce HCC and mortality. Furthermore, the costs associated with untreated HCV were modeled. Methods Hepatitis C disease progression and mortality were modeled. Baseline historical assumptions were collected from the literature and expert interviews and strategies were developed to show the impact of different levels of intervention (improved drug cure rates, treatment and diagnosis) until 2030. Results Under the historical standard of care, the number of advanced stage cases was projected to increase until 2030, at which point the annual economic burden of untreated viremic infections was projected to reach €96.8 (95% Uncertainty Interval: €36 – €232) million. Scenarios to reduce HCV liver-related mortality by 90% by 2030 required treatment of 4,190 ≥F2 or 3,200 ≥F3 patients annually by 2018 using antivirals with a 95% efficacy rate. Delaying the implementation of these scenarios by 2 or 5 years reduced the impact on mortality to 75% and 57%, respectively. Conclusions With today’s treatment efficacy and uptake rates, hepatitis C disease burden is expected to increase through 2030. A substantial reduction in disease burden can be achieved by means of both higher efficacy drugs and increased treatment uptake. However, these efforts cannot be undertaken without a simultaneous effort to diagnose more infections. PMID:26107467

  7. A Novel Murine Model to Deplete Hepatic Stellate Cells Uncovers Their Role In Amplifying Liver Damage

    PubMed Central

    Puche, Juan E.; Lee, Youngmin A.; Jiao, Jingjing; Aloman, Costica; Fiel, Maria I.; Muñoz, Ursula; Kraus, Thomas; Lee, Tingfang; Yee, Hal F.; Friedman, Scott L.

    2012-01-01

    We have developed a novel model for depleting mouse HSCs that has allowed us to clarify their contributions to hepatic injury and fibrosis. Transgenic mice (TG) expressing the herpes simplex virus-Thymidine kinase gene (HSV-Tk) driven by the mouse GFAP promoter were used to render proliferating HSCs susceptible to killing in response to ganciclovir (GCV). Effects of GCV were explored in primary HSCs and in vivo. Panlobular damage was provoked to maximize HSC depletion by combining carbon tetrachloride (CCl4) (centrilobular injury) with allyl alcohol (AA) (periportal injury), as well as in a bile duct ligation (BDL) model. Cell depletion in situ was quantified using dual-immunofluorescence (IF) for desmin and GFAP. In primary HSCs isolated from both untreated wild type (WT) and TG mice, GCV induced cell death in ~50% of HSCs from TG but not WT mice. In TG mice treated with CCl4+AA+GCV, there was a significant decrease in GFAP & desmin positive cells compared to WT mice (~65% reduction, p<0.01), which was accompanied by a decrease in the expression of HSC activation markers (α-SMA, β-PDGFR and collagen I). Similar results were seen following BDL. Associated with HSC depletion in both fibrosis models, there was marked attenuation of fibrosis and liver injury, as indicated by Sirius Red/Fast Green, H&E quantification and serum ALT/AST. Hepatic expression of IL-10 and IFN-γ was increased following HSC depletion. No toxicity of GCV in either WT or TG mice accounted for the differences in injury. Conclusion Activated HSCs significantly amplify the hepatic response to liver injury, further expanding this cell type's repertoire in orchestrating hepatic injury and repair. PMID:22961591

  8. Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp

    PubMed Central

    Dalla Man, Chiara; Piccinini, Francesca; Basu, Rita; Basu, Ananda; Rizza, Robert A.

    2013-01-01

    Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (SILmeal) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, SILmeal has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (SILclamp). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3-3H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and SILmeal was estimated with good precision. Correlation between SILclamp and SILmeal was good (r = 0.72, P < 0.001); however, SILmeal was lower than SILclamp (4.60 ± 0.64 vs. 8.73 ± 1.07 10−4 dl·kg−1·min−1 per μU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔIclamp = 15.60 ± 1.61 vs. ΔImeal= 83.37 ± 10.71 μU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test. PMID:23443923

  9. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism.

    PubMed

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.

  10. Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

    PubMed Central

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. PMID:22761565

  11. Anti-fibrotic effects of the Masson pine pollen aqueous extract on hepatic fibrosis rat model

    PubMed Central

    Cong, Tao; Jin, Xue-Yuan; Zhao, Lin; Ma, Long; Li, Rui-Sheng; Zhao, Ping; Guo, Chang-Jiang

    2015-01-01

    Aim: To observe the antifibrotic effects of Masson Pine Pollen aqueous extract. Methods: Adult Sprague-Dawley rats were randomly divided into control (CG), hepatic fibrosis model (MG), MPPAE low dose (LG), MPPAE high dose (HG), and MPP original powder (MPPOP; OG) groups. Each group was treated with specific protocols and sacrificed 8 weeks later. Multiple indicators such as serum transaminase, HE staining of the liver tissue, and relevant indexes to fibrosis were determined. Results: Severe hyperplasia of fibrous connective tissues was observed in livers of the MG group rats, while aspartate transaminase and alanine transaminase levels and collagen content obviously increased, superoxide dismutase and glutathione peroxidase activities and MMPs expression decreased, malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine concentrations increased, while mRNA expressions of hepatic stellate cell (HSC)-related cytokines such as transforming growth factor-β1 and platelet-derived growth factor, transcription factors such as nuclear factor-κB p65, and signaling protein α-smooth muscle actin were all increased significantly. Conclusions: MPPAE effectively inhibited the fibrotic process in this CCl4-induced hepatic fibrosis rat model. It may be associated with synergic functions of antioxidant activity, inhibitory activity on HSC proliferation, collagen synthesis, and MMPs expression induction. PMID:26191155

  12. Fulminant liver failure model with hepatic encephalopathy in the mouse

    PubMed Central

    Hori, Tomohide; Chen, Feng; Baine, Ann-Marie T.; Gardner, Lindsay B.; Nguyen, Justin H.

    2011-01-01

    Aim To develop a reliable murine model for fulminant liver failure (FLF). Material and Methods We treated three groups of male C57BL/6 mice:as controls, with azoxymethane (AOM), and with galactosamine (Gal) and tumor necrosis factor-alpha (TNFα). Effects of body temperature (BT) control on survival, in all three groups were investigated. Using BT control, survival, histopathological findings and biochemical/coagulation profiles were compared between the experimental groups. Effects of hydration on international normalized ratios of prothrombin time (PT-INR) were also checked. Dose-dependent survival curves were made for both experimental groups. Neurological behaviors were assessed using a coma scale. Results No unexpected BT effects were seen in the control group. The AOM group, but not the Gal+TNFα group, showed significant differences in survival curves between those with and without BT care. Histopathological assessment showed consistent FLF findings in both experimental groups with BT care. Between the experimental groups, there were significant differences in aspartate aminotransferase levels and PT-INR; and significant differences in PT-INRs between sufficiently- and insufficiently-hydrated groups. There were significant differences between FLF models, in the duration of each coma stage, with significant differences in stages 1 and 3 as percentages of the diseased state (stages 1-4). The two FLF models with BT care showed different survival curves in the dose-dependent survival study. Conclusion Azoxymethane can provide a good FLF model, but requires a specialized environment and careful BT control. Other FLF models may also be useful, depending on research purpose. Thoughtful attention to caregiving and close observation are indispensable for successful FLF models. PMID:24713795

  13. Resuscitation fluid composition affects hepatic inflammation in a murine model of early sepsis.

    PubMed

    Patrick, Amanda L; Grin, Peter M; Kraus, Nicole; Gold, Michelle; Berardocco, Matthew; Liaw, Patricia C; Fox-Robichaud, Alison E

    2017-12-01

    Fluid resuscitation is a crucial therapy for sepsis, and the use of balanced fluids and/or isotonic albumin may improve patient survival. We have previously demonstrated that resuscitation with normal saline results in increased hepatic leukocyte recruitment in a murine model of sepsis. Given that clinical formulations of albumin are in saline, our objectives were to develop a novel balanced electrolyte solution specifically for sepsis and to determine if supplementing this solution with albumin would improve the inflammatory response in sepsis. We developed two novel buffered electrolyte solutions that contain different concentrations of acetate and gluconate, named Seplyte L and Seplyte H, and administered these solutions with or without 5% albumin. Normal saline with or without albumin and Ringer's lactate served as controls. Sepsis was induced by cecal ligation and puncture (CLP), and the liver microvasculature was imaged in vivo at 6 h after CLP to quantify leukocyte recruitment. Hepatic cytokine expression and plasma cell-free DNA (cfDNA) concentrations were also measured. Septic mice receiving either Seplyte fluid showed significant reductions in hepatic post-sinusoidal leukocyte rolling and adhesion compared to normal saline. Hepatic cytokine concentrations varied in response to different concentrations of acetate and gluconate in the novel resuscitation fluids but were unaffected by albumin. All Seplyte fluids significantly increased hepatic TNF-α levels at 6 h compared to control fluids. However, Seplyte H exhibited a similar cytokine profile to the control fluids for all other cytokines, whereas mice given Seplyte L had significantly elevated IL-6, IL-10, KC (CXCL1), and MCP-1 (CCL2). Plasma cfDNA was generally increased during sepsis, but resuscitation fluid composition did not significantly affect cfDNA concentrations. Electrolyte concentrations and buffer constituents of resuscitation fluids can modulate hepatic cytokine production and leukocyte

  14. History, ethics, advantages and limitations of experimental models for hepatic ablation.

    PubMed

    Ong, Seok Ling; Gravante, Gianpiero; Metcalfe, Matthew S; Dennison, Ashley R

    2013-01-14

    Numerous techniques developed in medicine require careful evaluation to determine their indications, limitations and potential side effects prior to their clinical use. At present this generally involves the use of animal models which is undesirable from an ethical standpoint, requires complex and time-consuming authorization, and is very expensive. This process is exemplified in the development of hepatic ablation techniques, starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies. The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models. Ex vivo non perfused models are less expensive, easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours. In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines. Isolated perfused ex vivo liver models have been used to study drug toxicity, liver failure, organ transplantation and hepatic ablation and combine advantages of both previous models.

  15. History, ethics, advantages and limitations of experimental models for hepatic ablation

    PubMed Central

    Ong, Seok Ling; Gravante, Gianpiero; Metcalfe, Matthew S; Dennison, Ashley R

    2013-01-01

    Numerous techniques developed in medicine require careful evaluation to determine their indications, limitations and potential side effects prior to their clinical use. At present this generally involves the use of animal models which is undesirable from an ethical standpoint, requires complex and time-consuming authorization, and is very expensive. This process is exemplified in the development of hepatic ablation techniques, starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies. The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models. Ex vivo non perfused models are less expensive, easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours. In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines. Isolated perfused ex vivo liver models have been used to study drug toxicity, liver failure, organ transplantation and hepatic ablation and combine advantages of both previous models. PMID:23345935

  16. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

    PubMed Central

    Tuñón, María Jesús; Alvarez, Marcelino; Culebras, Jesús M; González-Gallego, Javier

    2009-01-01

    Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed. PMID:19575487

  17. Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

    PubMed Central

    Ju, Ying; Hou, Nan; Zhang, Xiaoning; Zhao, Di; Liu, Ying; Wang, Jinjin; Luan, Fang; Shi, Wei; Zhu, Faliang; Sun, Wensheng; Zhang, Lining; Gao, Chengjiang; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong

    2009-01-01

    T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus (HBV) infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8+ T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-γ production from hepatic CD8+ T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8+ T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection. PMID:19254478

  18. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

    PubMed Central

    Chirehwa, Maxwell T.; Rustomjee, Roxana; Mthiyane, Thuli; Onyebujoh, Philip; Smith, Peter; McIlleron, Helen

    2015-01-01

    Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials. PMID:26552972

  19. Modeling hepatitis C virus kinetics under therapy using pharmacokinetic and pharmacodynamic information

    SciTech Connect

    Perelson, Alan S; Shudo, Emi; Ribeiro, Ruy M

    2008-01-01

    Mathematical models have proven helpful in analyzing the virological response to antiviral therapy in hepatitis C virus (HCY) infected subjects. Objective: To summarize the uses and limitations of different models for analyzing HCY kinetic data under pegylated interferon therapy. Methods: We formulate mathematical models and fit them by nonlinear least square regression to patient data in order estimate model parameters. We compare the goodness of fit and parameter values estimated by different models statistically. Results/Conclusion: The best model for parameter estimation depends on the availability and the quality of data as well as the therapy used. We also discuss the mathematical models that will be needed to analyze HCV kinetic data from clinical trials with new antiviral drugs.

  20. Modeling O2 transport within engineered hepatic devices.

    PubMed

    McClelland, Randall E; MacDonald, Jeffrey M; Coger, Robin N

    2003-04-05

    Predicting and improving oxygen transport within bioartificial liver (BAL) devices continues to be an important engineering challenge since oxygen is one of the critical nutrients necessary for maintaining hepatocyte viability and function. Such a computational model would not only help predict outcomes but it would also allow system modifications to be analyzed prior to developing experimental protocols. This would help to facilitate future design improvements while reducing both experimental time and capital resource costs, and is the focus of the current study. Specifically, a computational model of O(2) transport through collagen and microporous collagen ECMs is analyzed for hollow fiber (HF), flat plate (FP), and spheroid BAL designs. By modifying the O(2) boundary conditions, hepatocyte O(2) consumption levels, O(2) permeability of the ECM, and ECM void fractions, O(2) transport predictions are determined for each system as a function of time and distance. Accuracy of the predictive model is confirmed by comparing computational vs. experimental results for the HF BAL system. The model's results indicate that O(2) transport within all three BAL designs can be improved significantly by incorporating the enhancement technique. This technique modifies a diffusion-dominant gel ECM into a porous matrix with diffusive and convective flows that mutually transport O(2) through the ECMs. Although tortuous pathways increase the porous ECM's overall effective length of O(2) travel, the decreased transport resistances of these pathways allow O(2) to permeate more effectively into the ECMs. Furthermore, because the HF design employs convective flow on both its inner and outer ECM surfaces, greater control of O(2) transport through its ECM is predicted, as compared with the single O(2) source inputs of the flat plate and spheroid systems. The importance of this control is evaluated by showing how modifying the O(2) concentration and/or transfer coefficients of the

  1. Modelling hepatitis C therapy—predicting effects of treatment

    SciTech Connect

    Perelson, Alan S.; Guedj, Jeremie

    2015-06-30

    Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In addition, there also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.

  2. Modelling hepatitis C therapy—predicting effects of treatment

    DOE PAGES

    Perelson, Alan S.; Guedj, Jeremie

    2015-06-30

    Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of themore » initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In addition, there also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.« less

  3. Methodological quality of economic modelling studies. A case study with hepatitis B vaccines.

    PubMed

    Jefferson, T; Demicheli, V

    1998-09-01

    The notable increase in the quantity of economic evaluations in the last 2 decades has not been matched by good methodological standards. This problem is particularly evident in the field of economic evaluations of hepatitis B vaccines. The results of 2 systematic reviews conducted by us in 1993 and 1996 showed three problem areas. A sizeable minority of study reports failed to provide a clear study aim, showing a basic ignorance of the first rule of conducting scientific research. The basic epidemiological assumptions upon which the economic models were based showed variability which persisted even after stratification, raising the question of the accuracy of the epidemiological knowledge base of hepatitis B infection and its progression. Lastly, many of the studies showed weaknesses in basic methods of conducting and reporting economic evaluations. Examination of these problem areas led us to conclude that no conclusions about the efficiency of hepatitis B vaccines could be drawn from the available evidence. Addressing the problem of poor methodological standards concerns the whole research community. However, as a proportion of economic evaluations are published, one obvious means of exerting pressure to increase and maintain methodological standards is the editorial and peer review process. Editors of specialist and general medical journals should agree on and enforce common explicit guidelines for study conduct and reporting, following the example of the British Medical Journal.

  4. Immunosuppressive Drugs Modulate the Replication of Hepatitis B Virus (HBV) in a Hydrodynamic Injection Mouse Model

    PubMed Central

    Huang, Shunmei; Song, Zhitao; Wu, Jun; Zhang, Ejuan; Zhu, Zhenni; Zhu, Bin; Yin, Ying; Lin, Yong; Xu, Yang; Zheng, Xin; Lu, Mengji; Yang, Dongliang

    2014-01-01

    Hepatitis B virus (HBV) reactivation and recurrence are common in patients under immunosuppression and can be controlled by hepatitis B immunoglobulin, antivirals, and hepatitis B vaccine. However, the detailed analysis of HBV infection under immunosuppression is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV replication and T cell responses were analyzed in a HBV-transfected mouse model under immunosuppressive therapy. During the treatment, HBV replication was at a high level in mice treated with dexamethasone, cyclosporine, and cyclophosphamide, whereas was terminated in mice treated with mycophenolate mofetil. After the withdrawal, HBV replication was at low or high levels in the dexamethasone-treated mice or in both cyclosporine- and cyclophosphamide-treated mice. The early withdrawal of cyclosporine allowed the recovery of suppressed T cell responses and led to subsequent HBV clearance, while the adoptive immune transfer to the mice with HBV persistence led to HBV suppression. Taken together, long-term HBV persistence under immunosuppression depends on the immunosuppressive drugs used and on the treatment duration and is mediated by the suppressed intrahepatic CD8 T cell response. These data may be helpful for individualized immunosuppressive therapy in patients with high risk of HBV reactivation and recurrence, and the mouse system is suitable for studying HBV reactivation and recurrence under immunosuppression. PMID:24465734

  5. The hepatic role in carcinogenesis and its early detection--the vinyl chloride model.

    PubMed

    Tamburro, C H

    1978-01-01

    The liver's role in vinyl chloride toxicity and carcinogenicity is providing a better understanding of the chemical carcinogenesis mechanism. A variety of both malignant and benign hepatic tumors has been demonstrated with prolonged exposure to vinyl chloride. The multi-system involvment of this carcinogen and toxin has provided a model for the study of chemical carcinogenesis common to both man and animal. Clinical studies have shown the usefulness of biochemical, radioisotopic, and radiological studies in the detection of toxic and carcinogenic lesions. Animal studies have demonstrated the biochemical metabolism by the liver of vinyl chloride-produced intermediates which are mutagenic in bacterial systems and may be the ultimate carcinogens. Hepatic subcellular enzyme studies prove preliminary evidence of cellular adaptation and increased detoxification. Disruption of this oxidization and detoxification balance may be the key to the malignant transformation of cells. A working hypothesis is presented which may explain the metabolism of vinyl chloride into mutagenic intermediates by the liver cell and the development of malignant transformation by extra hepatic sinusoidal lining cells, lung cells, and brain tissue.

  6. Enhanced Laws textures: A potential MRI surrogate marker of hepatic fibrosis in a murine model.

    PubMed

    Li, Baojun; Jara, Hernan; Yu, Heishun; O'Brien, Michael; Soto, Jorge; Anderson, Stephan W

    2017-04-01

    To compare enhanced Laws textures derived from parametric proton density (PD) maps to other MRI surrogate markers (T2, PD, apparent diffusion coefficient (ADC)) in assessing degrees of liver fibrosis in an ex vivo murine model of hepatic fibrosis imaged using 11.7T MRI. This animal study was IACUC approved. Fourteen male, C57BL/6 mice were divided into control and experimental groups. The latter were fed a 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC) supplemented diet to induce hepatic fibrosis. Ex vivo liver specimens were imaged using an 11.7T scanner, from which the parametric PD, T2, and ADC maps were generated from spin-echo pulsed field gradient and multi-echo spin-echo acquisitions. A sequential enhanced Laws texture analysis was applied to the PD maps: automated dual-clustering algorithm, optimal thresholding algorithm, global grayscale correction, and Laws texture features extraction. Degrees of fibrosis were independently assessed by digital image analysis (a.k.a. %Area Fibrosis). Scatterplot graphs comparing enhanced Laws texture features, T2, PD, and ADC values to degrees of fibrosis were generated and correlation coefficients were calculated. Hepatic fibrosis and the enhanced Laws texture features were strongly correlated with higher %Area Fibrosis associated with higher Laws textures (r=0.89). Without the proposed enhancements, only a moderate correlation was detected between %Area Fibrosis and unenhanced Laws texture features (r=0.70). Correlation also existed between %Area Fibrosis and ADC (r=0.86), PD (r=0.65), and T2 (r=0.66). Higher degrees of hepatic fibrosis are associated with increased Laws textures. The proposed enhancements could improve the accuracy of Laws texture features significantly. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus.

    PubMed

    Ramsay, Joshua D; Evanoff, Ryan; Wilkinson, Tom E; Divers, Thomas J; Knowles, Donald P; Mealey, Robert H

    2015-05-01

    Equine hepacivirus (EHCV; nonprimate hepacivirus) is a hepatotropic member of the Flaviviridae family that infects horses. Although EHCV is the closest known relative to hepatitis C virus (HCV), its complete replication kinetics in vivo have not been described, and direct evidence that it causes hepatitis has been lacking. In this study, we detected EHCV in 2 horses that developed post-transfusion hepatitis. Plasma and serum from these horses were used to experimentally transmit EHCV to 4 young adult Arabian horses, two 1-month-old foals (1 Arabian and 1 Arabian-pony cross), and 2 foals (1 Arabian and 1 Arabian-pony cross) with severe combined immunodeficiency (SCID). Our results demonstrated that EHCV had infection kinetics similar to HCV and that infection was associated with acute and chronic liver disease as measured by elevations of liver-specific enzymes and/or by histopathology. Although most of these animals were coinfected with equine pegivirus (EPgV), also a flavivirus, EPgV viral loads were much lower and often undetectable in both liver and blood. Three additional young adult Arabian-pony crosses and 1 SCID foal were then inoculated with plasma containing only EHCV, and evidence of mild hepatocellular damage was observed. The different levels of liver-specific enzyme elevation, hepatic inflammation, and duration of viremia observed during EHCV infection suggested that the magnitude and course of liver disease was mediated by the virus inoculum and/or by host factors, including breed, age, and adaptive immune status. This work documents the complete infection kinetics and liver pathology associated with acute and chronic EHCV infection in horses and further justifies it as a large animal model for HCV. © 2015 by the American Association for the Study of Liver Diseases.

  8. Novel robust in vitro hepatitis B virus infection model using fresh human hepatocytes isolated from humanized mice.

    PubMed

    Ishida, Yuji; Yamasaki, Chihiro; Yanagi, Ami; Yoshizane, Yasumi; Fujikawa, Kazuyuki; Watashi, Koichi; Abe, Hiromi; Wakita, Takaji; Hayes, C Nelson; Chayama, Kazuaki; Tateno, Chise

    2015-05-01

    The molecular mechanisms underlying the hepatitis B virus (HBV) life cycle are poorly understood because of the lack of appropriate in vitro infection models. Herein, we report a highly effective in vitro HBV infection system using fresh human hepatocytes (HHs) isolated from chimeric mice with humanized livers. After the inoculation of sera collected from HBV-infected chimeric mice or patients to HHs, we measured levels of HBV DNA, mRNA, covalently closed circular DNA, and viral protein expression in HHs. We investigated the neutralization activity of hepatitis B immune globulin and the effects of siRNA against sodium taurocholate-cotransporting polypeptide and clathrin heavy chain on HBV infection. We confirmed the expression of viral antigens in HHs and the presence of extracellular HBV DNA and hepatitis B surface antigen. The maximum infection rate was approximately 80%. Lamivudine and hepatitis B immune globulin treatment reduced HBV DNA levels in a dose-dependent manner. Knockdown of sodium taurocholate-cotransporting polypeptide and clathrin heavy chain significantly reduced the levels of hepatitis B surface antigen. Infection was successfully established using different donor HHs and inocula. Elevation of extracellular HBV DNA levels and the increase of HBV-positive HHs were blocked by continuous hepatitis B immune globulin treatment, indicating virus spread in this model. Chimeric mouse-derived HHs provide a robust in vitro infection model that can completely support the HBV life cycle. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  9. (18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.

    PubMed

    Kao, Hao-Wen; Chen, Chuan-Lin; Chang, Wen-Yi; Chen, Jenn-Tzong; Lin, Wuu-Jyh; Liu, Ren-Shyan; Wang, Hsin-Ell

    2013-02-15

    Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P <0.0001) was observed using confocal microscopy when co-incubated with 0.5μM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P <0.01) at 30min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30min post-injection) of hepatic fibrosis mice derived from both microPET imaging and biodistribution study were significantly lower (P <0.01) than those of normal mice. The pharmacokinetic parameters (T(1/2)α, T(1/2)β, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of (18)F-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that (18)F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction.

  10. Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma

    PubMed Central

    Chiu, Amy P; Tschida, Barbara R; Lo, Lilian H; Moriarity, Branden S; Rowlands, Dewi K; Largaespada, David A; Keng, Vincent W

    2015-01-01

    The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV-associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia. PMID:26576100

  11. Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model.

    PubMed

    Rothweiler, Sonja; Dill, Michael T; Terracciano, Luigi; Makowska, Zuzanna; Quagliata, Luca; Hlushchuk, Ruslan; Djonov, Valentin; Heim, Markus H; Semela, David

    2015-03-01

    Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.

  12. Optimization,Modeling, and Control: Applications to Klystron Designing and Hepatitis C Virus Dynamics

    NASA Astrophysics Data System (ADS)

    Lankford, George Bernard

    In this dissertation, we address applying mathematical and numerical techniques in the fields of high energy physics and biomedical sciences. The first portion of this thesis presents a method for optimizing the design of klystron circuits. A klystron is an electron beam tube lined with cavities that emit resonant frequencies to velocity modulate electrons that pass through the tube. Radio frequencies (RF) inserted in the klystron are amplified due to the velocity modulation of the electrons. The routine described in this work automates the selection of cavity positions, resonant frequencies, quality factors, and other circuit parameters to maximize the efficiency with required gain. The method is based on deterministic sampling methods. We will describe the procedure and give several examples for both narrow and wide band klystrons, using the klystron codes AJDISK (Java) and TESLA (Python). The rest of the dissertation is dedicated to developing, calibrating and using a mathematical model for hepatitis C dynamics with triple drug combination therapy. Groundbreaking new drugs, called direct acting antivirals, have been introduced recently to fight off chronic hepatitis C virus infection. The model we introduce is for hepatitis C dynamics treated with the direct acting antiviral drug, telaprevir, along with traditional interferon and ribavirin treatments to understand how this therapy affects the viral load of patients exhibiting different types of response. We use sensitivity and identifiability techniques to determine which parameters can be best estimated from viral load data. We use these estimations to give patient-specific fits of the model to partial viral response, end-of-treatment response, and breakthrough patients. We will then revise the model to incorporate an immune response dynamic to more accurately describe the dynamics. Finally, we will implement a suboptimal control to acquire a drug treatment regimen that will alleviate the systemic cost

  13. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    PubMed

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  14. Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.

    PubMed

    Buettner, R; Bettermann, I; Hechtl, C; Gäbele, E; Hellerbrand, C; Schölmerich, J; Bollheimer, L C

    2010-10-01

    The AMP activated kinase plays an important role in metabolic control, and pharmacologic enhancement of AMPK activity is used to improve insulin resistance. We hypothesized that high dose of folic acid supplementation might improve insulin sensitivity and hepatic inflammation and examined this by a dietary intervention in (a) the high fat fed rat model of the metabolic syndrome, which shows sole hepatic steatosis as well as (b) in rats fed with a high cholesterol, high cholate diet inducing nonalcoholic steatohepatitis (NASH). Male Wistar rats were fed with folic acid supplemented (40 mg/kg) high fat diet [based on lard, fat content 25% (wt/wt)] or NASH inducing diet (containing 15% fat, 1.25% cholesterol, 0.5% sodium cholate). Metabolic profiling was performed by measuring the animals' visceral fat pads, fasting plasma glucose, insulin, and adipokines as well as in vivo insulin tolerance tests. Hepatic steatosis and inflammation were analyzed semiquantitatively by histological analysis. Folic acid supplementation reduced visceral obesity and improved plasma adiponectin levels. In vivo insulin sensitivity was improved, and in HF-FA rats folic acid increased activation of hepatic AMPK. Further, folic acid supplementation improved hepatic inflammation in animals fed with NASH-inducing diet. Dietary folic acid improved parameters of insulin resistance and hepatic inflammation in rodent models. This might be due to an increased AMK activation. © Georg Thieme Verlag KG Stuttgart · New York.

  15. The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection.

    PubMed

    Menne, Stephan; Cote, Paul J

    2007-01-07

    This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, and for the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and

  16. Effect of Green Tea Extract Encapsulated Into Chitosan Nanoparticles on Hepatic Fibrosis Collagen Fibers Assessed by Atomic Force Microscopy in Rat Hepatic Fibrosis Model.

    PubMed

    Safer, Abdel-Majeed A; Hanafy, Nomany A; Bharali, Dhruba J; Cui, Huadong; Mousa, Shaker A

    2015-09-01

    The present study examined the effect of Green Tea Extract (GTE) encapsulated into Chitosan Nanoparticles (CS-NPs) on hepatic fibrosis in rat model as determined by atomic force microscopy (AFM). The bioactive compounds in GTE encapsulated into CS-NPs were determined using LC-MS/MS method. Additionally, the uptake of GTE-CS NPs in HepG2 cells showed enhanced uptake. In experimental fibrosis model, AFM was used as a high resolution microscopic tool to investigate collagen fibers as an indicator of hepatic fibrosis induced by treatment with CCl4. Paraffin sections of fibrotic liver tissues caused by CC4 treatment of rats and the effect of GTE-CS NPs treatment with or without CCl4 on hepatic fibrosis were examined. Liver tissues from the different groups of animals were de-waxed and processed as for normal H/E staining and Masson's trichrome staining to locate the proper area of ECM collagen in the CCl4 group versus collagen in liver tissues treated with the GTE-CS NPs with or without CCl4. Selected areas of paraffin sections were trimmed off and fixed flat on top of mica and inserted in the AFM stage. H/E staining, Masson's trichrome stained slides, and AFM images revealed that collagen fibers of 250 to 300 nm widths were abundant in the fibrotic liver samples while those of GTE-CS NPs were clear as in the control group. Data confirmed the hypothesis that GTE-CS NPs are effective in removing all the extracellular collagen caused by CCl4 in the hepatic fibrosis rat liver.

  17. Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model

    PubMed Central

    Bard-Chapeau, Emilie A.; Nguyen, Anh-Tuan; Rust, Alistair G.; Sayadi, Ahmed; Lee, Philip; Chua, Belinda Q; New, Lee-Sun; de Jong, Johann; Ward, Jerrold M.; Chin, Christopher KY.; Chew, Valerie; Toh, Han Chong; Abastado, Jean-Pierre; Benoukraf, Touati; Soong, Richie; Bard, Frederic A.; Dupuy, Adam J.; Johnson, Randy L.; Radda, George K.; Chan, Eric CY.; Wessels, Lodewyk FA.; Adams, David J.

    2014-01-01

    The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC we performed a near saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers, and a bewildering number (2860) of candidate later stage drivers, that were enriched for genes mutated, deregulated, or that function in signaling pathways important for human HCC, with a striking 1199 genes linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC. PMID:24316982

  18. An experimental model for Staphylococcus aureus hepatic abscess in Bama minipig.

    PubMed

    Zhang, R G; Wang, X D; Zhang, X L; Yang, Y S

    2014-02-21

    Pyogenic hepatic abscess (PHA) is a rare but potentially serious disease. Investigations of new therapeutic methods urgently need experimental support in corresponding animal models. However, to date, few studies have evaluated PHA in the minipig. The linear regression equation of the Staphylococcus aureus ATCC 25923 strain was established. PHA was successfully mocked, and S. aureus ATCC 29213 was the only pathogenic bacterium identified. The abscess formation stage was observed on the 21st day of the operation. This study will provide a baseline for further studies evaluating new treatment methods for PHA.

  19. Dynamic analysis and optimal control for a model of hepatitis C with treatment

    NASA Astrophysics Data System (ADS)

    Zhang, Suxia; Xu, Xiaxia

    2017-05-01

    A model for hepatitis C is formulated to study the effects of treatment and public concern on HCV transmission dynamics. The stability of equilibria and persistence of the model are analyzed, and an optimal control measure is performed to prevent the spread of HCV with minimal infected individuals and cost. The dynamical analysis reveals that the disease-free equilibrium of the model is asymptotically stable if the basic reproductive number R0 is less than unity. On the other hand, if R0 > 1 , the disease is uniformly persistent. Numerical simulations are conducted to investigate the influence of different vital parameters on R0. For the corresponding optimality system, the optimal solution is discussed by Pontryagin Maximum Principle, and the comparisons of model-predicted consequences with control or not are presented.

  20. Small animal model systems for studying hepatitis B virus replication and pathogenesis.

    PubMed

    Dandri, Maura; Lutgehetmann, Marc; Volz, Tassilo; Petersen, Jörg

    2006-05-01

    The lack of reliable in vitro infection systems and convenient animal models has hindered progress in hepatitis B virus (HBV) research and the development of new treatment options. Due to various restraints encountered using chimpanzees and other models of HBV infection that are based on HBV-related viruses, and due to the necessity to work with small and well-characterized animal systems, it is not surprising that most recent developments have focused on mice. Various strains of transgenic mice harboring the entire HBV genome, or selected viral genes, were developed and proved to be very useful to elucidate mechanisms of HBV replication and pathogenesis. Furthermore, novel, exciting alternative mouse models have been developed recently, which allow not only studies on viral replication, but also the investigation of mechanisms of viral entry and clearance. This article provides an overview and discussion of the different mouse models of HBV replication and infection that are currently available.

  1. Statewide hepatitis C model of care for rural and remote regions.

    PubMed

    Cheng, Wendy; Nazareth, Saroj; Flexman, James Patrick

    2015-03-01

    The evolution of management of hepatitis C virus (HCV) has seen a majority of patients treated being regarded as cured. Despite this development, uptake of treatment remains low in Australia, and this is particularly true in rural and remote areas. The largest state in Australia, Western Australia (WA), covers an area of 2500 km(2). As the rural and remote population of WA is scattered in small areas rather than major centers, poor accessibility to remote areas and lack of adequate of medical and nursing resources pose major problems in providing equity of care to patients with chronic HCV. A statewide hepatitis model of care, established in 2009, has led to an increase in identification and treatment of patients living with HCV. Strategies used to facilitate these changes include telehealth, a nurse practitioner model, and general practitioner shared-care model. The statewide program will be modified to meet the changing needs of patients as all-oral treatment regimens become available, with further emphasis being placed on the role of rural and remote health professionals in identifying patients with HCV and initiating and monitoring treatment.

  2. A model of bi-mode transmission dynamics of hepatitis C with optimal control.

    PubMed

    Imran, Mudassar; Rafique, Hassan; Khan, Adnan; Malik, Tufail

    2014-06-01

    In this paper, we present a rigorous mathematical analysis of a deterministic model for the transmission dynamics of hepatitis C. The model is suitable for populations where two frequent modes of transmission of hepatitis C virus, namely unsafe blood transfusions and intravenous drug use, are dominant. The susceptible population is divided into two distinct compartments, the intravenous drug users and individuals undergoing unsafe blood transfusions. Individuals belonging to each compartment may develop acute and then possibly chronic infections. Chronically infected individuals may be quarantined. The analysis indicates that the eradication and persistence of the disease is completely determined by the magnitude of basic reproduction number R(c). It is shown that for the basic reproduction number R(c) < 1, the disease-free equilibrium is locally and globally asymptotically stable. For R(c) > 1, an endemic equilibrium exists and the disease is uniformly persistent. In addition, we present the uncertainty and sensitivity analyses to investigate the influence of different important model parameters on the disease prevalence. When the infected population persists, we have designed a time-dependent optimal quarantine strategy to minimize it. The Pontryagin's Maximum Principle is used to characterize the optimal control in terms of an optimality system which is solved numerically. Numerical results for the optimal control are compared against the constant controls and their efficiency is discussed.

  3. Viral Hepatitis

    MedlinePlus

    ... with hepatitis? How does a pregnant woman pass hepatitis B virus to her baby? If I have hepatitis B, what does my baby need so that she ... Can I breastfeed my baby if I have hepatitis B? More information on viral hepatitis What is hepatitis? ...

  4. Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp.

    PubMed

    Dalla Man, Chiara; Piccinini, Francesca; Basu, Rita; Basu, Ananda; Rizza, Robert A; Cobelli, Claudio

    2013-04-15

    Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3-(3)H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 ± 0.64 vs. 8.73 ± 1.07 10(-4) dl·kg(-1)·min(-1) per μU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔI(clamp) = 15.60 ± 1.61 vs. ΔI(meal)= 83.37 ± 10.71 μU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test.

  5. A review of the long-term protection after hepatitis A and B vaccination.

    PubMed

    Van Damme, Pierre; Van Herck, Koen

    2007-03-01

    on early projections of observed antibody levels. However, recent follow-up studies with up to 12 year observation, as well as studies employing mathematical models predict that following primary vaccination, antibodies will persist for at least 25 years. In addition, experimental studies confirm that vaccination against hepatitis A induces immunological memory. Therefore hepatitis A booster vaccination is presently considered as unnecessary in fully vaccinated individuals. The above findings are of importance in the context of administering combined hepatitis A and B vaccine for which similar long-term data have been observed. All available data on monovalent and combined hepatitis A and hepatitis B vaccines indicates that there is no support for a hepatitis A or hepatitis B booster when a complete primary vaccination course is offered to immunocompetent individuals.

  6. The pharmacokinetics and hepatic disposition of repaglinide in pigs: mechanistic modeling of metabolism and transport.

    PubMed

    Sjögren, Erik; Bredberg, Ulf; Lennernäs, Hans

    2012-04-02

    The predictive power of using in vitro systems in combination with physiologically based pharmacokinetic (PBPK) modeling to elucidate the relative importance of metabolism and carrier-mediated transport for the pharmacokinetics was evaluated using repaglinide as a model compound and pig as the test system. Repaglinide was chosen as model drug as previous studies in humans have shown that repaglinide is subject to both carrier-mediated influx to the liver cells and extensive hepatic metabolism. A multiple sampling site model in pig was chosen since it provides detailed in vivo information about the liver disposition. The underlying assumption was that both metabolism and carrier-mediated transport are also important for the hepatic disposition of repaglinide in pigs. Microsomes and primary hepatocytes were used for in vitro evaluation of enzyme kinetics and cellular disposition, respectively. In vitro data were generated both with and without metabolism inhibitors (ketoconazole, bezafibrate and trimethoprim) and transport inhibitors (diclofenac and quinine) providing input into a semi-PBPK model. In vivo data were also generated with and without the same enzyme and transporter inhibitors, alone and in combination. The pigs were given repaglinide as intravenous infusions with and without inhibitors in a sequential manner, i.e., a control phase and a test phase. Parameters describing the passive and carrier-mediated flux as well as metabolism were estimated in the control phase. The result from test phase was used to gain further knowledge of the findings from the control phase. The in vivo pig model enabled simultaneous sampling from plasma (pre- and postliver and peripheral) as well as from bile and urine. A semi-PBPK model consisting of 11 compartments (6 tissues + 5 sampling sites) was constructed for the mechanistic elucidation of the liver disposition, in vitro based in vivo predictions, sensitivity analyses and estimations of individual pharmacokinetic

  7. New models of hepatitis E virus replication in human and porcine hepatocyte cell lines

    USDA-ARS?s Scientific Manuscript database

    Hepatitis E virus (HEV) causes acute, enterically-transmitted hepatitis. It is associated with large epidemics in tropical and subtropical regions where it is endemic or with sporadic cases in non-endemic regions. Unlike other hepatitis viruses, HEV has several animal reservoirs. Phylogenetic studie...

  8. Dynamic analysis of a hepatitis B model with three-age-classes

    NASA Astrophysics Data System (ADS)

    Zhang, Suxia; Zhou, Yicang

    2014-07-01

    Based on the fact that the likelihood of becoming chronically infected is dependent on age at primary infection Kane (1995) [2], Edmunds et al. (1993) [3], Medley et al. (2001) [4], and Ganem and Prince (2004) [6], we formulate a hepatitis B transmission model with three age classes. The reproduction number, R0 is defined and the dynamical behavior of the model is analyzed. It is proved that the disease-free equilibrium is globally stable if R0<1, and there exists at least one endemic equilibrium and that the disease is uniformly persistent if R0>1. The unique endemic equilibrium and its global stability is obtained in a special case. Simulations are also conducted to compare the dynamical behavior of the model with and without age classes.

  9. Cell Culture Models for the Investigation of Hepatitis B and D Virus Infection.

    PubMed

    Verrier, Eloi R; Colpitts, Che C; Schuster, Catherine; Zeisel, Mirjam B; Baumert, Thomas F

    2016-09-20

    Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infections are major causes of liver disease and hepatocellular carcinoma worldwide. Despite the presence of an efficient preventive vaccine, more than 250 million patients are chronically infected with HBV. Current antivirals effectively control but only rarely cure chronic infection. While the molecular biology of the two viruses has been characterized in great detail, the absence of robust cell culture models for HBV and/or HDV infection has limited the investigation of virus-host interactions. Native hepatoma cell lines do not allow viral infection, and the culture of primary hepatocytes, the natural host cell for the viruses, implies a series of constraints restricting the possibilities of analyzing virus-host interactions. Recently, the discovery of the sodium taurocholate co-transporting polypeptide (NTCP) as a key HBV/HDV cell entry factor has opened the door to a new era of investigation, as NTCP-overexpressing hepatoma cells acquire susceptibility to HBV and HDV infections. In this review, we summarize the major cell culture models for HBV and HDV infection, discuss their advantages and limitations and highlight perspectives for future developments.

  10. Cell Culture Models for the Investigation of Hepatitis B and D Virus Infection

    PubMed Central

    Verrier, Eloi R.; Colpitts, Che C.; Schuster, Catherine; Zeisel, Mirjam B.; Baumert, Thomas F.

    2016-01-01

    Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infections are major causes of liver disease and hepatocellular carcinoma worldwide. Despite the presence of an efficient preventive vaccine, more than 250 million patients are chronically infected with HBV. Current antivirals effectively control but only rarely cure chronic infection. While the molecular biology of the two viruses has been characterized in great detail, the absence of robust cell culture models for HBV and/or HDV infection has limited the investigation of virus-host interactions. Native hepatoma cell lines do not allow viral infection, and the culture of primary hepatocytes, the natural host cell for the viruses, implies a series of constraints restricting the possibilities of analyzing virus-host interactions. Recently, the discovery of the sodium taurocholate co-transporting polypeptide (NTCP) as a key HBV/HDV cell entry factor has opened the door to a new era of investigation, as NTCP-overexpressing hepatoma cells acquire susceptibility to HBV and HDV infections. In this review, we summarize the major cell culture models for HBV and HDV infection, discuss their advantages and limitations and highlight perspectives for future developments. PMID:27657111

  11. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    PubMed

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.

  12. UNFEASIBLE EXPERIMENTAL MODEL OF NORMOTHERMIC HEPATIC ISCHEMIA AND REPERFUSION IN RATS USING THE PRINGLE MANEUVER

    PubMed Central

    GOMES, Helbert Minuncio Pereira; SERIGIOLLE, Leonardo Carvalho; RODRIGUES, Daren Athiê Boy; LOPES, Carolina Marques; STUDART, Sarah do Valle; LEME, Pedro Luiz Squilacci

    2014-01-01

    Background The negative result of a research does not always indicate failure, and when the data do not permit a proper conclusion, or are contrary to the initial project, should not simply be discarded and archived. Aim To report failure after performing experimental model of liver ischemia and reperfusion normothermic, continuous or intermittent, in small animals aiming at the study of biochemical and histological parameters after postoperative recovery. Methods Fifteen Wistar rats were divided into three groups of five animals each; all underwent surgery, the abdomen was sutured after the proposed procedures for each group and the animals were observed for 6 h or until they died, and then were reoperated. In Group 1, control (sham-operated): dissection of the hepatic hilum was performed; in Group 2: clamping of the hepatic hilum for 30 m; in Group 3: clamping of the hepatic hilum for 15 m, reperfusion for 5 m and another 15 m of clamping. Data from Groups 2 and 3 were compared with Student's t test. Results All animals of Group 1 survived for 6 h. Two animals in Group 2 died before the 6 h needed to validate the experiment; two did not recover from anesthesia and one survived until the end. In Group 3, four animals died before the 6 h established and one of them survived the required time. Only one animal in Group 2 and one in Group 3 survived and were able to accomplish the study. There was no statistical significance when the results of Groups 2 and 3 were compared (p>0.05). Conclusion The death of six animals before the necessary period of observation turned the initial proposal of the experiment unfeasible. PMID:25184771

  13. Hepatic perfusion in a tumor model using DCE-CT: an accuracy and precision study

    NASA Astrophysics Data System (ADS)

    Stewart, Errol E.; Chen, Xiaogang; Hadway, Jennifer; Lee, Ting-Yim

    2008-08-01

    In the current study we investigate the accuracy and precision of hepatic perfusion measurements based on the Johnson and Wilson model with the adiabatic approximation. VX2 carcinoma cells were implanted into the livers of New Zealand white rabbits. Simultaneous dynamic contrast-enhanced computed tomography (DCE-CT) and radiolabeled microsphere studies were performed under steady-state normo-, hyper- and hypo-capnia. The hepatic arterial blood flows (HABF) obtained using both techniques were compared with ANOVA. The precision was assessed by the coefficient of variation (CV). Under normo-capnia the microsphere HABF were 51.9 ± 4.2, 40.7 ± 4.9 and 99.7 ± 6.0 ml min-1 (100 g)-1 while DCE-CT HABF were 50.0 ± 5.7, 37.1 ± 4.5 and 99.8 ± 6.8 ml min-1 (100 g)-1 in normal tissue, tumor core and rim, respectively. There were no significant differences between HABF measurements obtained with both techniques (P > 0.05). Furthermore, a strong correlation was observed between HABF values from both techniques: slope of 0.92 ± 0.05, intercept of 4.62 ± 2.69 ml min-1 (100 g)-1 and R2 = 0.81 ± 0.05 (P < 0.05). The Bland-Altman plot comparing DCE-CT and microsphere HABF measurements gives a mean difference of -0.13 ml min-1 (100 g)-1, which is not significantly different from zero. DCE-CT HABF is precise, with CV of 5.7, 24.9 and 1.4% in the normal tissue, tumor core and rim, respectively. Non-invasive measurement of HABF with DCE-CT is accurate and precise. DCE-CT can be an important extension of CT to assess hepatic function besides morphology in liver diseases.

  14. Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus

    PubMed Central

    2016-01-01

    Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms. T cell clearance number is defined as the minimum number of infected cells needed to be killed by each T cell at peak infection that results in infection clearance within 12 weeks with hepatocyte turnover (HT, number of equivalent livers) ≤3. We find that CCT has very little impact on the establishment of infection as the mean cccDNA copies/cell remains between 15 to 20 at the peak of the infection regardless of CCT strength. In contrast, CCT inhibit immune-mediated clearance of acute HBV infection as higher CCT strength requires higher T cell clearance number and increases the probability of T cell exhaustion. An effective non-CTL inhibition can counter these negative effects of higher strengths of CCT by supporting rapid, efficient viral clearance and with little liver destruction. This is evident as the T cell clearance number drops by approximately 50% when non-CTL inhibition is increased from 10% to 80%. Higher CCT strength also increases the probability of the incidence of fulminant hepatitis with this phenomenon being unlikely to arise for no CCT. In conclusion, we report the possibility of CCT impacting HBV clearance and its contribution to fulminant hepatitis. PMID:27560827

  15. Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

    PubMed Central

    Ma, Xuanyi; Qu, Xin; Zhu, Wei; Li, Yi-Shuan; Yuan, Suli; Zhang, Hong; Liu, Justin; Wang, Pengrui; Lai, Cheuk Sun Edwin; Zanella, Fabian; Feng, Gen-Sheng; Sheikh, Farah; Chien, Shu; Chen, Shaochen

    2016-01-01

    The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling. PMID:26858399

  16. Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting.

    PubMed

    Ma, Xuanyi; Qu, Xin; Zhu, Wei; Li, Yi-Shuan; Yuan, Suli; Zhang, Hong; Liu, Justin; Wang, Pengrui; Lai, Cheuk Sun Edwin; Zanella, Fabian; Feng, Gen-Sheng; Sheikh, Farah; Chien, Shu; Chen, Shaochen

    2016-02-23

    The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

  17. 3D haptic modelling for preoperative planning of hepatic resection: A systematic review.

    PubMed

    Soon, David S C; Chae, Michael P; Pilgrim, Charles H C; Rozen, Warren Matthew; Spychal, Robert T; Hunter-Smith, David J

    2016-09-01

    Three dimensional (3D) printing has gained popularity in the medical field because of increased research in the field of haptic 3D modeling. We review the role of 3D printing with specific reference to liver directed applications. A literature search was performed using the scientific databases Medline and PubMed. We performed this in-line with the PRISMA [20] statement. We only included articles in English, available in full text, published about adults, about liver surgery and published between 2005 and 2015. The 3D model of a patient's liver venous vasculature and metastasis was prepared from a CT scan using Osirix software (Pixmeo, Gineva, Switzerland) and printed using our 3D printer (MakerBot Replicator Z18, US). To validate the model, measurements from the inferior vena cava (IVC) were compared between the CT scan and the 3D printed model. A total of six studies were retrieved on 3D printing directly related to a liver application. While stereolithography (STL) remains the gold standard in medical additive manufacturing, Fused Filament Fabrication (FFF), is cheaper and may be more applicable. We found our liver 3D model made by FFF had a 0.1 ± 0.06 mm margin of error (mean ± standard deviation) compared with the CT scans. 3D printing in general surgery is yet to be thoroughly exploited. The most relevant feature of interest with regard to liver surgery is the ability to view the 3D dimensional relationship of the various hepatic and portal veins with respect to tumor deposits when planning hepatic resection. Systematic review registration number: researchregistry1348.

  18. Modelling Hepatitis B Virus Antiviral Therapy and Drug Resistant Mutant Strains

    NASA Astrophysics Data System (ADS)

    Bernal, Julie; Dix, Trevor; Allison, Lloyd; Bartholomeusz, Angeline; Yuen, Lilly

    Despite the existence of vaccines, the Hepatitis B virus (HBV) is still a serious global health concern. HBV targets liver cells. It has an unusual replication process involving an RNA pre-genome that the reverse transcriptase domain of the viral polymerase protein translates into viral DNA. The reverse transcription process is error prone and together with the high replication rates of the virus, allows the virus to exist as a heterogeneous population of mutants, known as a quasispecies, that can adapt and become resistant to antiviral therapy. This study presents an individual-based model of HBV inside an artificial liver, and associated blood serum, undergoing antiviral therapy. This model aims to provide insights into the evolution of the HBV quasispecies and the individual contribution of HBV mutations in the outcome of therapy.

  19. Changes in the hepatic gene expression profile in a rat model of chronic ethanol treatment.

    PubMed

    Park, Sung-Hee; Choi, Myung-Sook; Park, Taesun

    2008-04-01

    The purpose of this study was to perform a comprehensive analysis of hepatic gene expression in a standard model of an alcohol-induced fatty liver using the cDNA microarray analysis. Male Sprague-Dawley rats were randomly divided into two groups and were given either an ethanol diet (ED), or a control diet (CD) for eight weeks. The ED rats showed significantly elevated levels of plasma total and HDL cholesterol as well as hepatic cholesterol and triglyceride compared to the pair-fed control rats. Among the 5185 genes on the rat cDNA microarray used in the current study, 74 genes were up-regulated and 108 genes were down-regulated greater than 2.0-fold in the liver of ED rats compared with those in the CD rats. The microarray results were verified by conducting real-time RT-PCR on the fourteen selected genes with varied expression ratios. After clustering the regulated genes based on their biological function, it was found that chronic ethanol consumption regulated mainly the genes implicated in the processes of signal transduction, transcription, immune response, and protein/amino acid metabolism. The microarray results obtained in this study revealed, for the first time, that several genes, including beta-glucuronidase, UDP-glycosyltransferase 1, UDP-glucose dehydrogenase, apoC-III, and gonadotropin-releasing hormone receptor, were regulated by chronic ethanol exposure in the rat liver.

  20. Effects of Ankaferd Blood Stopper and calcium alginate in experimental model of hepatic parenchymal bleeding.

    PubMed

    Aydin, O; Tuncal, S; Kilicoglu, B; Onalan, A K; Gonultas, M A; Ozer, H; Durhan, A; Tasova, V; Hucumenoglu, S; Kismet, K

    2015-01-01

    This experimental study compared the hemostatic effects of calcium alginate and Anka-ferd Blood Stopper in hepatic parenchymal bleedings. The study comprised 39 male Wistar albino rats (weight 230±30 g). Laceration model was created in the left lateral lobe of the liver. Standard cotton gauze that was impregnated 0.9% NaCl solution and Calcium alginate cover was compared to ABS tampon. The amount of preoperative bleeding, preoperative and postoperative Day 1 hematocrit levels, and the difference between them were assessed and statistically analyzed. Comparing the hematocrit levels between the groups, we found that the amount of bleeding was significantly higher in the control group versus the study groups (p<0.001). Histopathological examination revealed the portal area enlargement and biliary canaliculi proliferation. In the Ca2+ Alginate group, it was observed that the fibres were still present in the incision line with massive fibrotic area around. In the Ankaferd group, examination of the preparations revealed patchy focal necrosis areas but no fibrotic area. With this study, we demonstrated that both calcium alginate and Ankaferd have hemostatic effect in preventing hepatic parenchymal bleeding and that calcium alginate causes fibrosis in the liver, where ABS causes focal necrosis areas(Tab. 2, Fig. 4, Ref. 19).

  1. Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease.

    PubMed

    Galloway, Chad A; Lee, Hakjoo; Brookes, Paul S; Yoon, Yisang

    2014-09-15

    Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mitochondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochondrial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mitochondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD. Copyright © 2014 the American Physiological Society.

  2. MRI-based assessment of liver perfusion and hepatocyte injury in the murine model of acute hepatitis.

    PubMed

    Byk, Katarzyna; Jasinski, Krzysztof; Bartel, Zaneta; Jasztal, Agnieszka; Sitek, Barbara; Tomanek, Boguslaw; Chlopicki, Stefan; Skorka, Tomasz

    2016-12-01

    To assess alterations in perfusion and liver function in the concanavalin A (ConA)-induced mouse model of acute liver failure (ALF) using two magnetic resonance imaging (MRI)-based methods: dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA contrast agent and arterial spin labelling (ASL). BALB/c mice were studied using a 9.4 T MRI system. The IntraGateFLASH(TM) and FAIR-EPI pulse sequences were used for optimum mouse abdomen imaging. The average perfusion values for the liver of the control and ConA group were equal to 245 ± 20 and 200 ± 32 ml/min/100 g (p = 0.008, respectively). DCE-MRI showed that the time to the peak of the image enhancement was 6.14 ± 1.07 min and 9.72 ± 1.69 min in the control and ConA group (p < 0.001, respectively), while the rate of the contrast wash-out in the control and ConA group was 0.037 ± 0.008 and 0.021 ± 0.008 min(-1) (p = 0.004, respectively). These results were consistent with hepatocyte injury in the ConA-treated mice as confirmed by histopathological staining. Both the ASL and DCE-MRI techniques represent a reliable methodology to assess alterations in liver perfusion and hepatocyte integrity in murine hepatitis.

  3. (-)-Epigallocatechin-3-gallate suppresses hepatic preneoplastic lesions developed in a novel rat model of non-alcoholic steatohepatitis.

    PubMed

    Sumi, Takafumi; Shirakami, Yohei; Shimizu, Masahito; Kochi, Takahiro; Ohno, Tomohiko; Kubota, Masaya; Shiraki, Makoto; Tsurumi, Hisashi; Tanaka, Takuji; Moriwaki, Hisataka

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH, which is accompanied by increased oxidative stress and inflammation in the liver, is associated with hepatic carcinogenesis. Green tea catechins (GTCs) possess anti-oxidant, anti-inflammatory, and cancer-preventive properties. In this study, we investigated whether (-)-epigallocatechin-3-gallate (EGCG), a major component of GTCs, inhibits NAFLD/NASH-related liver tumorigenesis. Male 8-week-old Sprague-Dawley (SD) rats were administered a single intraperitoneal injection of a hepatic carcinogen diethylnitrosamine (DEN, 30 mg/kg body weight) and then fed a high-fat diet (HFD) for 7 weeks. The rats were also provided tap water containing 0.01% or 0.1% EGCG during the experiment. At sacrifice, the livers of SD rats treated with DEN and HFD exhibited marked development of glutathione S-transferase placental form (GST-P)-positive foci, a hepatic preneoplastic lesion, and this was associated with hepatic steatosis, oxidative stress and inflammation, and hepatocyte proliferation. EGCG administration, however, inhibited the development of GST-P-positive foci by decreasing hepatic triglyceride content, reducing hepatic fibrosis, lowering oxidative stress, attenuating inflammation, and inhibiting excessive hepatocyte proliferation in DEN- and HFD-treated SD rats. These findings suggest that the experimental model of SD rats treated with HFD and DEN, in which histopathological and pathophysiological characteristics of NASH and the development of hepatic premalignant lesions were observed, might facilitate the evaluation of liver tumorigenesis associated with NAFLD/NASH. Administering EGCG, a GTC, might serve as an effective chemoprevention modality for NAFLD/NASH-related liver tumorigenesis.

  4. IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier.

    PubMed

    Zeng, Zhutian; Kong, Xiaohui; Li, Fenglei; Wei, Haiming; Sun, Rui; Tian, Zhigang

    2013-10-15

    Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV)-carrier mouse model, we report that IL-12-based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12-based vaccination therapy, the majority of treated mice became HBsAg(-) in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12-based vaccination therapy strongly enhanced hepatic HBV-specific CD8(+) T cell responses, including proliferation and IFN-γ secretion. Systemic HBV-specific CD4(+) T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th-germinal center B cell responses and anti-hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4(+)Foxp3(+) regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12-based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4(+) T cell responses, eliciting robust hepatic HBV-specific CD8(+) T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B.

  5. Integrated internist — addiction medicine — hepatology model for hepatitis C management for individuals on methadone maintenance

    PubMed Central

    Martinez, A. D.; Dimova, R.; Marks, K. M.; Beeder, A. B.; Zeremski, M.; Kreek, M. J.; Talal, A. H.

    2013-01-01

    SUMMARY Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co-localized care model in which an internist-addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti-HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6-22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty-four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices. PMID:21129131

  6. Costs of a Public Health Model to Increase Receipt of Hepatitis-Related Services for Persons with Mental Illness

    PubMed Central

    Slade, Eric P.; Rosenberg, Stanley D.; Dixon, Lisa B.; Goldberg, Richard W.; Wolford, George; Himelhoch, Seth; Tapscott, Stephanie

    2013-01-01

    Objective The objective was to contextualize the costs associated with implementation of a specialized HIV/hepatitis preventive services model designed to reach persons with serious mental illness and co-occurring disorders, an underserved population. Methods Between 2006 and 2008, a random sample of 236 non-elderly, predominantly African American, male participants with serious mental illness and a co-occurring substance use disorder were recruited at four community mental health outpatient programs in a large metropolitan area. All participants had been diagnosed with a psychotic or major depressive disorder. Participants were randomized within site to receive either the experimental intervention Screen, Test, Immunize, Reduce risk, and Refer (STIRR) or enhanced treatment as usual, which consisted of education and referral to medical testing. We estimated STIRR’s standardized costs, the costs of STIRR per person who received hepatitis testing, HIV testing, and/or hepatitis A/B vaccination during the 6-months post-randomization. Results The average cost of delivering the STIRR intervention was $423 (SD±$90) per participant (in 2008 dollars) and the average cost of delivering the eTAU intervention was $24 (SD±$22) per participant (test of difference t=52.9, P<.001). The standardized costs per person who received hepatitis C testing, hepatitis B testing, HIV testing, and hepatitis A/B vaccination were $706 (SD±$165), $776 (SD±$181), $3,630 (SD±$846), and $561 (SD±131). Conclusions The STIRR model’s standardized costs suggest that hepatitis and HIV prevention services delivered in outpatient mental health settings to persons with serious mental illness can be at least as cost-effective as similar interventions designed for other at-risk populations. PMID:23475451

  7. Morphometric characterization of the human portal and hepatic venous trees: A quantitative support to the liver micro-anatomic models free of subunits.

    PubMed

    Almenar-Medina, Sergio; Palomar-De Lucas, Brenda; Guerrero-Albors, Ester; Ruiz-Sauri, Amparo

    2017-06-01

    Conventional models of liver microanatomy assume the presence of subunits. Nevertheless, some researchers propose that the liver is a continuous structure, free of these subunits, but with a characteristic vascular pattern. The present study describes a morphometric analysis of portal and hepatic veins in 50 human autopsy non-pathological liver samples. The main objective was to measure three proportions: 1. portal tracts / hepatic veins, 2. distributing portal veins / distributing hepatic veins and 3. terminal portal veins / terminal hepatic veins. These ratios were compared with the traditional microcirculatory liver models. Our material comprised 3,665 portal veins and 3,761 hepatic veins. The minimum diameter of half of the venous vessels of both types belongs to the interval (25μm , 60μm), given that 1881 portal veins (49.434%) and 1924 hepatic veins (50.565%) fall within this interval. We have statistically shown with the χ² test (α=0.990) that the portal and hepatic veins belonging to the interval (25μm , 400μm) (distributing veins) had an identical proportion. If the portal and hepatic veins are arranged according to the principle of interdigitation of Takashasi (1970), there should be an almost identical number of both types of veins. Our results contradict the presumably numeric preponderance of distributing portal veins with regard to the distributing hepatic veins that is inherent in the models of Kiernan, Matsumoto and Rappaport.

  8. Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

    PubMed Central

    Daga, Pankaj R; Duan, Jinsong; Doerksen, Robert J

    2010-01-01

    Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 Å. The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates. PMID:20162615

  9. Non-alcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model.

    PubMed

    Müller, Peter; Messmer, Marie; Bayer, Monika; Pfeilschifter, Josef M; Hintermann, Edith; Christen, Urs

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) and its more severe development non-alcoholic steatohepatitis (NASH) are increasing worldwide. In particular NASH, which is characterized by an active hepatic inflammation, has often severe consequences including progressive fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Here we investigated how metabolic liver injury is influencing the pathogenesis of autoimmune hepatitis (AIH). We used the CYP2D6 mouse model in which wild type C57BL/6 mice are infected with an Adenovirus expressing the major liver autoantigen cytochrome P450 2D6 (CYP2D6). Such mice display several features of human AIH, including interface hepatitis, formation of LKM-1 antibodies and CYP2D6-specific T cells, as well as hepatic fibrosis. NAFLD was induced with a high-fat diet (HFD). We found that pre-existing NAFLD potentiates the severity of AIH. Mice fed for 12 weeks with a HFD displayed increased cellular infiltration of the liver, enhanced hepatic fibrosis and elevated numbers of liver autoantigen-specific T cells. Our data suggest that a pre-existing metabolic liver injury constitutes an additional risk for the severity of an autoimmune condition of the liver, such as AIH.

  10. AIC649 Induces a Bi-Phasic Treatment Response in the Woodchuck Model of Chronic Hepatitis B

    PubMed Central

    Paulsen, Daniela; Weber, Olaf; Ruebsamen-Schaeff, Helga; Tennant, Bud C.; Menne, Stephan

    2015-01-01

    AIC649 has been shown to directly address the antigen presenting cell arm of the host immune defense leading to a regulated cytokine release and activation of T cell responses. In the present study we analyzed the antiviral efficacy of AIC649 as well as its potential to induce functional cure in animal models for chronic hepatitis B. Hepatitis B virus transgenic mice and chronically woodchuck hepatitis virus (WHV) infected woodchucks were treated with AIC649, respectively. In the mouse system AIC649 decreased the hepatitis B virus titer as effective as the “gold standard”, Tenofovir. Interestingly, AIC649-treated chronically WHV infected woodchucks displayed a bi-phasic pattern of response: The marker for functional cure—hepatitis surface antigen—first increased but subsequently decreased even after cessation of treatment to significantly reduced levels. We hypothesize that the observed bi-phasic response pattern to AIC649 treatment reflects a physiologically “concerted”, reconstituted immune response against WHV and therefore may indicate a potential for inducing functional cure in HBV-infected patients. PMID:26656974

  11. Hepatitis C

    MedlinePlus

    ... your doctor may want you to get the hepatitis B vaccine (and maybe the hepatitis A vaccine, too), if you don't already have these viruses. If you have hepatitis C, you are more likely to catch hepatitis A or hepatitis B, which would cause more damage to your liver. ...

  12. Application of a hybrid method combining grey model and back propagation artificial neural networks to forecast hepatitis B in china.

    PubMed

    Gan, Ruijing; Chen, Xiaojun; Yan, Yu; Huang, Daizheng

    2015-01-01

    Accurate incidence forecasting of infectious disease provides potentially valuable insights in its own right. It is critical for early prevention and may contribute to health services management and syndrome surveillance. This study investigates the use of a hybrid algorithm combining grey model (GM) and back propagation artificial neural networks (BP-ANN) to forecast hepatitis B in China based on the yearly numbers of hepatitis B and to evaluate the method's feasibility. The results showed that the proposal method has advantages over GM (1, 1) and GM (2, 1) in all the evaluation indexes.

  13. Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model.

    PubMed

    Kim, In Hee; Kim, Sang Wook; Kim, Seong Hun; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae Ghon; Lee, Mi Jin; Park, Woo Hyun

    2012-07-31

    Parthenolide (PT), a sesquiterpene lactone derived from the plant feverfew, has pro-apoptotic activity in a number of cancer cell types. We assessed whether PT induces the apoptosis of hepatic stellate cells (HCSs) and examined its effects on hepatic fibrosis in an in vivo model. The effects of PT on rat HSCs were investigated in relation to cell growth inhibition, apoptosis, NF-κB binding activity, intracellular reactive oxygen species (ROS) generation, and glutathione (GSH) levels. In addition, the anti-fibrotic effects of PT were investigated in a thioacetamide-treated rat model. PT induced growth inhibition and apoptosis in HSCs, as evidenced by cell growth inhibition and apoptosis assays. PT increased the expression of Bax proteins during apoptosis, but decreased the expression of Bcl-2 and Bcl-X(L) proteins. PT also induced a reduction in mitochondrial membrane potential, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. PT inhibited TNF-α-stimulated NF-κB binding activity in HSCs. The pro-apoptotic activity of PT in HSCs was associated with increased intracellular oxidative stress as evidenced by increased intracellular ROS levels and depleted intracellular GSH levels. Furthermore, PT ameliorated hepatic fibrosis significantly in a thioacetamide- treated rat model. In conclusion, PT exhibited pro-apoptotic effects in rat HSCs and ameliorated hepatic fibrosis in a thioacetamide-induced rat model.

  14. From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations

    PubMed Central

    Green, Charlotte J.; Pramfalk, Camilla; Morten, Karl J.

    2014-01-01

    The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD. PMID:25352434

  15. Use of labeled oral minimal model to measure hepatic insulin sensitivity.

    PubMed

    Man, Chiara Dalla; Toffolo, Gianna; Basu, Rita; Rizza, Robert A; Cobelli, Claudio

    2008-11-01

    The ability to accurately quantify indexes of the individual role of glucose (GE(L)) and insulin (S(I)(L)) in the suppression of endogenous glucose production (EGP) would improve the understanding of liver metabolism. Measuring these indexes during an IVGTT by minimal modeling of tracer labeled and unlabeled glucose data is often unreliable, possibly due to an inadequate description of EGP included in the Minimal Model. Moreover, a validation of the assumptions of the Minimal Model on EGP data has never been done. Recently, Krudys et al. (Krudys KM, Dodds MG, Nissen SM, Vicini P. Am J Physiol Endocrinol Metab 288: E1038-E1046, 2005) have proposed a PK/PD (pharmacokinetic/pharmacodynamic) model of the EGP profile that occurs during an intravenous glucose tolerance test (IVGTT); however, this model has also not been validated. The aim of this study was thus to test the Minimal Model, the PK/PD model, and six alternative EGP descriptions on recent model-independent EGP data of 20 subjects obtained with a triple-tracer meal protocol. Model performance was compared in terms of data fit, precision of the estimated parameters, and physiological plausibility. Neither the PK/PD nor the traditional Minimal Model were able to accurately describe EGP data or provide reliable estimates of the indexes. In contrast, one of the new models performed best by showing a good fit and providing accurate and precise estimates of hepatic sensitivity indexes: GE(L) = 0.013 +/- 0.001 dl x kg(-1) x min(-1); S(I)(L) = 5.34 +/- 0.47 10(-4) dl x kg(-1) x min(-1) per microU/ml (42 and 34%, respectively, of total sensitivity indexes GE(TOT) and S(I)(TOT)). Although this model requires further validation, it has the potential to improve our understanding of the role of the liver in pathophysiological states.

  16. Multi-scale model for hepatitis C viral load kinetics under treatment with direct acting antivirals.

    PubMed

    Clausznitzer, Diana; Harnisch, Julia; Kaderali, Lars

    2016-06-15

    Hepatitis C virus (HCV) infections are a global health problem, and extensive research over the last decades has been targeted at understanding its molecular biology and developing effective antiviral treatments. Recently, a number of potent direct acting antiviral drugs have been developed targeting specific processes in the viral life cycle. Here, we developed a mathematical multi-scale model of the within-host dynamics of HCV infection by integrating a standard model for viral infection with a detailed model of the viral replication cycle inside infected cells. We use this model to study patient time courses of viral load under treatment with daclatasvir, an inhibitor of the viral non-structural protein NS5A. Model analysis predicts that treatment efficacy can be increased by combining daclatasvir with dedicated viral polymerase inhibitors, corresponding to promising current strategies in drug development. Hence, our model presents a predictive tool for in silico simulations, which can be used to study and optimize direct acting antiviral drug treatment.

  17. Serological validation of an alveolar echinococcosis rat model with a single hepatic lesion

    PubMed Central

    YAMASHITA, Masamichi; IMAGAWA, Tomohiro; SAKO, Yasuhito; OKAMOTO, Munehiro; YANAGIDA, Tetsuya; OKAMOTO, Yoshiharu; TSUKA, Takeshi; OSAKI, Tomohiro; ITO, Akira

    2016-01-01

    Serology is important for the diagnosis and follow-up of human alveolar echinococcosis (AE). However, patient conditions are highly variable among those with AE, and antibody responses in serological follow-up have not been well-defined. We recently described a new AE rat model established by implantation of small AE tissue into a single arbitrary location in the liver; no metastasis and dissemination were observed. In the present study, we examined the serological characteristics in our rat model before and after surgical treatment. The results showed that antibody responses against crude antigens were increased at one month after transplantation and similar to those of other model animals. For the antigen Em18, antibody responses were slower in our rat model than in other animal models. After surgical resection, changes in antibody responses against Em18 were similar to those observed in human patients with AE. Because of the slow growth of lesions, establishment of a single hepatic lesion and patterns of antibody responses, our rat model may be useful for clarifying follow-up serodiagnoses in human AE and determining the mechanisms of multi-organ involvement by primary infection with oncospheres rather than metastasis. PMID:27890868

  18. Score model for predicting acute-on-chronic liver failure risk in chronic hepatitis B

    PubMed Central

    Gao, Fang-Yuan; Liu, Yao; Li, Xiao-Shu; Ye, Xie-Qiong; Sun, Le; Geng, Ming-Fan; Wang, Rui; Liu, Hui-Min; Zhou, Xiao-Bing; Gu, Li-Li; Liu, Yan-Min; Wan, Gang; Wang, Xian-Bo

    2015-01-01

    AIM: To establish a clinical scoring model to predict risk of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients. METHODS: This was a retrospective study of 1457 patients hospitalized for CHB between October 2008 and October 2013 at the Beijing Ditan Hospital, Capital Medical University, China. The patients were divided into two groups: severe acute exacerbation (SAE) group (n = 382) and non-SAE group (n = 1075). The SAE group was classified as the high-risk group based on the higher incidence of ACLF in this group than in the non-SAE group (13.6% vs 0.4%). Two-thirds of SAE patients were randomly assigned to risk-model derivation and the other one-third to model validation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. Model discrimination and calibration were assessed using area under the receiver operating characteristic curve and the Hosmer-Lemeshow test. RESULTS: The risk prediction scoring model included the following four factors: age ≥ 40 years, total bilirubin ≥ 171 μmol/L, prothrombin activity 40%-60%, and hepatitis B virus DNA > 107 copies/mL. The sum risk score ranged from 0 to 7; 0-3 identified patients with lower risk of ACLF, whereas 4-7 identified patients with higher risk. The Kaplan-Meier analysis showed the cumulative risk for ACLF and ACLF-related death in the two risk groups (0-3 and 4-7 scores) of the primary cohort over 56 d, and log-rank test revealed a significant difference (2.0% vs 33.8% and 0.8% vs 9.4%, respectively; both P < 0.0001). In the derivation and validation data sets, the model had good discrimination (C index = 0.857, 95% confidence interval: 0.800-0.913 and C index = 0.889, 95% confidence interval: 0.820-0.957, respectively) and calibration

  19. A network model for the propagation of Hepatitis C with HIV co-infection

    NASA Astrophysics Data System (ADS)

    Nucit, Arnaud; Randon-Furling, Julien

    2017-05-01

    We define and examine a model of epidemic propagation for a virus such as Hepatitis C (with HIV co-infection) on a network of networks, namely the network of French urban areas. One network level is that of the individual interactions inside each urban area. The second level is that of the areas themselves, linked by individuals travelling between these areas and potentially helping the epidemic spread from one city to another. We choose to encode the second level of the network as extra, special nodes in the first level. We observe that such an encoding leads to sensible results in terms of the extent and speed of propagation of an epidemic, depending on its source point.

  20. Models and methods for in vitro testing of hepatic gap junctional communication

    PubMed Central

    Willebrords, Joost; Vinken, Mathieu

    2015-01-01

    Inherent to their pivotal roles in controlling all aspects of the liver cell life cycle, hepatocellular gap junctions are frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity. Hepatic gap junctions, which are mainly built up by connexin32, are specifically targeted by tumor promoters and epigenetic carcinogens. This renders inhibition of gap junction functionality a suitable indicator for the in vitro detection of nongenotoxic hepatocarcinogenicity. The establishment of a reliable liver gap junction inhibition assay for routine in vitro testing purposes requires a cellular system in which gap junctions are expressed at an in vivo-like level as well as an appropriate technique to probe gap junction activity. Both these models and methods are discussed in the current paper, thereby focusing on connexin32-based gap junctions. PMID:26420514

  1. Hepatic differentiation of human amniotic epithelial cells and in vivo therapeutic effect on animal model of cirrhosis.

    PubMed

    Lin, Jaymie Siqi; Zhou, Lei; Sagayaraj, Antony; Jumat, Nur Halisah Bte; Choolani, Mahesh; Chan, Jerry Kok Yen; Biswas, Arijit; Wong, Peng Cheang; Lim, Seng Gee; Dan, Yock Young

    2015-11-01

    Human amniotic epithelial cells (hAECs) have been touted as an ideal stem cell candidate, being ethically neutral, immunologically naïve, plentiful in origin, and retaining plasticity in its fetal stage. We hypothesized that by applying natural physiological signals of the developing liver, hAECs can be coaxed into becoming functional immunopermissive hepatocyte-like cells. These cells would have tremendous potential for allogenic cellular transplantation in the treatment of chronic liver insufficiency. hAECs were obtained from term placentas and subjected to hepatic trans-differentiation. Hepatic differentiated cells were analyzed with immunophenotyping, electron microscopy, reverse transcription-polymerase chain reaction as well as characterized for hepatic metabolic function. In vivo efficacy was tested using intrasplenic transplantation into non-obese diabetic (NOD) Scid Gamma mice with thioacetamide-induced chronic liver failure and analyzed for engraftment and improvement in liver indices. With hepatic differentiation, hAECs assumed a hepatocytic polygonal morphology with upregulation of transcription factors responsible for liver specification. These hepatic differentiated-hAECs (HD-AECs) demonstrated bile canaliculi formation, secreted albumin, eliminated indo-cyanine green, uptook low-density lipoprotein, and inducible CYP3A4 and CYP2C9 enzymatic activities. Transplantation of HD-AECs and de novo hAECs in mice model of cirrhosis showed successful in vivo engraftment and differentiation into functional hepatocytes positive for human-specific albumin. HD-AEC cells that had undergone hepatic differentiation showed the greatest improvement in albumin function while preserving human leukocyte antigen-G expression postdifferentiation. hAECs were able to differentiate into functional hepatocyte-like cells both in vivo and in vitro. They showed therapeutic efficacy after transplantation in mice model of cirrhosis, offering an exciting source of cells for

  2. Calycosin attenuates triglyceride accumulation and hepatic fibrosis in murine model of non-alcoholic steatohepatitis via activating farnesoid X receptor.

    PubMed

    Duan, Xingping; Meng, Qiang; Wang, Changyuan; Liu, Zhihao; Liu, Qi; Sun, Huijun; Sun, Pengyuan; Yang, Xiaobo; Huo, Xiaokui; Peng, Jinyong; Liu, Kexin

    2017-02-15

    Non-alcoholic steatohepatitis (NASH) represents the more severe end of hepatic steatosis and is associated with progressive liver disease. Calycosin, derived from the root of Radix Astragali, has been demonstrated to have favorable efficacy on acute liver injury. The present study was to investigate the hepatoprotective effect of calycosin on attenuating triglyceride accumulation and hepatic fibrosis, as well as explore the potential mechanism in murine model of NASH. The C57BL/6 male mice were fed with methionine choline deficient (MCD) diet for 4 weeks to induce NASH and treated with or without calycosin by oral gavage for 4 weeks. The body weight, liver weight and the liver to body weight ratios were measured. Serum ALT, AST, TG, TC, FFA, MCP-1 and mKC levels were accessed by biochemical methods. H&E staining and Oil red O staining were used to identify the amelioration of liver histopathology. Immunohistochemistry of a-SMA, Masson trichrome staining and Sirius red staining were used to identify the amelioration of hepatic fibrosis. The quantitative real-time-PCR and Western blot were applied to observe the expression changes of key factors involved in triglyceride synthesis, free fatty acid β-oxidation and hepatic fibrosis. Calycosin significantly inhibited body weight loss induced by MCD diet, decreased the ALT and AST activities, MCP-1 and mKC in a dose-dependent manner. The H&E and Oil red O staining indicated calycosin effectively improved hepatic steatosis, improved the degree of triglyceride accumulation. Masson trichrome and Sirius red staining indicated that calycosin treatment remarkably attenuated the degree of hepatic fibrosis. Immunohistochemistry of a-SMA demonstrated that calycosin attenuated hepatic fibrosis by inhibiting hepatic stellate cell activation. Further, calycosin inhibited the expression of SREBP-1c, FASN, ACC and SCD1 involved in triglyceride synthesis, promoted the expression of PPARa, CPT1, Syndecan-1 and LPL involved in free fatty

  3. Genistein Alleviates Neuroinflammation and Restores Cognitive Function in Rat Model of Hepatic Encephalopathy: Underlying Mechanisms.

    PubMed

    Ganai, Ajaz Ahmad; Husain, Mohammad

    2017-02-21

    Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from acute liver failure. Previously, we demonstrated hepatoprotective effects of genistein in D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). In this study, we evaluated behavioural and neuroprotective effects of genistein in rat model of HE. HE was induced by intraperitonial administration of D-GalN (250 mg/kg BW) twice a week for 30 days Genistein was given as co-treatment through oral gavage daily at dose of 5 mg/kg BW. D-GalN administration significantly resulted in acute liver failure which was further associated with hyperammonemia, neurological dysfunction, as evident from behavioural and functional impairment and reduced learning ability in Morris water maze. Genistein significantly alleviated behavioural and functional impairment and restored learning ability in Morris water maze. Considerable histopathological changes, including portal inflammation, sinusoidal dilation, necrotic lesions and swelled astrocytes with pale nuclei, were seen in the liver and brain sections of D-GalN-challenged rats while genistein co-treated rats revealed normal cellular and morphological architecture as no pathological features were seen. Furthermore, pro-inflammatory markers (interleukin (IL)-10, IL-4, IL-1β and TNF-α) and membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA marked significant increase, while subunits GluR1 of AMPA receptors showed reduced expression in D-GalN-challenged rats leading to neuroinflammation and dysregulated neurotransmission. Genistein significantly normalized altered expression of pro-inflammatory cytokines and membrane receptor of GABA and GluR. Our study suggests strong therapeutic potential of genistein in animal model of HE. Genistein can be used a strong anti-oxidant to attenuate neurotoxic effects of xenobiotics.

  4. Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

    PubMed Central

    Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

    2015-01-01

    The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

  5. Simple clinical variables predict liver histology in hepatitis C: prospective validation of a clinical prediction model.

    PubMed

    Romagnuolo, Joseph; Andrews, Christopher N; Bain, Vincent G; Bonacini, Maurizio; Cotler, Scott J; Ma, Mang; Sherman, Morris

    2005-11-01

    A recent single-center multivariate analysis of hepatitis C (HCV) patients showed that having any two criteria: 1) ferritin > or =200 microg/l and 2) spider nevi and/or albumin < or = 35 g/l predicted grade 2 or greater histological inflammation; the presence of any two of the following criteria: spider nevi, platelets < or =150 x 109/l, palpable splenomegaly and/or albumin < or =35 g/l predicted stage 2 or greater histological fibrosis. Absence of predictors also predicted a lack of inflammation and fibrosis. Our aim was prospectively to validate this clinical prediction model using an independent multicenter sample. Eighty-one patients with previously untreated active chronic HCV underwent physical examination, laboratory investigation, and liver biopsy. Biopsies were read, in blinded fashion, by a single pathologist, using a modified Hytiroglou (1995) scale. The clinical scoring system was correlated with histology; likelihood ratios (LRs), Fisher's exact p-values, and receiver operating characteristics (ROCs) were calculated. Data recording was complete in 77 and 38 patients regarding fibrotic stage and inflammatory grade, respectively. For fibrosis, 3/3 patients with any three criteria (LR 17, positive predictive value (PPV) 100%), 4/5 patients with any two criteria (LR 5.1), and 15/47 with no criteria (LR 0.6, negative predictive value (NPV) 68%) had stage 2 or greater fibrosis on biopsy (p=0.01). For inflammation, 5/5 patients with both criteria (LR 15, PPV 100%), and 8/19 patients with no criteria (LR 0.5, NPV 58%) had moderate-severe inflammation on liver biopsy (p=0.036). When missing variables were assumed to be normal, recalculated LRs were almost identical. An alanine aminotransferase (ALAT) level <60 U/l may increase the NPVs. This independent multicenter data set has validated our published model which uses simple clinical variables accurately and significantly to predict hepatic fibrosis and inflammation in HCV patients.

  6. Design evaluation and optimization for models of hepatitis C viral dynamics.

    PubMed

    Guedj, Jeremie; Bazzoli, Caroline; Neumann, Avidan U; Mentré, France

    2011-05-10

    Mathematical modeling of hepatitis C viral (HCV) kinetics is widely used for understanding viral pathogenesis and predicting treatment outcome. The standard model is based on a system of five non-linear ordinary differential equations (ODE) that describe both viral kinetics and changes in drug concentration after treatment initiation. In such complex models parameter estimation is challenging and requires frequent sampling measurements on each individual. By borrowing information between study subjects, non-linear mixed effect models can deal with sparser sampling from each individual. However, the search for optimal designs in this context has been limited by the numerical difficulty of evaluating the Fisher information matrix (FIM). Using the software PFIM, we show that a linearization of the statistical model avoids most of the computational burden, while providing a good approximation to the FIM. We then compare the precision of the parameters that can be expected using five study designs from the literature. We illustrate the usefulness of rationalizing data sampling by showing that, for a given level of precision, optimal design could reduce the total number of measurements by up 50 per cent. Our approach can be used by a statistician or a clinician aiming at designing an HCV viral kinetics study.

  7. Zebrafish as a Potential Model Organism for Drug Test Against Hepatitis C Virus

    PubMed Central

    Ding, Cun-Bao; Zhang, Jing-Pu; Zhao, Ye; Peng, Zong-Gen; Song, Dan-Qing; Jiang, Jian-Dong

    2011-01-01

    Screening and evaluating anti- hepatitis C virus (HCV) drugs in vivo is difficult worldwide, mainly because of the lack of suitable small animal models. We investigate whether zebrafish could be a model organism for HCV replication. To achieve NS5B-dependent replication an HCV sub-replicon was designed and created with two vectors, one with HCV ns5b and fluorescent rfp genes, and the other containing HCV's 5′UTR, core, 3′UTR and fluorescent gfp genes. The vectors containing sub-replicons were co-injected into zebrafish zygotes. The sub-replicon amplified in liver showing a significant expression of HCV core RNA and protein. The sub-replicon amplification caused no abnormality in development and growth of zebrafish larvae, but induced gene expression change similar to that in human hepatocytes. As the amplified core fluorescence in live zebrafish was detectable microscopically, it rendered us an advantage to select those with replicating sub-replicon for drug experiments. Ribavirin and oxymatrine, two known anti-HCV drugs, inhibited sub-replicon amplification in this model showing reduced levels of HCV core RNA and protein. Technically, this method had a good reproducibility and is easy to operate. Thus, zebrafish might be a model organism to host HCV, and this zebrafish/HCV (sub-replicon) system could be an animal model for anti-HCV drug screening and evaluation. PMID:21857967

  8. Experimental in vitro and in vivo models for the study of human hepatitis B virus infection.

    PubMed

    Allweiss, Lena; Dandri, Maura

    2016-04-01

    Chronic infection with the hepatitis B virus (HBV) affects an estimate of 240 million people worldwide despite the availability of a preventive vaccine. Medication to repress viral replication is available but a cure is rarely achieved. The narrow species and tissue tropism of the virus and the lack of reliable in vitro models and laboratory animals susceptible to HBV infection, have limited research progress in the past. As a result, several aspects of the HBV life cycle as well as the network of virus host interactions occurring during the infection are not yet understood. Only recently, the identification of the functional cellular receptor enabling HBV entry has opened new possibilities to establish innovative infection systems. Regarding the in vivo models of HBV infection, the classical reference was the chimpanzee. However, because of the strongly restricted use of great apes for HBV research, major efforts have focused on the development of mouse models of HBV replication and infection such as the generation of humanized mice. This review summarizes the animal and cell culture based models currently available for the study of HBV biology. We will discuss the benefits and caveats of each model and present a selection of the most important findings that have been retrieved from the respective systems.

  9. Hepatitis C

    MedlinePlus

    Hepatitis C Overview By Mayo Clinic Staff Hepatitis C is a viral infection that causes liver inflammation, sometimes leading to serious liver damage. The hepatitis C virus (HCV) spreads through contaminated ...

  10. Hepatitis B

    MedlinePlus

    ... receive the hepatitis B vaccine. Since then, the rate of new hepatitis B infections has gone down ... 1 Asian Americans and African Americans have higher rates of chronic hepatitis B. 2 Many people in ...

  11. Public Health Impact and Cost-Effectiveness of Hepatitis A Vaccination in the United States: A Disease Transmission Dynamic Modeling Approach.

    PubMed

    Dhankhar, Praveen; Nwankwo, Chizoba; Pillsbury, Matthew; Lauschke, Andreas; Goveia, Michelle G; Acosta, Camilo J; Elbasha, Elamin H

    2015-06-01

    To assess the population-level impact and cost-effectiveness of hepatitis A vaccination programs in the United States. We developed an age-structured population model of hepatitis A transmission dynamics to evaluate two policies of administering a two-dose hepatitis A vaccine to children aged 12 to 18 months: 1) universal routine vaccination as recommended by the Advisory Committee on Immunization Practices in 2006 and 2) Advisory Committee on Immunization Practices's previous regional policy of routine vaccination of children living in states with high hepatitis A incidence. Inputs were obtained from the published literature, public sources, and clinical trial data. The model was fitted to hepatitis A seroprevalence (National Health and Nutrition Examination Survey II and III) and reported incidence from the National Notifiable Diseases Surveillance System (1980-1995). We used a societal perspective and projected costs (in 2013 US $), quality-adjusted life-years, incremental cost-effectiveness ratio, and other outcomes over the period 2006 to 2106. On average, universal routine hepatitis A vaccination prevented 259,776 additional infections, 167,094 outpatient visits, 4781 hospitalizations, and 228 deaths annually. Compared with the regional vaccination policy, universal routine hepatitis A vaccination was cost saving. In scenario analysis, universal vaccination prevented 94,957 infections, 46,179 outpatient visits, 1286 hospitalizations, and 15 deaths annually and had an incremental cost-effectiveness ratio of $21,223/quality-adjusted life-year when herd protection was ignored. Our model predicted that universal childhood hepatitis A vaccination led to significant reductions in hepatitis A mortality and morbidity. Consequently, universal vaccination was cost saving compared with a regional vaccination policy. Herd protection effects of hepatitis A vaccination programs had a significant impact on hepatitis A mortality, morbidity, and cost-effectiveness ratios

  12. A molecular thermodynamic model for the stability of hepatitis B capsids

    SciTech Connect

    Kim, Jehoon; Wu, Jianzhong

    2014-06-21

    Self-assembly of capsid proteins and genome encapsidation are two critical steps in the life cycle of most plant and animal viruses. A theoretical description of such processes from a physiochemical perspective may help better understand viral replication and morphogenesis thus provide fresh insights into the experimental studies of antiviral strategies. In this work, we propose a molecular thermodynamic model for predicting the stability of Hepatitis B virus (HBV) capsids either with or without loading nucleic materials. With the key components represented by coarse-grained thermodynamic models, the theoretical predictions are in excellent agreement with experimental data for the formation free energies of empty T4 capsids over a broad range of temperature and ion concentrations. The theoretical model predicts T3/T4 dimorphism also in good agreement with the capsid formation at in vivo and in vitro conditions. In addition, we have studied the stability of the viral particles in response to physiological cellular conditions with the explicit consideration of the hydrophobic association of capsid subunits, electrostatic interactions, molecular excluded volume effects, entropy of mixing, and conformational changes of the biomolecular species. The course-grained model captures the essential features of the HBV nucleocapsid stability revealed by recent experiments.

  13. A molecular thermodynamic model for the stability of hepatitis B capsids

    NASA Astrophysics Data System (ADS)

    Kim, Jehoon; Wu, Jianzhong

    2014-06-01

    Self-assembly of capsid proteins and genome encapsidation are two critical steps in the life cycle of most plant and animal viruses. A theoretical description of such processes from a physiochemical perspective may help better understand viral replication and morphogenesis thus provide fresh insights into the experimental studies of antiviral strategies. In this work, we propose a molecular thermodynamic model for predicting the stability of Hepatitis B virus (HBV) capsids either with or without loading nucleic materials. With the key components represented by coarse-grained thermodynamic models, the theoretical predictions are in excellent agreement with experimental data for the formation free energies of empty T4 capsids over a broad range of temperature and ion concentrations. The theoretical model predicts T3/T4 dimorphism also in good agreement with the capsid formation at in vivo and in vitro conditions. In addition, we have studied the stability of the viral particles in response to physiological cellular conditions with the explicit consideration of the hydrophobic association of capsid subunits, electrostatic interactions, molecular excluded volume effects, entropy of mixing, and conformational changes of the biomolecular species. The course-grained model captures the essential features of the HBV nucleocapsid stability revealed by recent experiments.

  14. Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

    PubMed Central

    Hendriks, Delilah F. G.; Fredriksson Puigvert, Lisa; Messner, Simon; Mortiz, Wolfgang; Ingelman-Sundberg, Magnus

    2016-01-01

    Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID:27759057

  15. Diagnostic non-invasive model of large risky esophageal varices in cirrhotic hepatitis C virus patients

    PubMed Central

    Elalfy, Hatem; Elsherbiny, Walid; Abdel Rahman, Ashraf; Elhammady, Dina; Shaltout, Shaker Wagih; Elsamanoudy, Ayman Z; El Deek, Bassem

    2016-01-01

    AIM To build a diagnostic non-invasive model for screening of large varices in cirrhotic hepatitis C virus (HCV) patients. METHODS This study was conducted on 124 post-HCV cirrhotic patients presenting to the clinics of the Endemic Medicine Department at Mansoura University Hospital for evaluation before HCV antiviral therapy: 78 were Child A and 46 were Child B (score ≤ 8). Inclusion criteria for patients enrolled in this study was presence of cirrhotic HCV (diagnosed by either biopsy or fulfillment of clinical basis). Exclusion criteria consisted of patients with other etiologies of liver cirrhosis, e.g., hepatitis B virus and patients with high MELD score on transplant list. All patients were subjected to full medical record, full basic investigations, endoscopy, and computed tomography (CT), and then divided into groups with no varices, small varices, or large risky varices. In addition, values of Fibrosis-4 score (FIB-4), aminotransferase-to-platelet ratio index (APRI), and platelet count/splenic diameter ratio (PC/SD) were also calculated. RESULTS Detection of large varies is a multi-factorial process, affected by many variables. Choosing binary logistic regression, dependent factors were either large or small varices while independent factors included CT variables such coronary vein diameter, portal vein (PV) diameter, lieno-renal shunt and other laboratory non-invasive variables namely FIB-4, APRI, and platelet count/splenic diameter. Receiver operating characteristic (ROC) curve was plotted to determine the accuracy of non-invasive parameters for predicting the presence of large esophageal varices and the area under the ROC curve for each one of these parameters was obtained. A model was established and the best model for prediction of large risky esophageal varices used both PC/SD and PV diameter (75% accuracy), while the logistic model equation was shown to be (PV diameter × -0.256) plus (PC/SD × -0.006) plus (8.155). Values nearing 2 or more denote

  16. ELEVATED COPPER REMODELS HEPATIC RNA PROCESSING MACHINERY IN THE MOUSE MODEL OF WILSON'S DISEASE

    PubMed Central

    Burkhead, Jason L.; Ralle, Martina; Wilmarth, Phillip; David, Larry; Lutsenko, Svetlana

    2011-01-01

    Copper is essential to mammalian physiology and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson's disease (WD). Previous studies in the mouse model for WD (Atp7b-/-) revealed copper accumulation in hepatic nuclei and specific changes in the mRNA profile prior to pathology onset. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome we utilized quantitative ionomic and proteomic approaches. X-ray fluorescence and ICP-MS analysis indicate that copper in Atp7b-/- nucleus, while highly elevated, does not markedly alter nuclear ion content. Widespread protein oxidation is also not observed, although glutathione reductase SelH is upregulated, likely to maintain redox balance. We further demonstrate that accumulating copper affects abundance and/or modification of a distinct subset of nuclear proteins. These proteins populate pathways most significantly associated with RNA processing. An alteration in the splicing pattern was observed for hnRNP A2/B1, itself the RNA shuttling factor and spliceosome component. Analysis of hnRNP A2/B1 mRNA and protein revealed an increased retention of exon 2 and a selective 2-fold upregulation of a corresponding protein spliced variant. Mass-spectrometry measurements suggest that the nucleo-cytoplasmic distribution of RNA binding proteins, including A2/B1, is altered in the Atp7b-/- liver. We conclude that remodeling of RNA processing machinery is an important component in cells’ response to elevated copper that may guide pathology development in early stages of WD. PMID:21146535

  17. Characterization and evaluation of nanoencapsulated diethylcarbamazine in model of acute hepatic inflammation.

    PubMed

    Rodrigues, Gabriel Barros; Oliveira, Elquio Eleamen; Junior, Francisco Jaime Bezerra Mendonça; Santos, Laise Aline Martins Dos; Oliveira, Wilma Helena de; França, Maria Eduarda Rocha de; Lós, Deniele Bezerra; Gabínio, Brennda Martins; de Lira, Fábia Cristiane Melo Leite; Peixoto, Christina Alves

    2017-09-01

    Previous studies from our laboratory have demonstrated that Diethylcarbamazine (DEC) is a potent anti-inflammatory drug. The aim of the present study was to characterize the nanoencapsulation of DEC and to evaluate its effectiveness in a model of inflammation for the first time. C57BL/6 mice were divided into six groups: 1) Control; 2) Carbon tetrachloride (CCl4); 3) DEC 25mg/kg+CCl4; 4) DEC 50mg/kg+CCl4; 5) DEC-NANO 05mg/kg+CCl4 and 6) DEC-NANO 12.5mg/kg+CCl4. Liver fragments were stained with hematoxylin-eosin, and processed for Western blot, ELISA and immunohistochemistry. Serum was also collected for biochemical measurements. Carbon tetrachloride induced hepatic injury, observed through increased inflammatory markers (TNF-α, IL-1β, PGE2, COX-2 and iNOS), changes in liver morphology, and increased serum levels of total cholesterol, triglycerides, TGO and TGP, LDL, as well as reduced HDL levels. Nanoparticles containing DEC were characterized by diameter, polydispersity index and zeta potential. Treatment with 12.5 nanoencapsulated DEC exhibited a superior anti-inflammatory action to the DEC traditional dose (50mg/kg) used in murine assays, restoring liver morphology, improving serological parameters and reducing the expression of inflammatory markers. The present formulation of nanoencapsulated DEC is therefore a potential therapeutic tool for the treatment of inflammatory hepatic disorders, permitting the use of smaller doses and reducing treatment time, while maintaining high efficacy. Copyright © 2017. Published by Elsevier B.V.

  18. Ethyl pyruvate reduces hepatic mitochondrial swelling and dysfunction in a rat model of sepsis

    PubMed Central

    Jiang, Zhiyi; Li, Xiaoyue; Lin, Zongqin; Chen, Juan; Guan, Xiangdong; Chen, Minying

    2015-01-01

    Sepsis causes mitochondrial oxidative injury and swelling. Ethyl pyruvate (EP) is a cytoprotective agent, while aquaporin-8 (AQP8) is a mitochondrial water channel that can induce mitochondrial swelling. We assessed whether EP protects mitochondria during sepsis, and whether AQP8 contributes to the underlying mechanisms. A cecal ligation and puncture (CLP) sepsis model was established in Sprague-Dawley rats, randomized to 3 groups: sham (n=20), CLP (n=59) and CLP+EP (n=51). All rats received postoperative intraperitoneal fluid resuscitation (30 ml/kg); the CLP+EP group also received intraperitoneal EP (100 mg/kg). Survival was assessed at 24 hours. Hepatic mitochondrial ultrastructure was characterized by electron microscopy. The membrane potential of isolated hepatic mitochondria was determined using JC-1 and flow cytometry. Mitochondrial AQP8 expression and cytochrome C (Cyt C) release were measured by Western blotting (values normalized to ß-actin). Survival in the sham, CLP and CLP+EP groups was 100%, 21% and 41%, respectively. Mitochondrial cross-sectional area was smaller in the CLP+EP group than in the CLP group (0.231±0.110 vs. 0.641±0.460 µm2; P<0.001), with a tendency for a lower form factor (a measure of contour irregularity) in the CLP+EP group. Mitochondrial depolarization by CLP was inhibited by EP. Mitochondrial Cyt C release was higher in the CLP group than in the sham (1.211±0.24 vs. 0.48±0.03) or CLP+EP (0.35±0.39) groups. AQP8 expression was similar between groups, with a trend for lower expression in the CLP+EP group compared with the CLP group. EP improves sepsis outcome by targeting the mitochondrion, possibly through modulation of AQP8 expression. PMID:26339342

  19. Development and application of an in vitro model for screening anti-hepatitis B virus therapeutics.

    PubMed

    Lampertico, P; Malter, J S; Gerber, M A

    1991-03-01

    The development of effective anti-hepatitis B virus agents has been hampered by the lack of reliable in vitro systems for the screening of new therapeutics. In an effort to circumvent this problem, we have developed an in vitro system for screening anti-hepatitis B virus drugs using hepatitis B virus DNA-transfected Hep G2 cells. The cell line designated 2.2.15 produces replicative viral DNA intermediates, mature Dane particles and high levels of viral antigens. Subconfluent 2.2.15 cells were treated with a variety of commonly used anti-hepatitis B virus therapeutics, and their efficacy was determined by analyzing changes in the replicative cellular or extracellular hepatitis B virus DNA content by Southern blotting or slot-blot hybridization. The slot-blot method was sensitive, reproducible and rapid and correlated well with Southern blotting. Analysis of the media for hepatitis B virus DNA was indicative of changes in intracellular, replicative hepatitis B virus DNA, permitting sampling of the media. Therefore 2.2.15 cells may provide a valuable method for identifying and monitoring effective anti-hepatitis B virus therapeutics. Using this system to test various agents, we confirm that 2'-deoxyguanosine strongly inhibited viral replication, whereas others tested were less effective. Correlation with in vivo systems is now needed.

  20. Comparative Analysis of Hepatic CD14 Expression between Two Different Endotoxin Shock Model Mice: Relation between Hepatic Injury and CD14 Expression

    PubMed Central

    Hozumi, Hiroyasu; Tada, Rui; Murakami, Taisuke; Adachi, Yoshiyuki; Ohno, Naohito

    2013-01-01

    CD14 is a glycoprotein that recognizes gram-negative bacterial lipopolysaccharide (LPS) and exists in both membrane-bound and soluble forms. Infectious and/or inflammatory diseases induce CD14 expression, which may be involved in the pathology of endotoxin shock. We previously found that the expression of CD14 protein differs among the endotoxin shock models used, although the reasons for these differences are unclear. We hypothesized that the differences in CD14 expression might be due to liver injury, because the hepatic tissue produces CD14 protein. We investigated CD14 expression in the plasma and liver in the carrageenan (CAR)-primed and D-galN-primed mouse models of endotoxin shock. Our results showed that severe liver injury was not induced in CAR-primed endotoxin shock model mice. In this CAR-primed model, the higher mRNA and protein expression of CD14 was observed in the liver, especially in the interlobular bile duct in contrast to D-galN-primed-endotoxin shock model mice. Our findings indicated that the molecular mechanism(s) underlying septic shock in CAR-primed and D-galN-primed endotoxin shock models are quite different. Because CD14 expression is correlated with clinical observations, the CAR-primed endotoxin shock model might be useful for studying the functions of CD14 during septic shock in vivo. PMID:23308276

  1. Peromyscus as a model system for human hepatitis C: An opportunity to advance our understanding of a complex host parasite system.

    PubMed

    Vandegrift, Kurt J; Critchlow, Justin T; Kapoor, Amit; Friedman, David A; Hudson, Peter J

    2017-01-01

    Worldwide, there are 185 million people infected with hepatitis C virus and approximately 350,000 people die each year from hepatitis C associated liver diseases. Human hepatitis C research has been hampered by the lack of an appropriate in vivo model system. Most of the in vivo research has been conducted on chimpanzees, which is complicated by ethical concerns, small sample sizes, high costs, and genetic heterogeneity. The house mouse system has led to greater understanding of a wide variety of human pathogens, but it is unreasonable to expect Mus musculus to be a good model system for every human pathogen. Alternative animal models can be developed in these cases. Ferrets (influenza), cotton rats (human respiratory virus), and woodchucks (hepatitis B) are all alternative models that have led to a greater understanding of human pathogens. Rodent models are tractable, genetically amenable and inbred and outbred strains can provide homogeneity in results. Recently, a rodent homolog of hepatitis C was discovered and isolated from the liver of a Peromyscus maniculatus. This represents the first small mammal (mouse) model system for human hepatitis C and it offers great potential to contribute to our understanding and ultimately aid in our efforts to combat this serious public health concern. Peromyscus are available commercially and can be used to inform questions about the origin, transmission, persistence, pathology, and rational treatment of hepatitis C. Here, we provide a disease ecologist's overview of this new virus and some suggestions for useful future experiments.

  2. Geometric modeling of hepatic arteries in 3D ultrasound with unsupervised MRA fusion during liver interventions.

    PubMed

    Gérard, Maxime; Michaud, François; Bigot, Alexandre; Tang, An; Soulez, Gilles; Kadoury, Samuel

    2017-06-01

    Modulating the chemotherapy injection rate with regard to blood flow velocities in the tumor-feeding arteries during intra-arterial therapies may help improve liver tumor targeting while decreasing systemic exposure. These velocities can be obtained noninvasively using Doppler ultrasound (US). However, small vessels situated in the liver are difficult to identify and follow in US. We propose a multimodal fusion approach that non-rigidly registers a 3D geometric mesh model of the hepatic arteries obtained from preoperative MR angiography (MRA) acquisitions with intra-operative 3D US imaging. The proposed fusion tool integrates 3 imaging modalities: an arterial MRA, a portal phase MRA and an intra-operative 3D US. Preoperatively, the arterial phase MRA is used to generate a 3D model of the hepatic arteries, which is then non-rigidly co-registered with the portal phase MRA. Once the intra-operative 3D US is acquired, we register it with the portal MRA using a vessel-based rigid initialization followed by a non-rigid registration using an image-based metric based on linear correlation of linear combination. Using the combined non-rigid transformation matrices, the 3D mesh model is fused with the 3D US. 3D US and multi-phase MRA images acquired from 10 porcine models were used to test the performance of the proposed fusion tool. Unimodal registration of the MRA phases yielded a target registration error (TRE) of [Formula: see text] mm. Initial rigid alignment of the portal MRA and 3D US yielded a mean TRE of [Formula: see text] mm, which was significantly reduced to [Formula: see text] mm ([Formula: see text]) after affine image-based registration. The following deformable registration step allowed for further decrease of the mean TRE to [Formula: see text] mm. The proposed tool could facilitate visualization and localization of these vessels when using 3D US intra-operatively for either intravascular or percutaneous interventions to avoid vessel perforation.

  3. Retrospective analysis of hepatitis C infected patients treated through an integrated care model

    PubMed Central

    Levin, James M; Dabirshahsahebi, Shabnam; Bauer, Mindy; Huckins, Eric

    2016-01-01

    AIM To determine if our health system’s integrated model reflects sustained virologic response (SVR) outcomes similar to those in clinical trial data, maximizes adherence, and averts drug interactions. METHODS Subjects with chronic hepatitis C had their medical records reviewed from November 1st, 2014 through March 1st, 2016. Patients eligible for treatment were entered into an integrated care model therapy algorithm. The primary outcome was SVR12 based on intention to treat (ITT) analysis. Inclusion criteria consisted of both treatment naïve and experienced patients over the age of 18 who were at least twelve weeks post-therapy completion with any genotype (GT) or METAVIR score. Secondary outcomes included adherence, adverse events, and number of drug interaction interventions. RESULTS At the time of analysis, 133 patients had reached twelve weeks post therapy with ITT. In the ITT analysis 70 patients were GT 1a, 26 GT 1b, 23 could not be differentiated between GT 1a or 1b, 8 GT 2, 4 GT 3, and 2 patients with multiple genotypes. The ITT treatment regimens consisted of 97 sofosbuvir (SOF)/ledipasvir (LDV), 8 SOF/LDV and ribavirin (RBV), 7 SOF and Simeprevir (SMV), 6 3D and RBV, 1 3D, 11 SOF and RBV, and 1 SOF, peg interferon alpha, and RBV. The overall SVR12 rate was 93% in the ITT analysis with a total of 6 patients relapsing. In patients with cirrhosis, 89% obtained SVR12. All 33 patients who were previous treatment failures achieved SVR12. Drug-drug interactions were identified in 56.4% of our patient population, 69 of which required interventions made by the pharmacist. The most common side effects were fatigue (41.4%), headache (28.6%), nausea (18.1%), and diarrhea (8.3%). No serious adverse effects were reported. CONCLUSION Dean Health System’s integrated care model successfully managed patients being treated for hepatitis C virus (HCV). The integrated care model demonstrates high SVR rates amongst patients with different levels of fibrosis, genotypes

  4. Quantitative analysis and modelling of hepatic iron stores using stereology and spatial statistics.

    PubMed

    Ghugre, N R; Gonzalez-Gomez, I; Shimada, H; Coates, T D; Wood, J C

    2010-06-01

    Hepatic iron overload is a common clinical problem resulting from hyperabsorption syndromes and from chronic transfusion therapy. Not only does iron loading vary between reticuloendothelial stores and hepatocytes, but iron is heterogeneously distributed within hepatocytes as well. Since the accessibility of iron particles to chelation may depend, in part, on their distribution, we sought to characterize the shape and scale of iron deposition in humans with transfusional iron overload. Toward this end, we performed a histological analysis of iron stores in liver biopsy specimens of 20 patients (1.3-57.8 mg iron/g dry tissue weight) with aid of electron and light microscopy. We estimated distributions related to variability in siderosomal size, proximity of iron centres and inter-cellular iron loading. These distributions could be well modelled by Gamma distribution functions over most of the pathologic range of iron concentrations. Thus, for a given liver iron burden, a virtual iron-overloaded liver could be created that served as a model for the true histologic appearance. Such a model may be helpful for understanding the mechanics of iron loading or in predicting response to iron removal therapy.

  5. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes

    PubMed Central

    Teng, Yuan-Chi; Shen, Zhao-Qing; Kao, Cheng-Heng; Tsai, Ting-Fen

    2016-01-01

    The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine. PMID:26755878

  6. Computational design of hepatitis C vaccines using maximum entropy models and population dynamics

    NASA Astrophysics Data System (ADS)

    Hart, Gregory; Ferguson, Andrew

    Hepatitis C virus (HCV) afflicts 170 million people and kills 350,000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic. Despite 20 years of research, no vaccine is available. A major obstacle is the virus' extreme genetic variability and rapid mutational escape from immune pressure. Improvements in the vaccine design process are urgently needed. Coupling data mining with spin glass models and maximum entropy inference, we have developed a computational approach to translate sequence databases into empirical fitness landscapes. These landscapes explicitly connect viral genotype to phenotypic fitness and reveal vulnerable targets that can be exploited to rationally design immunogens. Viewing these landscapes as the mutational ''playing field'' over which the virus is constrained to evolve, we have integrated them with agent-based models of the viral mutational and host immune response dynamics, establishing a data-driven immune simulator of HCV infection. We have employed this simulator to perform in silico screening of HCV immunogens. By systematically identifying a small number of promising vaccine candidates, these models can accelerate the search for a vaccine by massively reducing the experimental search space.

  7. A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD

    PubMed Central

    Ashworth, William B.; Bogle, I. David L.

    2016-01-01

    In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the

  8. A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD.

    PubMed

    Ashworth, William B; Davies, Nathan A; Bogle, I David L

    2016-09-01

    In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the

  9. Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a self-perpetuating crosstalk?

    PubMed

    Vairetti, Mariapia; Ferrigno, Andrea; Rizzo, Vittoria; Ambrosi, Giulia; Bianchi, Alberto; Richelmi, Plinio; Blandini, Fabio; Armentero, Marie-Therese

    2012-02-01

    In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

  10. Protective Effects of White Button Mushroom (Agaricus bisporus) against Hepatic Steatosis in Ovariectomized Mice as a Model of Postmenopausal Women

    PubMed Central

    Kanaya, Noriko; Kubo, Makoto; Liu, Zheng; Chu, Peiguo; Wang, Charles; Chen, Yate-Ching Yuan, Shiuan

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) includes various hepatic pathologies ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Estrogen provides a protective effect on the development of NAFLD in women. Therefore, postmenopausal women have a higher risk of developing NAFLD. Hepatic steatosis is an early stage of fatty liver disease. Steatosis can develop to the aggressive stages (nonalcoholic steatohepatitis, fibrosis and cirrhosis). Currently, there is no specific drug to prevent/treat these liver diseases. In this study, we found that white button mushroom (WBM), Agaricus Bisporus, has protective effects against liver steatosis in ovariectomized (OVX) mice (a model of postmenopausal women). OVX mice were fed a high fat diet supplemented with WBM powder. We found that dietary WBM intake significantly lowered liver weight and hepatic injury markers in OVX mice. Pathological examination of liver tissue showed less fat accumulation in the livers of mice on WBM diet; moreover, these animals had improved glucose clearance ability. Microarray analysis revealed that genes related to the fatty acid biosynthesis pathway, particularly the genes for fatty acid synthetase (Fas) and fatty acid elongase 6 (Elovl6), were down-regulated in the liver of mushroom-fed mice. In vitro mechanistic studies using the HepG2 cell line showed that down-regulation of the expression of FAS and ELOVL6 by WBM extract was through inhibition of Liver X receptor (LXR) signaling and its downstream transcriptional factor SREBP1c. These results suggest that WBM is protective against hepatic steatosis and NAFLD in OVX mice as a model for postmenopausal women. PMID:22046322

  11. Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

    PubMed

    Varma, Manthena V; El-Kattan, Ayman F

    2016-07-01

    A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay. © 2016, The American College of Clinical Pharmacology.

  12. Efficacy of a topical bovine-derived thrombin solution as a hemostatic agent in a rodent model of hepatic injury

    PubMed Central

    Rosselli, Desiree D.; Brainard, Benjamin M.; Schmiedt, Chad W.

    2015-01-01

    Hemorrhage is a major concern in patients undergoing hepatic surgery or in those with hepatic trauma. In these cases, employing traditional hemostatic strategies can be problematic due to the diffuse nature of hepatic hemorrhage and limited opportunities for direct hemostasis. This study assessed the efficacy of a bovine-derived thrombin solution, (BT), as a topical liquid agent to augment hemostasis and survival following severe hepatic hemorrhage in a rat model. Heart rate (HR), arterial blood pressure (ABP), packed cell volume (PCV), and overall survival were evaluated in 54 rats randomly assigned to receive topical application of BT, saline, or suture ligation applied immediately to a liver lobe following controlled laceration. Six additional rats received liver laceration with no applied treatment. Intravenous fluid resuscitation was initiated and HR and ABP were recorded for 60 min, after which survivors were recovered from anesthesia. Rats were then monitored for 72 h, after which survivors were euthanized. There was no significant difference in survival time, percentage survival, intra-operative ABP or HR, or post-operative PCV between treatment groups. There is insufficient evidence to recommend BT as the sole therapy using this delivery method for mitigating severe hemorrhage from liver injury. PMID:26424911

  13. Efficacy of a topical bovine-derived thrombin solution as a hemostatic agent in a rodent model of hepatic injury.

    PubMed

    Rosselli, Desiree D; Brainard, Benjamin M; Schmiedt, Chad W

    2015-10-01

    Hemorrhage is a major concern in patients undergoing hepatic surgery or in those with hepatic trauma. In these cases, employing traditional hemostatic strategies can be problematic due to the diffuse nature of hepatic hemorrhage and limited opportunities for direct hemostasis. This study assessed the efficacy of a bovine-derived thrombin solution, (BT), as a topical liquid agent to augment hemostasis and survival following severe hepatic hemorrhage in a rat model. Heart rate (HR), arterial blood pressure (ABP), packed cell volume (PCV), and overall survival were evaluated in 54 rats randomly assigned to receive topical application of BT, saline, or suture ligation applied immediately to a liver lobe following controlled laceration. Six additional rats received liver laceration with no applied treatment. Intravenous fluid resuscitation was initiated and HR and ABP were recorded for 60 min, after which survivors were recovered from anesthesia. Rats were then monitored for 72 h, after which survivors were euthanized. There was no significant difference in survival time, percentage survival, intra-operative ABP or HR, or post-operative PCV between treatment groups. There is insufficient evidence to recommend BT as the sole therapy using this delivery method for mitigating severe hemorrhage from liver injury.

  14. Hepatitis B

    MedlinePlus

    ... of the liver), liver cancer, and even death.Hepatitis A can cause varying symptoms, but most often causes fever, tiredness, ... important? The hepatitis B vaccine prevents infection with hepatitis B virus, which causes liver cancer. The hepatitis B virus is 100 ...

  15. Hepatitis A

    MedlinePlus

    ... transaminase enzyme levels Treatment There is no specific treatment for hepatitis A. You should rest when the symptoms are ... and have not had hepatitis A or the hepatitis A vaccine. Common reasons for getting one or both of these treatments include: You live with someone who has hepatitis ...

  16. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

    PubMed Central

    Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

    2016-01-01

    Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

  17. Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling

    PubMed Central

    Thomas, Maria; Dräger, Andreas; Metzger, Ute; Templin, Markus F.; Joos, Thomas O.; Thasler, Wolfgang E.; Zell, Andreas; Zanger, Ulrich M.

    2016-01-01

    During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXRα playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRα gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism. PMID:26727233

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

    SciTech Connect

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    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.

  19. Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

    PubMed Central

    Baron, Matthew G.; Mintram, Kate S.; Owen, Stewart F.; Hetheridge, Malcolm J.; Moody, A. John; Purcell, Wendy M.; Jackson, Simon K.; Jha, Awadhesh N.

    2017-01-01

    At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control. PMID:28045944

  20. Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

    PubMed

    Keller, Roland; Klein, Marcus; Thomas, Maria; Dräger, Andreas; Metzger, Ute; Templin, Markus F; Joos, Thomas O; Thasler, Wolfgang E; Zell, Andreas; Zanger, Ulrich M

    2016-01-01

    During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXRα playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRα gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.

  1. Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model.

    PubMed

    Zou, Yu-Hong; Liu, Xin; Khlentzos, Alexander M; Asadian, Peyman; Li, Peng; Thorling, Camilla A; Robertson, Thomas A; Fletcher, Linda M; Crawford, Darrell H G; Roberts, Michael S

    2010-01-01

    This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl(4)-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl(4)-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.

  2. Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy.

    PubMed

    Bustamante, J; Lores-Arnaiz, S; Tallis, S; Roselló, D M; Lago, N; Lemberg, A; Boveris, A; Perazzo, J C

    2011-08-01

    In this study, we describe the presence of apoptosis, associated with a mitochondrial dysfunction in the hippocampus of animals in an experimental model defined as minimal hepatic encephalopathy (MHE). This experimental model was studied after 10 days of induced portal vein calibrated stricture, leading to portal hypertension and to a moderate hyperammonemia, without the presence of other evident central nervous system changes. The molecular mechanisms here proposed indicate the presence of apoptotic intrinsic pathways that point to hippocampal mitochondria as an important mediator of apoptosis in this experimental model. In this model of MHE, the presence of DNA fragmentation is documented by 2.3-times increased number of TUNEL-positive cells. These findings together with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane of the MHE animals together with 11% of cytochrome c release indicate the presence of apoptosis in this experimental model. A detailed analysis of the hippocampal mitochondrial physiology was performed after mitochondrial isolation. The determination of the respiratory rate in the presence of malate plus glutamate and ADP showed a 45% decrease in respiratory control in MHE animals as compared with the sham group. A marked decrease of cytochrome oxidase (complex IV of the electron transport chain) was also observed, showing 46% less activity in hippocampal mitochondria from MHE animals. In addition, mitochondria from these animals showed less ability to maintain membrane potential (ΔΨ (m)) which was 13% lower than the sham group. Light scattering experiments showed that mitochondria from MHE animals were more sensitive to swell in the presence of increased calcium concentrations as compared with the sham group. In addition, in vitro studies performed in mitochondria from sham animals showed that mitochondrial permeability transition (MPT) could be a mitochondrial mediator of the apoptotic signaling in the

  3. Comparison of TGF-β, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA.

    PubMed

    Park, Hye-Jung; Kim, Hyeong-Geug; Wang, Jing-Hua; Choi, Min-Kyung; Han, Jong-Min; Lee, Jin-Seok; Son, Chang-Gue

    2016-01-01

    Three chemotoxins including dimethylnitrosamine (DMN), carbon tetrachloride (CCl4), and thioacetamide (TAA) are commonly used in hepatofibrotic models. We aimed to draw characteristics of histopathology and pro-fibrogenic cytokines including TGF-β, PDGF and CTGF among three models. Rats were divided into six groups and intra-peritoneally injected with DMN (10 mg/kg, for three weeks, three consecutive days weekly), CCl4 (1.6 g/kg, for 10 weeks, twice weekly), TAA (200 mg/kg, for 12 weeks, twice weekly) or their corresponded treatment for each control group. The liver weights were decreased in DMN model, but not other models. Ascites were occurred as 3-, 2-, and 7-rats in DMN, CCl4, and TAA model, respectively. The lipid peroxidation was highest in CCl4 model, serum levels of liver enzymes were increased as similar severity. The hepatofibrotic alterations were remarkable in DMN and TAA model, but not CCl4 as evidenced by the Masson trichrome staining and hydroxyproline. The immunohistochemistry for α-SAM showed that the DMN model was most severely enhanced than other models. On the other hand, hepatic tissue levels of pro-fibrogenic cytokines including TGF-β, PDGF, and CTGF were generally increased in three models, but totally different among models or measurement resources. Especially, serum levels of three cytokines were remarkably increased by CCl4 injection and CTGF levels in both hepatic tissue and serum were highest in CCl4 group. Our results firstly demonstrated comparative study for features of morphological finding and pro-fibrogenic cytokines in serum and hepatic protein levels among three models. Above results would be a helpful reference for hepatofibrotic studies.

  4. Differential Fmo3 Gene Expression in Various Liver Injury Models Involving Hepatic Oxidative Stress in Mice

    PubMed Central

    Rudraiah, Swetha; Moscovitz, Jamie E.; Donepudi, Ajay C.; Campion, Sarah N.; Slitt, Angela L.; Aleksunes, Lauren M.; Manautou, José E.

    2015-01-01

    Flavin-containing monooxygenase-3 (FMO3) catalyzes metabolic reactions similar to cytochrome P450 monooxygenase however, most metabolites of FMO3 are considered non-toxic. Recent findings in our laboratory demonstrated Fmo3gene induction following toxic acetaminophen (APAP) treatment in mice.The goal of this study was to evaluate Fmo3gene expression in diverseother mouse models of hepatic oxidative stress and injury. Fmo3 gene regulation by Nrf2 was also investigated using Nrf2 knockout (Nrf2 KO) mice. In our studies, male C57BL/6J mice were treated with toxic dosesof hepatotoxicants or underwent bile duct ligation (BDL, 10d). Hepatotoxicants included APAP (400 mg/kg, 24 to 72h), alpha-naphthylisothiocyanate (ANIT; 50 mg/kg, 2 to 48h), carbontetrachloride (CCl4;10 or 30 μL/kg, 24 and 48h) and allyl alcohol (AlOH; 30 or 60 mg/kg, 6 and 24h). Because oxidative stress activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), additional studies investigated Fmo3 gene regulation by Nrf2 using Nrf2 knockout (Nrf2 KO) mice. At appropriate time-points, blood and liver samples were collected for assessment of plasma alanine aminotransferase (ALT) activity, plasma and hepatic bile acid levels, as well as liver Fmo3 mRNA and protein expression. Fmo3 mRNA expression increased significantly by 43-fold at 12h after ANIT treatment,and this increase translates to a 4-fold change in protein levels. BDL also increased Fmo3 mRNA expression by 1899-fold, but with no change in protein levels. Treatment of mice with CCl4decreased liver Fmo3gene expression, whileno change in expression was detected with AlOH treatment. Nrf2 KO mice are more susceptible to APAP (400 mg/kg, 72h) treatment compared to their wild-type (WT) counterparts, which is evidenced by greater plasma ALT activity. Fmo3 mRNA and protein expression increased in Nrf2 KO mice after APAP treatment. Collectively, not all hepatotoxicantsthat produce oxidative stress alter Fmo3gene expression. Along with APAP, toxic ANIT

  5. Hepatic phosphorus-31 magnetic resonance spectroscopy in primary biliary cirrhosis and its relation to prognostic models.

    PubMed Central

    Jalan, R; Sargentoni, J; Coutts, G A; Bell, J D; Rolles, K; Burroughs, A K; Taylor Robinson, S D

    1996-01-01

    BACKGROUND: In vivo hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) provides biochemical information about phosphorus metabolism. AIM: To assess 31P MRS as a prognostic marker in patients with primary biliary cirrhosis (PBC) in relation to the current clinical prognostic models. PATIENTS AND METHODS: Twenty three patients with PBC of varying functional severity and 16 matched healthy volunteers were studied using in vivo 31P MRS. Spectra were acquired using a 1.5 T spectroscopy system. Peak area ratios of phosphomonoesters (PME), inorganic phosphate (Pi), and phosphodiesters (PDE) and nucleotide triphosphate (NTP) were calculated. Pugh score, Christensen prognostic index, and R value according to the Mayo model were calculated from the clinical data. RESULTS: The PME/NTP, Pi/NTP, PME/PDE, and PME/Pi ratios and the PME signal height ratio (SHR) were significantly higher, while the PDE/NTP and PDE/SHR were significantly lower in PBC patients compared with healthy volunteers (p < 0.01). Significant correlations were seen between PME/Pi ratio and the prognostic index according to Christensen (r = 0.63, p < 0.001), R value according to the Mayo model (r = 0.45, p < 0.03), and with the Pugh score (r = 0.55, p < 0.007). CONCLUSIONS: This study shows that PME/Pi ratio obtained from 31P MRS correlates well with all three of the commonly used models of prognosis in patients with PBC. A longitudinal study with larger number of patients is required to confirm these findings and elucidate the biochemical changes underlying this phenomenon. PMID:8881826

  6. Induction of Hepatic and Endothelial Differentiation by Perfusion in a Three-Dimensional Cell Culture Model of Human Fetal Liver

    PubMed Central

    Pekor, Christopher; Gerlach, Jörg C.; Nettleship, Ian

    2015-01-01

    The development of functional engineered tissue constructs depends on high cell densities and appropriate vascularization. In this study we implemented a four-compartment three-dimensional perfusion bioreactor culture model for studying the effects of medium perfusion on endothelial, hepatic, and hematopoietic cell populations of primary human fetal liver in an in vivo-like environment. Human fetal liver cells were cultured in bioreactors configured to provide either perfusion or diffusion conditions. Metabolic activities of the cultures were monitored daily by measuring glucose consumption and lactate production. Cell viability during culture was analyzed by lactate dehydrogenase activity. Hepatic functionality was determined by the release of albumin and alpha-fetoprotein (AFP) in culture medium samples. After 4 days of culture, cells were analyzed for the expression of a variety of endothelial, hepatic, and hematopoietic genes, as well as the surface marker expression of CD31 and CD34 in flow cytometry. We found that medium perfusion increased the gene expression of endothelial markers such as CD31, von Willebrand factor (vWF), CD140b, CD309, and CD144 while decreasing the gene expression of the erythrocyte-surface marker CD235a. Hepatic differentiation was promoted under perfusion conditions as demonstrated by lower AFP and higher albumin secretion compared with cultures not exposed to medium perfusion. Additionally, cultures exposed to medium perfusion gave higher rates of glucose consumption and lactate production, indicating increased metabolic activity. In conclusion, high-density bioreactors configured to provide constant medium perfusion significantly induced hepatic and endothelial cell differentiation and provided improved conditions for the culture of human fetal liver cells compared with cultures without perfusion. PMID:25559936

  7. Induction of Hepatic and Endothelial Differentiation by Perfusion in a Three-Dimensional Cell Culture Model of Human Fetal Liver.

    PubMed

    Pekor, Christopher; Gerlach, Jörg C; Nettleship, Ian; Schmelzer, Eva

    2015-07-01

    The development of functional engineered tissue constructs depends on high cell densities and appropriate vascularization. In this study we implemented a four-compartment three-dimensional perfusion bioreactor culture model for studying the effects of medium perfusion on endothelial, hepatic, and hematopoietic cell populations of primary human fetal liver in an in vivo-like environment. Human fetal liver cells were cultured in bioreactors configured to provide either perfusion or diffusion conditions. Metabolic activities of the cultures were monitored daily by measuring glucose consumption and lactate production. Cell viability during culture was analyzed by lactate dehydrogenase activity. Hepatic functionality was determined by the release of albumin and alpha-fetoprotein (AFP) in culture medium samples. After 4 days of culture, cells were analyzed for the expression of a variety of endothelial, hepatic, and hematopoietic genes, as well as the surface marker expression of CD31 and CD34 in flow cytometry. We found that medium perfusion increased the gene expression of endothelial markers such as CD31, von Willebrand factor (vWF), CD140b, CD309, and CD144 while decreasing the gene expression of the erythrocyte-surface marker CD235a. Hepatic differentiation was promoted under perfusion conditions as demonstrated by lower AFP and higher albumin secretion compared with cultures not exposed to medium perfusion. Additionally, cultures exposed to medium perfusion gave higher rates of glucose consumption and lactate production, indicating increased metabolic activity. In conclusion, high-density bioreactors configured to provide constant medium perfusion significantly induced hepatic and endothelial cell differentiation and provided improved conditions for the culture of human fetal liver cells compared with cultures without perfusion.

  8. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse).

    PubMed

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-08-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.

  9. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)

    PubMed Central

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-01-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence. PMID:27446562

  10. A Comprehensive Screening And Treatment Model For Reducing Disparities In Hepatitis B

    PubMed Central

    Pollack, Henry; Wang, Su; Wyatt, Laura; Peng, Chia-hui; Wan, Kejia; Trinh-Shevrin, Chau; Chun, Kay; Kwon, Simona

    2012-01-01

    Chronic hepatitis B affects Asian Americans at a much higher rate than the general US population. Appropriate care can limit morbidity and mortality from hepatitis B. However, access to care for many Asian Americans and other immigrant groups is limited by their lack of knowledge about the disease, as well as cultural, linguistic, and financial challenges. This article describes the results of BfreeNYC, a New York City pilot program that, from 2004 to 2008, provided hepatitis B community education and awareness, free screening and vaccinations, and free or low-cost treatment primarily to immigrants from Asia, but also to residents from other racial and ethnic minority groups. The program was the largest citywide screening program in the United States, reaching nearly 9,000 people, and the only one providing comprehensive care to those who were infected. During the program, new hepatitis B cases reported annually from predominantly Asian neighborhoods in the city increased 34 percent. More than two thousand people were vaccinated; 57 percent of the 1,162 patients who tested positive for hepatitis B and were evaluated by program clinical services were still in care at the end of the program. Our analysis found that the program was effective in reaching the target population and providing care. Although follow-up care data will be needed to demonstrate long-term costeffectiveness, the program may serve as a useful prototype for addressing hepatitis B disparities in communities across the United States. PMID:21976342

  11. Effect of bovine lactoferrin in a therapeutic hamster model of hepatic amoebiasis.

    PubMed

    Ordaz-Pichardo, Cynthia; León-Sicairos, Nidia; Hernández-Ramírez, Verónica Ivonne; Talamás-Rohana, Patricia; de la Garza, Mireya

    2012-06-01

    Entamoeba histolytica is the causative agent of amoebiasis, a disease that produces dysentery as a result of the perforation of the large intestine. This parasite often invades other organs, primarily the liver, leading to an amoebic liver abscess (ALA), which can cause death. Metronidazole is the drug of choice for the treatment of ALA; however, it produces toxic side effects in patients. Lactoferrin (Lf) is a glycoprotein of the innate immune response that sequesters iron in the mucosae. Lf possesses immune-regulatory properties, such as antiinflammatory and antioxidant activities. Moreover, the microbicidal activity of apoLf, which lacks bound iron, has been shown. In this study, we evaluated the therapeutic effect of bovine Lf (bLf) against ALA in a model of hepatic amoebiasis in hamsters. Interestingly, hamsters treated intragastrically with Lf (2.5 mg/100 g mass) over a period of 8 days showed no clinical signs of disease and ALA was effectively decreased, with only 0.63% detectable lesion, compared with 63% in untreated animals. Furthermore, liver function and blood cells approached normal levels among those receiving bLf treatment. These results suggest that bLf may aid in the therapy of amoebiasis, likely without producing undesirable effects in patients.

  12. Viral Dynamic Modeling of Hepatitis C and Resistance-associated Variants in Hemophiliacs

    PubMed Central

    Sherman, Kenneth E.; Ke, Ruian; Rouster, Susan D.; Abdel-Hameed, Enass A.; Park, Cathleen; Palascak, Joseph; Perelson, Alan S.

    2016-01-01

    Aim Chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among hemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants. Methods Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. Results No dominant RAVs were identified at baseline but low level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (ε) for lead-in ranged from 0 to 0.9745 (mean= 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only 1 patient. Adverse event profiles were similar to that observed in non-hemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy. Conclusion These data support DAA-based therapy in those with inherited bleeding disorders. PMID:26936587

  13. Optical fluorescence spectroscopy to detect hepatic necrosis after normothermic ischemia: animal model

    NASA Astrophysics Data System (ADS)

    Romano, Renan A.; Vollet-Filho, Jose D.; Pratavieira, Sebastião.; Fernandez, Jorge L.; Kurachi, Cristina; Bagnato, Vanderlei S.; Castro-e-Silva, Orlando; Sankarankutty, Ajith K.

    2015-06-01

    Liver transplantation is a well-established treatment for liver failure. However, the success of the transplantation procedure depends on liver graft conditions. The tissue function evaluation during the several transplantation stages is relevant, in particular during the organ harvesting, when a decision is made concerning the viability of the graft. Optical fluorescence spectroscopy is a good option because it is a noninvasive and fast technique. A partial normothermic hepatic ischemia was performed in rat livers, with a vascular occlusion of both median and left lateral lobes, allowing circulation only for the right lateral lobe and the caudate lobe. Fluorescence spectra under excitation at 532 nm (doubled frequency Nd:YAG laser) were collected using a portable spectrometer (USB2000, Ocean Optics, USA). The fluorescence emission was collected before vascular occlusion, after ischemia, and 24 hours after reperfusion. A morphometric histology analysis was performed as the gold standard evaluation - liver samples were analyzed, and the percentage of necrotic tissue was obtained. The results showed that changes in the fluorescence emission after ischemia can be correlated with the amount of necrosis evaluated by a morphometric analysis, the Pearson correlation coefficient of the generated model was 0.90 and the root mean square error was around 20%. In this context, the laser-induced fluorescence spectroscopy technique after normothermic ischemia showed to be a fast and efficient method to differentiate ischemic injury from viable tissues.

  14. Hepatic Mitochondrial Alterations and Increased Oxidative Stress in Nutritional Diabetes-Prone Psammomys obesus Model

    PubMed Central

    Bouderba, Saida; Sanz, M. Nieves; Sánchez-Martín, Carlos; El-Mir, M. Yehia; Villanueva, Gloria R.; Detaille, Dominique; Koceïr, E. Ahmed

    2012-01-01

    Mitochondrial dysfunction is considered to be a pivotal component of insulin resistance and associated metabolic diseases. Psammomys obesus is a relevant model of nutritional diabetes since these adult animals exhibit a state of insulin resistance when fed a standard laboratory chow, hypercaloric for them as compared to their natural food. In this context, alterations in bioenergetics were studied. Using liver mitochondria isolated from these rats fed such a diet for 18 weeks, oxygen consumption rates, activities of respiratory complexes, and content in cytochromes were examined. Levels of malondialdehyde (MDA) and gluthatione (GSH) were measured in tissue homogenates. Diabetic Psammomys showed a serious liver deterioration (hepatic mass accretion, lipids accumulation), accompanied by an enhanced oxidative stress (MDA increased, GSH depleted). On the other hand, both ADP-dependent and uncoupled respirations greatly diminished below control values, and the respiratory flux to cytochrome oxydase was mildly lowered. Furthermore, an inhibition of complexes I and III together with an activation of complex II were found. With emergence of oxidative stress, possibly related to a defect in oxidative phosphorylation, some molecular adjustments could contribute to alleviate, at least in part, the deleterious outcomes of insulin resistance in this gerbil species. PMID:22675340

  15. Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model

    PubMed Central

    Lagaye, Sylvie; Brun, Sonia; Gaston, Jesintha; Shen, Hong; Stranska, Ruzena; Camus, Claire; Dubray, Clarisse; Rousseau, Géraldine; Massault, Pierre-Philippe; Courcambeck, Jerôme; Bassisi, Firas; Halfon, Philippe; Pol, Stanislas

    2016-01-01

    AIM: To evaluate the antiviral potency of a new anti-hepatitis C virus (HCV) antiviral agent targeting the cellular autophagy machinery. METHODS: Non-infected liver slices, obtained from human liver resection and cut in 350 μm-thick slices (2.7 × 106 cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant (multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real-time quantitative reverse transcription - polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays. RESULTS: The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dose-dependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect (compared to hydroxychloroquine EC50 = 1.17 μmol/L). CONCLUSION: Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dose-dependent manner without cytotoxic effect. PMID:27478540

  16. Molecular models of NS3 protease variants of the Hepatitis C virus

    PubMed Central

    da Silveira, Nelson JF; Arcuri, Helen A; Bonalumi, Carlos E; de Souza, Fátima P; Mello, Isabel MVGC; Rahal, Paula; Pinho, João RR; de Azevedo, Walter F

    2005-01-01

    Background Hepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed. Results The atomic coordinates of crystallographic structure 1CU1 and 1DY9 were used as starting model for modeling of the NS3 protease variant structures. The NS3 protease variant structures are composed of six subdomains, which occur in sequence along the polypeptide chain. The protease domain exhibits the dual beta-barrel fold that is common among members of the chymotrypsin serine protease family. The helicase domain contains two structurally related beta-alpha-beta subdomains and a third subdomain of seven helices and three short beta strands. The latter domain is usually referred to as the helicase alpha-helical subdomain. The rmsd value of bond lengths and bond angles, the average G-factor and Verify 3D values are presented for NS3 protease variant structures. Conclusions This project increases the certainty that homology modeling is an useful tool in structural biology and that it can be very valuable in annotating genome sequence information and contributing to structural and functional genomics from virus. The structural models will be used to guide future efforts in the structure-based drug design of a new

  17. Molecular models of NS3 protease variants of the Hepatitis C virus.

    PubMed

    da Silveira, Nelson J F; Arcuri, Helen A; Bonalumi, Carlos E; de Souza, Fátima P; Mello, Isabel M V G C; Rahal, Paula; Pinho, João R R; de Azevedo, Walter F

    2005-01-21

    Hepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed. The atomic coordinates of crystallographic structure 1CU1 and 1DY9 were used as starting model for modeling of the NS3 protease variant structures. The NS3 protease variant structures are composed of six subdomains, which occur in sequence along the polypeptide chain. The protease domain exhibits the dual beta-barrel fold that is common among members of the chymotrypsin serine protease family. The helicase domain contains two structurally related beta-alpha-beta subdomains and a third subdomain of seven helices and three short beta strands. The latter domain is usually referred to as the helicase alpha-helical subdomain. The rmsd value of bond lengths and bond angles, the average G-factor and Verify 3D values are presented for NS3 protease variant structures. This project increases the certainty that homology modeling is an useful tool in structural biology and that it can be very valuable in annotating genome sequence information and contributing to structural and functional genomics from virus. The structural models will be used to guide future efforts in the structure-based drug design of a new generation of NS3 protease variants

  18. Modeling chronic hepatitis B or C virus infection during antiviral therapy using an analogy to enzyme kinetics: long-term viral dynamics without rebound and oscillation.

    PubMed

    Takayanagi, Toshiaki

    2013-12-01

    The basic model for chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection during therapy enables us to analyze short-term viral kinetics. However, the model is not useful for analyzing long-term viral kinetics. Here, I suggest a new model that was obtained by introducing Michaelis-Menten kinetics into the basic model. The new model can exhibit long-term viral kinetics without rebound and oscillation, unlike the basic model. The value of the parameter K in the new model is analogous to the Michaelis constant Km and is predicted to be approximately less than 10(10)/ml.

  19. Model-based projections of the population-level impact of hepatitis A vaccination in Mexico

    PubMed Central

    Van Effelterre, Thierry; De Antonio-Suarez, Rodrigo; Cassidy, Adrian; Romano-Mazzotti, Luis; Marano, Cinzia

    2012-01-01

    There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic. This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology. It was calibrated using Mexican age-specific seroprevalence and symptomatic HAV incidence data. With 70% first-dose coverage and 85% second-dose coverage, the calibrated model projected that HAV vaccination would reduce the incidence of all HAV infections (symptomatic and asymptomatic) after the first 25 y of vaccination by 71–76% (minimum and maximum for different transmission scenarios). The projected reduction in cumulative incidence of symptomatic HAV infections over the first 25 y of vaccination was 45–51%. With 90% first-dose coverage and 85% second-dose coverage, the projected reduction in incidence of all HAV infections was 85–93%, and the projected reduction in the cumulative incidence of symptomatic HAV infections was 61–67%, over a 25-y time frame. Sensitivity analyses indicated that second-dose coverage is important under the conservative base-case assumptions made about the duration of vaccine protection. The model indicated that universal infant HAV vaccination could substantially reduce the burden of HAV disease in Mexico. PMID:22854667

  20. Timing of hepatitis C antiviral therapy in patients with advanced liver disease: a decision analysis model.

    PubMed

    Saab, Sammy; Hunt, Douglas R; Stone, Michael A; McClune, Amy; Tong, Myron J

    2010-06-01

    Antiviral therapy for the treatment of hepatitis C virus (HCV) infection is used before and after liver transplantation. The objective of this study was to determine the most cost-effective timing for pegylated interferon/ribavirin therapy in patients with advanced liver disease infected with genotype 1 HCV. A Markov model was constructed to compare treatment strategies: (1) no treatment, (2) antiviral therapy in patients with compensated cirrhosis, (3) antiviral therapy in patients with decompensated cirrhosis, and (4) antiviral therapy in patients with progressive fibrosis due to recurrent HCV post-transplantation. Outcomes of interest included the total cost per patient, number of quality-adjusted life years (QALYs) saved, cost per QALY saved, number of deaths and hepatocellular carcinomas (HCCs), and number of transplants required. Compared to the no-antiviral treatment strategy, treatment during compensated cirrhosis increased QALYs by 0.950 and saved $55,314. Treatment during decompensated cirrhosis increased QALYs by 0.044 and saved $5511. Treatment during posttransplant advanced recurrence increased QALYs by 0.061 and saved $3223. Treatment of patients with compensated cirrhosis resulted in 119 fewer deaths, 54 fewer HCCs, and 66 fewer transplants with respect to the no-treatment strategy. The model was sensitive to the rate of graft failure in patients with and without sustained virological response. The model was otherwise robust to all variables tested in sensitivity analysis. In conclusion, the treatment of patients with compensated cirrhosis was found to be the most cost-effective strategy and resulted in improved survival and decreased cost in comparison with all other strategies. This study provides pharmacoeconomic evidence in support of treating HCV in patients with compensated cirrhosis before progression to more advanced liver disease. (c) 2010 AASLD.

  1. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.

    PubMed

    2017-03-01

    The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013. We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8-1·1) in 2015, corresponding to 71·1 million (62·5-79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. John C Martin Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. A cost-effectiveness model to personalize antiviral therapy in naive patients with genotype 1 chronic hepatitis C.

    PubMed

    Iannazzo, Sergio; Colombatto, Piero; Ricco, Gabriele; Oliveri, Filippo; Bonino, Ferruccio; Brunetto, Maurizia R

    2015-03-01

    Rapid virologic response is the best predictor of sustained virologic response with dual therapy in genotype-1 chronic hepatitis C, and its evaluation was proposed to tailor triple therapy in F0-F2 patients. Bio-mathematical modelling of viral dynamics during dual therapy has potentially higher accuracy than rapid virologic in the identification of patients who will eventually achieve sustained response. Study's objective was the cost-effectiveness analysis of a personalized therapy in naïve F0-F2 patients with chronic hepatitis C based on a bio-mathematical model (model-guided strategy) rather than on rapid virologic response (guideline-guided strategy). A deterministic bio-mathematical model of the infected cell dynamics was validated in a cohort of 135 patients treated with dual therapy. A decision-analytic economic model was then developed to compare model-guided and guideline-guided strategies in the Italian setting. The outcomes of the cost-effectiveness analysis with model-guided and guideline-guided strategy were 19.1-19.4 and 18.9-19.3 quality-adjusted-life-years. Total per-patient lifetime costs were €25,200-€26,000 with model-guided strategy and €28,800-€29,900 with guideline-guided strategy. When comparing model-guided with guideline-guided strategy the former resulted more effective and less costly. The adoption of the bio-mathematical predictive criterion has the potential to improve the cost-effectiveness of a personalized therapy for chronic hepatitis C, reserving triple therapy for those patients who really need it. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  3. An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C

    PubMed Central

    O'Brien, Thomas R.; Everhart, James E.; Morgan, Timothy R.; Lok, Anna S.; Chung, Raymond T.; Shao, Yongwu; Shiffman, Mitchell L.; Dotrang, Myhanh; Sninsky, John J.; Bonkovsky, Herbert L.; Pfeiffer, Ruth M.

    2011-01-01

    Background Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. Methods HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). Results Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. Conclusion A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC. PMID:21760886

  4. High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs.

    PubMed

    Dai, Wencong; Wang, Kunyuan; Zheng, Xinchun; Chen, Xiaohui; Zhang, Wenqing; Zhang, Yiyue; Hou, Jinlin; Liu, Li

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD), characterized as excessive lipid accumulation within hepatocytes, is growing in prevalence. The exploitation of effective drugs for NAFLD has been proven challenging. Herein, we aimed to establish a dietary model of hepatic steatosis using transparent zebrafish larvae in which high-throughput chemical screens could be conducted. Zebrafish larvae fed with high fat (HF) diet and high fat plus high cholesterol (HFC) diet were compared to the control. We analyzed intrahepatic lipid accumulation, biological indexes and various pathways including lipid metabolism, ER stress and inflammation. In addition, the effects of ezetimibe and simvastatin on HFC diet-induced steatosis were evaluated. Zebrafish larvae fed with HF and HFC diets developed steatosis for 7 and 10 days. The incidence and degree of steatosis were more severe in HFC diet-fed larvae compared with the control and HF diet-fed larvae, suggesting that adding cholesterol to the HF diet promotes the hepatic lipid accumulation. These data were confirmed by the pathological observation. Biological indexes, free cholesterol (FC), total cholesterol (TC) and triacylglycerol (TG) were elevated in the liver of HFC diet-fed larvae compared with the control and HF diet-fed larvae. Additionally, the expression levels of endoplasmic reticulum (ER) stress and lipolytic molecules (atf6, hspa5, hsp90b1, pparab, cpt1a and acox3) were significantly up-regulated in the liver of HF and HFC diets-fed larvae compared to the control, whereas the expression of lipogenic molecules (acaca, fasn, srebf2, hmgcs1 and hmgcra) were decreased in the liver of HF and HFC diets-fed larvae compared to the control. To validate the reliability of the HFC model and utility value for screening potential anti-steaotsis drugs, HFC-fed larvae were treated with two accepted lipid-lowing drugs (ezetimibe and simvastatin). The results showed that these drugs significantly ameliorated HFC-induced steatosis. Our

  5. Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis.

    PubMed

    Bennett, Robert G; Simpson, Ronda L; Hamel, Frederick G

    2017-06-14

    To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis. Hepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting. Treatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels. The combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy.

  6. Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

    PubMed Central

    Bennett, Robert G; Simpson, Ronda L; Hamel, Frederick G

    2017-01-01

    AIM To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis. METHODS Hepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting. RESULTS Treatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels. CONCLUSION The combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a

  7. Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication

    USGS Publications Warehouse

    Debing, Yannick; Winton, James; Neyts, Johan; Dallmeier, Kai

    2013-01-01

    Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non-pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2′-C-methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17β-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae.

  8. Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication.

    PubMed

    Debing, Yannick; Winton, James; Neyts, Johan; Dallmeier, Kai

    2013-10-01

    Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non-pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2'-C-methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17β-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae.

  9. Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method.

    PubMed

    Yoshikado, T; Yoshida, K; Kotani, N; Nakada, T; Asaumi, R; Toshimoto, K; Maeda, K; Kusuhara, H; Sugiyama, Y

    2016-11-01

    This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki ) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Ki values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  10. Reversibility of Hepatic Histological Damage after Surgical Temporary Obstruction of the Common Bile Duct in a Murine Model

    PubMed Central

    Olguín, H. Juárez; Hernández, J. L. Figueroa; Guzman, D. Calderón; Medina, R. Alemón

    2011-01-01

    The reversibility of hepatic histological damage after restoring bile flow in a murine model was assessed. 25 male Balb C mice (25-35 g, age 6 weeks) were divided into 5 groups and their common bile duct (CBD) fastened to obstruct the release of gall bladder and liver contents. Group I, CBD untied at day 10, group II at day 15, and groups III and IV at days 20 and 30, respectively. Hematoxilin-eosin stained liver slices were analysed 0, 5, 10 and 20 days after restoring bile flow. Group I showed slight histological lesions (second stage), as cholangiolar bile pigment concretion, pericholangiolar and portal collagen accumulation; group II, mild lesions (third stage), as cholangiolar hamartomatous proliferation and bile duct portal fibrosis; group III showed severe lesions (fourth stage), as loss of functional parenchyma, and also the second and first stage lesions. Group IV died before 30 days. First stage corresponds to absent lesions (control group). Group I recovered totally, group II recovered only from slight lesions and group III had irreversible damage. Severity of lesions increased gradually and accumulatively, irreversible hepatic damage was achieved at 20 days and is deadly at 30 days. Our model of temporary CBD obstruction was suitable to assess reversibility of hepatic histological damage. PMID:23675215

  11. Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro.

    PubMed

    Leite, Sofia B; Roosens, Tiffany; El Taghdouini, Adil; Mannaerts, Inge; Smout, Ayla J; Najimi, Mustapha; Sokal, Etienne; Noor, Fozia; Chesne, Christophe; van Grunsven, Leo A

    2016-02-01

    Current models for in vitro fibrosis consist of simple mono-layer cultures of rodent hepatic stellate cells (HSC), ignoring the role of hepatocyte injury. We aimed to develop a method allowing the detection of hepatocyte-mediated and drug-induced liver fibrosis. We used HepaRG (Hep) and primary human HSCs cultured as 3D spheroids in 96-well plates. These resulting scaffold-free organoids were characterized for CYP induction, albumin secretion, and hepatocyte and HSC-specific gene expression by qPCR. The metabolic competence of the organoid over 21 days allows activation of HSCs in the organoid in a drug- and hepatocyte-dependent manner. After a single dose or repeated exposure for 14 days to the pro-fibrotic compounds Allyl alcohol and Methotrexate, hepatic organoids display fibrotic features such as HSC activation, collagen secretion and deposition. Acetaminophen was identified by these organoids as an inducer of hepatotoxic-mediated HSC activation which was confirmed in vivo in mice. This novel hepatic organoid culture model is the first that can detect hepatocyte-dependent and compound-induced HSC activation, thereby representing an important step forward towards in vitro compound testing for drug-induced liver fibrosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model.

    PubMed

    Agmon-Levin, Nancy; Arango, María-Teresa; Kivity, Shaye; Katzav, Aviva; Gilburd, Boris; Blank, Miri; Tomer, Nir; Volkov, Alex; Barshack, Iris; Chapman, Joab; Shoenfeld, Yehuda

    2014-11-01

    Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events.

  13. Verapamil hepatic clearance in four preclinical rat models: towards activity-based scaling.

    PubMed

    Nicolaï, J; De Bruyn, T; Van Veldhoven, P P; Keemink, J; Augustijns, P; Annaert, P

    2015-10-01

    The current study was designed to cross-validate rat liver microsomes (RLM), suspended rat hepatocytes (SRH) and the isolated perfused rat liver (IPRL) model against in vivo pharmacokinetic data, using verapamil as a model drug. Michaelis-Menten constants (Km), for the metabolic disappearance kinetics of verapamil in RLM and SRH (freshly isolated and cryopreserved), were determined and corrected for non-specific binding. The 'unbound' Km determined with RLM (2.8 µM) was divided by the 'unbound' Km determined with fresh and cryopreserved SRH (3.9 µM and 2.1 µM, respectively) to calculate the ratio of intracellular to extracellular unbound concentration (Kpu,u). Kpu,u was significantly different between freshly isolated (0.71) and cryopreserved (1.31) SRH, but intracellular capacity for verapamil metabolism was maintained after cryopreservation (200 vs. 191 µl/min/million cells). Direct comparison of intrinsic clearance values (Clint) in RLM versus SRH, yielded an activity-based scaling factor (SF) of 0.28-0.30 mg microsomal protein/million cells (MPPMC). Merging the IPRL-derived Clint with the MPPMC and SRH data, resulted in scaling factors for MPPGL (80 and 43 mg microsomal protein/g liver) and HPGL (269 and 153 million cells/g liver), respectively. Likewise, the hepatic blood flow (61 ml/min/kg b.wt) was calculated using IPRL Clint and the in vivo Cl. The scaling factors determined here are consistent with previously reported CYP450-content based scaling factors. Overall, the results show that integrated interpretation of data obtained with multiple preclinical tools (i.e. RLM, SRH, IPRL) can contribute to more reliable estimates for scaling factors and ultimately to improved in vivo clearance predictions based on in vitro experimentation.

  14. A Descriptive Model of Patient Readiness, Motivators, and Hepatitis C Treatment Uptake among Australian Prisoners

    PubMed Central

    Yap, Lorraine; Carruthers, Susan; Thompson, Sandra; Cheng, Wendy; Jones, Jocelyn; Simpson, Paul; Richards, Alun; Thein, Hla-Hla; Haber, Paul; Lloyd, Andrew; Butler, Tony

    2014-01-01

    Background Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations. Method and Findings We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners. Conclusion This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for

  15. A novel challenge model to evaluate the efficacy of hepatitis C virus vaccines in mice.

    PubMed

    Yu, Wenbo; Grubor-Bauk, Branka; Gargett, Tessa; Garrod, Tamsin; Gowans, Eric J

    2014-06-05

    An effective hepatitis C virus (HCV) vaccine should elicit robust humoral and cell mediated immunity (CMI). A small animal challenge model is required to assess the efficacy of vaccines which elicit CMI. In this study, HCV proteins were expressed in hepatocytes of immunocompetent mice after hydrodynamic injection of a plasmid encoding the HCV NS3/4A protein. This vector, constructed as the "challenge", was optimized for long term, specific gene expression in hepatocytes. To monitor HCV antigen expression in transfected hepatocytes, the plasmid also encoded secreted alkaline phosphatase (SEAP), which was detected in the mouse serum. The design of this novel challenge plasmid was based on studies using luciferase and SEAP as reporter molecules to examine the kinetics of the proteins expressed in hepatocytes and secreted into blood. We designed two constructs to control SEAP expression. In one construct, SEAP expression was controlled by the EMCV IRES, while in the other, a SEAP and luciferase polyprotein was cleaved by the FMDV2A proteinase. We found that SEAP expressed after FMDV2A self cleavage was more sensitive and showed a higher correlation with luciferase expressed in liver. The NS3/4A challenge model using the FMDV2A design provided a window period of 50 days to monitor changes in SEAP expression after hydrodynamic injection of DNA. In a challenge experiment, mice which received an adenovirus-based HCV vaccine showed accelerated clearance of SEAP and thus, of NS3/4A positive hepatocytes compared with a mock vaccinated group, that coincided with an increased number of CD8(+) lymphocytes in the liver. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Hepatic Arterial Embolization with Doxorubicin-Loaded Superabsorbent Polymer Microspheres in a Rabbit Liver Tumor Model

    SciTech Connect

    Gupta, Sanjay Wright, Kenneth C.; Ensor, Joe; Van Pelt, Carolyn S.; Dixon, Katherine A.; Kundra, Vikas

    2011-10-15

    Objectives: The pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin was studied. Methods: Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured. Results: The peak plasma concentration of doxorubicin was lower in the QuadraSphere group (309.9 ng/ml) than in the HAI (673.4 ng/ml) or TACE (360.5 ng/ml) groups, suggesting higher tumor retention in the QuadraSphere group. Intratumoral doxorubicin levels declined to negligible levels at 1 and 3 days after treatment, respectively, in the HAI and TACE groups. In the QuadraSphere groups, intratumoral doxorubicin level declined after day 1, but was still detectable at 14 days after treatment and was higher than that in the other groups at 1, 3, and 7 days. Intratumoral doxorubicin fluorescence was detected at all time points in the QuadraSphere group, but only at 1 day after treatment in the TACE group. Conclusions: Hepatic arterial administration of doxorubicin-loaded QuadraSpheres enables the sustained release of doxorubicin to hepatic tumors.

  17. Evaluation of Rumex hastatus leaves against hepatic fibrosis: a rat model.

    PubMed

    Sahreen, Sumaira; Khan, Muhammad Rashid; Khan, Rahmat Ali

    2017-08-30

    Rumex hastatus leaves have been widely used as food additive and for the treatment of various liver ailments. According to our previous studies, ethyle acetate (ERL) and methanolic (MRL) fractions of R. hastatus leaves are an accessible source of natural antioxidants. In the present research work we arranged to investigate the R. hastatus leaves as hepaptoprotective agent verse hepatic damages caused by CCl4. During this project we divided 48 rats into eight groups randomly. CCl4-induced damages were assessed through liver function markers viz.; alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT) and lactate dehydrogenase (LDH). Changes in lipid profile were checked by measuring serum total cholesterol (TC), triglycerides (Tg), high density lipoproteins (HDL) and low density lipoproteins (LDL). Antioxidant status was checked by the activities of antioxidant enzymes, DNA damages and cellular abnormalities at histo level. Administration of CCl4 in rats caused significant increase in liver function and lipid profile indicating hepatic damages which were restored by co-administration of R. hastatus extracts. Cellular and DNA damages in hepatic tissues were caused by CCl4 which shown clear hepatic fibrosis in addition to disturb antioxidant enzyme level. Co-treatment with various fractions of R. hastatus leaves regulated these markers of oxidative dysfunctions. From the present report it was inferred that R. hastatus leaves have the ability to reverse CCl4 - induced hepatic damages.

  18. Hepatic Arterial Embolization with Doxorubicin-Loaded Superabsorbent Polymer Microspheres in an Animal Model

    PubMed Central

    Gupta, Sanjay; Wright, Kenneth C.; Ensor, Joe; Van Pelt, Carolyn S.; Dixon, Katherine A.; Kundra, Vikas

    2014-01-01

    Objectives To study the pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin. Materials and Methods Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured. Results The peak plasma concentration of doxorubicin was lower in the QuadraSphere group (309.9 ng/ml) than in the HAI (673.4 ng/ml) or TACE (360.5 ng/ml) groups, suggesting higher tumor retention in the QuadraSphere group. Intratumoral doxorubicin levels declined to negligible levels at 1 and 3 days after treatment, respectively in the HAI and TACE groups. In the QuadraSphere groups, intratumoral doxorubicin level declined after day 1, but was still detectable at 14 days after treatment and was higher than that in the other groups at 1, 3, and 7 days. Intratumoral doxorubicin fluorescence was detected at all time points in the QuadraSphere group, but only at 1 day after treatment in the TACE group. Conclusions Hepatic arterial administration of doxorubicin-loaded QuadraSpheres enables the sustained release of doxorubicin to hepatic tumors. PMID:21479746

  19. Pre-acute hepadnaviral infection is associated with activation-induced apoptotic death of lymphocytes in the woodchuck (Marmota monax) model of hepatitis B.

    PubMed

    Gujar, Shashi A; Jenkins, Adam K M; Macparland, Sonya A; Michalak, Tomasz I

    2010-09-01

    Woodchucks (Marmota monax) infected with woodchuck hepatitis virus (WHV) represent a highly valuable immunopathogenic model of hepatitis B virus (HBV) infection. Both WHV and HBV are noncytopathic hepadnaviruses which induce a strong but delayed virus-specific cellular immune response believed to be a cause of hepatitis. The reason behind this postponement is not well understood and its dissection in the woodchuck model has been hampered by the lack of appropriate research tools. In this study, we applied an assay for the simultaneous detection of cell apoptosis and proliferation to determine the fate of T lymphocytes after WHV infection leading to acute hepatitis. The results revealed that pre-acute WHV infection is associated with the significantly heightened susceptibility of T lymphocytes to activation-induced apoptotic death. This suggests that T lymphocyte function is compromised very early in the course of hepadnaviral infection and this may directly contribute to the postponement of virus-specific T cell response.

  20. Autoimmune hepatitis

    MedlinePlus

    ... them. Causes This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference ... inflammation, or hepatitis, may occur along with other autoimmune diseases. These include: Graves disease Inflammatory bowel disease Rheumatoid ...

  1. Hepatitis B

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000279.htm Hepatitis B To use the sharing features on this page, please enable JavaScript. Hepatitis B is irritation and swelling (inflammation) of the ...

  2. Hepatitis B

    MedlinePlus

    ... Financial Report (AFR) Budget Submission Recovery Act Resources Business Congressional Affairs Jobs Benefits Booklet Data & Statistics National ... with hepatitis B need to be on treatment. Choosing the right time for hepatitis B treatment is ...

  3. Hepatitis A

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... washed in untreated water Putting into your mouth a finger or object that came into contact with ...

  4. Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir.

    PubMed

    Walsh, Ann W; Langley, David R; Colonno, Richard J; Tenney, Daniel J

    2010-02-12

    Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position

  5. Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy

    SciTech Connect

    Bassett, M.L.; Mullen, K.D.; Scholz, B.; Fenstermacher, J.D.; Jones, E.A. )

    1990-03-01

    Transfer of the inhibitory neurotransmitter gamma-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for gamma-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of gamma-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain gamma-aminobutyric acid uptake is increased in rabbits with stage II-III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. (3H) gamma-aminobutyric acid, (14C) butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of gamma-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of (3H) gamma-aminobutyric acid and (113mIn) transferrin were calculated using (14C) butanol as the highly extracted reference compound. The (113mIn) transferrin data were also used to correct the brain uptake index of (3H) gamma-aminobutyric acid for intravascular retention of (3H) gamma-aminobutyric acid. The methodology adopted minimized problems attributable to rapid (3H) gamma-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the uncorrected and corrected brain uptake indices of gamma-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy.

  6. Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression.

    PubMed

    Caliari, Steven R; Perepelyuk, Maryna; Soulas, Elizabeth M; Lee, Gi Yun; Wells, Rebecca G; Burdick, Jason A

    2016-06-13

    The extracellular matrix (ECM) presents an evolving set of mechanical cues to resident cells. We developed methacrylated hyaluronic acid (MeHA) hydrogels containing both stable and hydrolytically degradable crosslinks to provide cells with a gradually softening (but not fully degradable) milieu, mimicking physiological events such as fibrosis regression. To demonstrate the utility of this cell culture system, we studied the phenotype of rat hepatic stellate cells, the major liver precursors of fibrogenic myofibroblasts, within this softening environment. Stellate cells that were mechanically primed on tissue culture plastic attained a myofibroblast phenotype, which persisted when seeded onto stiff (∼20 kPa) hydrogels. However, mechanically primed stellate cells on stiff-to-soft (∼20 to ∼3 kPa) hydrogels showed reversion of the myofibroblast phenotype over 14 days, with reductions in cell area, expression of the myofibroblast marker alpha-smooth muscle actin (α-SMA), and Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) nuclear localization when compared to stellate cells on stiff hydrogels. Cells on stiff-to-soft hydrogels did not fully revert, however. They displayed reduced expression of glial fibrillary acidic protein (GFAP), and underwent abnormally rapid re-activation to myofibroblasts in response to re-stiffening of the hydrogels through introduction of additional crosslinks. These features are typical of stellate cells with an intermediate phenotype, reported to occur in vivo with fibrosis regression and re-injury. Together, these data suggest that mechanics play an important role in fibrosis regression and that integrating dynamic mechanical cues into model systems helps capture cell behaviors observed in vivo.

  7. Comfrey (Symphytum Officinale. l.) and Experimental Hepatic Carcinogenesis: A Short-term Carcinogenesis Model Study

    PubMed Central

    Gomes, Maria Fernanda Pereira Lavieri; de Oliveira Massoco, Cristina; Xavier, José Guilherme

    2010-01-01

    Comfrey or Symphytum officinale (L.) (Boraginaceae) is a very popular plant used for therapeutic purposes. Since the 1980s, its effects have been studied in long-term carcinogenesis studies, in which Comfrey extract is administered at high doses during several months and the neoplastic hepatic lesions are evaluated. However, the literature on this topic is very poor considering the studies performed under short-term carcinogenesis protocols, such as the ‘resistant hepatocyte model’ (RHM). In these studies, it is possible to observe easily the phenomena related to the early phases of tumor development, since pre-neoplastic lesions (PNLs) rise in about 1–2 months of chemical induction. Herein, the effects of chronic oral treatment of rats with 10% Comfrey ethanolic extract were evaluated in a RHM. Wistar rats were sequentially treated with N-nitrosodiethylamine (ip) and 2-acetilaminofluorene (po), and submitted to hepatectomy to induce carcinogenesis promotion. Macroscopic/microscopic quantitative analysis of PNL was performed. Non-parametric statistical tests (Mann–Whitney and χ2) were used, and the level of significance was set at P ≤ 0.05. Comfrey treatment reduced the number of pre-neoplastic macroscopic lesions up to 1 mm (P ≤ 0.05), the percentage of oval cells (P = 0.0001) and mitotic figures (P = 0.007), as well as the number of Proliferating Cell Nuclear Antigen (PCNA) positive cells (P = 0.0001) and acidophilic pre-neoplastic nodules (P = 0.05). On the other hand, the percentage of cells presenting megalocytosis (P = 0.0001) and vacuolar degeneration (P = 0.0001) was increased. Scores of fibrosis, glycogen stores and the number of nucleolus organizing regions were not altered. The study indicated that oral treatment of rats with 10% Comfrey alcoholic extract reduced cell proliferation in this model. PMID:18955295

  8. Probiotics Supplemented with Omega-3 Fatty Acids are More Effective for Hepatic Steatosis Reduction in an Animal Model of Obesity.

    PubMed

    Kobyliak, Nazarii; Falalyeyeva, Tetyana; Bodnar, Petro; Beregova, Tetyana

    2016-09-22

    Today probiotics have been suggested as a treatment for the prevention of NAFLD. Omega-3 fatty acid supplementation may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function and inflammation. The present study was designed to determine whether probiotics plus omega-3 are superior to probiotics alone on the monosodium glutamate (MSG)-induced NAFLD model in rats. We included 60 rats divided into four groups, 15 animals in each. Rats of group I were intact. Newborn rats of groups II-IV were injected with MSG. The III (Symbiter) group received 2.5 ml/kg of multiprobiotic "Symbiter" containing concentrated biomass of 14 probiotic bacteria genera. The IV (Symbiter-Omega) groups received "Symbiter-Omega" combination of probiotic biomass supplemented with flax and wheat germ oil (250 mg of each, concentration of omega-3 fatty acids 1-5 %). In both interventional groups reduction in total NAS score was observed. Supplementation of alive probiotic mixture with omega-3 fatty acids lead to 20 % higher decrease in steatosis score (0.73 ± 0.11 vs 0.93 ± 0.22, p = 0.848) and reduction by 16.6 % of triglycerides content in liver as compared to probiotic alone. Our study demonstrated more pronounced reduction in hepatic steatosis and hepatic lipid accumulation after treatment with combination of alive probiotics and omega-3 as compared to probiotics alone.

  9. Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury.

    PubMed

    Deng, Wen-Sheng; Xu, Qing; Liu, Y E; Jiang, Chun-Hui; Zhou, Hong; Gu, Lei

    2016-05-01

    The present study aimed to investigate the effects of melatonin (MT) on liver function and lipid peroxidation following hepatic ischemia-reperfusion injury (IRI). A total of 66 male Sprague-Dawley rats were randomly assigned into three groups: Normal control (N) group, ischemia-reperfusion (IR) group and the MT-treated group. A hepatic IRI model was developed by blocking the first porta hepatis, and subsequently restoring hepatic blood inflow after 35 min. Following reperfusion, changes in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were detected by a chemical method at various time points. In the MT group, the MDA levels were significantly reduced (P<0.05) at all time points, as compared with the IR group. Furthermore, SOD activity was significantly increased (P<0.05) in the MT group, as compared with the IR group at all time points; and the levels of GSH in the MT group were significantly higher (P<0.05) than those of the IR group at 2, 4, and 8 h post-reperfusion. The levels of ALT, AST and LDH were significantly reduced in the MT group at each time point, as compared with that of the IR group (P<0.05). In conclusion, MT exhibits potent antioxidant properties that may create favorable conditions for the recovery of liver function following IRI.

  10. The pathology of halothane hepatotoxicity in a guinea-pig model: a comparison with human halothane hepatitis.

    PubMed Central

    Lunam, C. A.; Hall, P. M.; Cousins, M. J.

    1989-01-01

    The pathology of halothane hepatotoxicity is described in detail in a guinea-pig model. Twenty-two of 40 guinea-pigs developed liver damage after exposure to 1% halothane in 21% O2 for 4 h. The other 18 animals showed no evidence of hepatic injury. Two distinct patterns of damage were identified: mild damage, in which livers had focal areas of necrosis, and severe damage, where necrosis was confluent around the terminal hepatic venules, often extending to the portal tracts. Serum alanine aminotransferase activity was significantly elevated in guinea-pigs with severe liver damage. Hepatocytes in the damaged areas showed degenerative changes ranging from vacuolization to ballooning degeneration and necrosis. Inflammatory cells, predominantly lymphocytes, were often present in the areas of necrosis. The pathology of mild and severe liver injury in the guinea-pig closely resembles the spectrum of injury observed in non-fatal halothane hepatitis in man. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:2818932

  11. Age- and region-specific hepatitis B prevalence in Turkey estimated using generalized linear mixed models: a systematic review

    PubMed Central

    2011-01-01

    Background To provide a clear picture of the current hepatitis B situation, the authors performed a systematic review to estimate the age- and region-specific prevalence of chronic hepatitis B (CHB) in Turkey. Methods A total of 339 studies with original data on the prevalence of hepatitis B surface antigen (HBsAg) in Turkey and published between 1999 and 2009 were identified through a search of electronic databases, by reviewing citations, and by writing to authors. After a critical assessment, the authors included 129 studies, divided into categories: 'age-specific'; 'region-specific'; and 'specific population group'. To account for the differences among the studies, a generalized linear mixed model was used to estimate the overall prevalence across all age groups and regions. For specific population groups, the authors calculated the weighted mean prevalence. Results The estimated overall population prevalence was 4.57, 95% confidence interval (CI): 3.58, 5.76, and the estimated total number of CHB cases was about 3.3 million. The outcomes of the age-specific groups varied from 2.84, (95% CI: 2.60, 3.10) for the 0-14-yearolds to 6.36 (95% CI: 5.83, 6.90) in the 25-34-year-old group. Conclusion There are large age-group and regional differences in CHB prevalence in Turkey, where CHB remains a serious health problem. PMID:22151620

  12. Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury

    PubMed Central

    DENG, WEN-SHENG; XU, QING; LIU, YE; JIANG, CHUN-HUI; ZHOU, HONG; GU, LEI

    2016-01-01

    The present study aimed to investigate the effects of melatonin (MT) on liver function and lipid peroxidation following hepatic ischemia-reperfusion injury (IRI). A total of 66 male Sprague-Dawley rats were randomly assigned into three groups: Normal control (N) group, ischemia-reperfusion (IR) group and the MT-treated group. A hepatic IRI model was developed by blocking the first porta hepatis, and subsequently restoring hepatic blood inflow after 35 min. Following reperfusion, changes in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were detected by a chemical method at various time points. In the MT group, the MDA levels were significantly reduced (P<0.05) at all time points, as compared with the IR group. Furthermore, SOD activity was significantly increased (P<0.05) in the MT group, as compared with the IR group at all time points; and the levels of GSH in the MT group were significantly higher (P<0.05) than those of the IR group at 2, 4, and 8 h post-reperfusion. The levels of ALT, AST and LDH were significantly reduced in the MT group at each time point, as compared with that of the IR group (P<0.05). In conclusion, MT exhibits potent antioxidant properties that may create favorable conditions for the recovery of liver function following IRI. PMID:27168834

  13. Hepatitis C

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis C, is caused by the hepatitis C virus (HCV). It usually spreads through contact with ... childbirth. Most people who are infected with hepatitis C don't have any symptoms for years. If ...

  14. Modeling the long-term persistence of hepatitis A antibody after a two-dose vaccination schedule in Argentinean children.

    PubMed

    López, Eduardo L; Contrini, María Marta; Mistchenko, Alicia; Kieffer, Alexia; Baggaley, Rebecca F; Di Tanna, Gian Luca; Desai, Kamal; Rasuli, Anvar; Armoni, Judith

    2015-04-01

    Long-term seroprotection data are essential for decision-making on the need and timing of vaccine boosters. Based on data from longitudinal serological studies, modeling can provide estimates on long-term antibody persistence and inform such decision-making. We examined long-term anti-hepatitis A virus (anti-HAV) antibody persistence in Argentinean children ≤15 years after the initial study where they completed a 2-dose course of inactivated hepatitis A vaccine (Avaxim 80U Pediatric, Sanofi Pasteur, Lyon, France). Blood serum samples were taken at baseline, 2 weeks (post first dose), 6 months (pre-booster), 6.5 months (post-booster), 10 years and 14-15 years after first vaccine dose. We fitted 8 statistical model types, predominantly mixed effects models, to anti-HAV persistence data, to identify the most appropriate and best fitting models for our data set and to predict individuals' anti-HAV levels and seroprotection rates up to 30 years post vaccination. Fifty-four children (mean age at enrollment 30.4 months) were enrolled up to 15 years post first vaccine dose. There were 3 distinct periods of antibody concentration: rapid rise up to peak concentration post-booster, rapid decay from post-booster to 10 years, followed by slower decay. A 3-segmented linear mixed effects model was the most appropriate for the data set. Extrapolating based on the available 14-15-year follow-up, the analysis predicted that 88% of individuals anti-HAV seronegative prior to vaccination would remain seroprotected at 30 years post vaccination and lifelong seroprotection for vaccinees seropositive prior to vaccination. Currently available data demonstrate that Avaxim 80U Pediatric confers to most vaccinees a high level of seroprotection against hepatitis A infection for at least 20-30 years.

  15. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells.

    PubMed

    Hegde, Venkatesh L; Hegde, Shweta; Cravatt, Benjamin F; Hofseth, Lorne J; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2008-07-01

    Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. Natural cannabinoids such as Delta(9)-tetrahydrocannabinol (THC) effectively modulate immune cell function, and they have shown therapeutic potential in treating inflammatory diseases. We investigated the effects of THC in a murine model of concanavalin A (ConA)-induced hepatitis. Intraperitoneal administration of THC after ConA challenge inhibited hepatitis as shown by significant decrease in liver enzymes and reduced liver tissue injury. Furthermore, THC treatment resulted in significant suppression of crucial inflammatory cytokines in ConA-induced hepatitis. It is noteworthy that THC treatment in ConA-injected mice led to significant increase in absolute number of Forkhead helix transcription factor p3+ T regulatory cells in liver. We were surprised to find that select cannabinoid receptor (CB1 or CB2) agonists were not able to block hepatitis either independently or in combination. However, CB1/CB2 mixed agonists were able to efficiently attenuate hepatitis similar to THC. The modulatory effect of THC in ConA-induced hepatitis was reversed by both CB1 and CB2 antagonists. We also observed that endogenous cannabinoid anandamide was able to reduce hepatitis by suppressing cytokine levels. In addition, deficiency or inhibition of endocannabinoid hydrolyzing enzyme fatty acid amide hydrolase (FAAH), which leads to increased levels of endogenous cannabinoids, resulted in decreased liver injury upon ConA challenge. Our data demonstrate that targeting cannabinoid receptors using exogenous or endogenous cannabinoids and use of FAAH inhibitors may constitute novel therapeutic modalities to treat immune-mediated liver inflammation.

  16. Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): A model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans

    PubMed Central

    2012-01-01

    Background Hepatitis B virus (HBV) infection continues to be an escalating global health problem. Feasible and effective animal models for HBV infection are the prerequisite for developing novel therapies for this disease. The tree shrew (Tupaia) is a small animal species evolutionary closely related to humans, and thus is permissive to certain human viral pathogens. Whether tree shrews could be chronically infected with HBV in vivo has been controversial for decades. Most published research has been reported on adult tree shrews, and only small numbers of HBV infected newborn tree shrews had been observed over short time periods. We investigated susceptibility of newborn tree shrews to experimental HBV infection as well as viral clearance over a protracted time period. Results Forty-six newborn tree shrews were inoculated with the sera from HBV-infected patients or tree shrews. Serum and liver samples of the inoculated animals were periodically collected and analyzed using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Southern blot, and immunohistochemistry. Six tree shrews were confirmed and four were suspected as chronically HBV-infected for more than 48 (up to 228) weeks after inoculation, including three that had been inoculated with serum from a confirmed HBV-infected tree shrew. Conclusions Outbred neonatal tree shrews can be long-term chronically infected with HBV at a frequency comparable to humans. The model resembles human disease where also a smaller proportion of infected individuals develop chronic HBV related disease. This model might enable genetic and immunologic investigations which would allow determination of underlying molecular causes favoring susceptibility for chronic HBV infection and disease establishment vs. viral clearance. PMID:22913805

  17. Pathological and MR-DWI study of the acute hepatic injury model after stem cell transplantation

    PubMed Central

    Shang, Quan-Liang; Xiao, En-Hua; Zhou, Qi-Chang; Luo, Jian-Guang; Wu, Hai-Jun

    2011-01-01

    AIM: To investigate apparent diffusion coefficient (ADC) values as an indication of reconditioning of acute hepatic injury (AHI) after allogeneic mononuclear bone marrow cell (MBMC) transplantation. METHODS: Three groups were used in our study: a cell transplantation group (n = 21), transplantation control group (n = 21) and normal control group (n = 10). AHI model rabbits in the cell transplantation group were injected with 5 mL of MBMC suspension at multiple sites in the liver and the transplantation controls were injected with 5 mL D-Hanks solution. At the end of the 1st, 2nd and 4th wk, 7 rabbits were randomly selected from the cell transplantation group and transplantation control group for magnetic resonance diffusion-weighted imaging (MR-DWI) and measurement of the mean ADC values of injured livers. After MR-DWI examination, the rabbits were sacrificed and the livers subjected to pathological examination. Ten healthy rabbits from the normal control group were used for MR-DWI examination and measurement of the mean ADC value of normal liver. RESULTS: At all time points, the liver pathological scores from the cell transplantation group were significantly lower than those in the transplantation control group (27.14 ± 1.46 vs 69.29 ± 6.16, 22.29 ± 2.29 vs 57.00 ± 1.53, 19.00 ± 2.31 vs 51.86 ± 6.04, P = 0.000). The mean ADC values of the cell transplantation group were significantly higher than the transplantation control group ((1.07 ± 0.07) × 10-3 mm2/s vs (0.69 ± 0.05) × 10-3 mm2/s, (1.41 ± 0.04) × 10-3 mm2/s vs (0.84 ± 0.06) × 10-3 mm2/s, (1.68 ± 0.04) × 10-3 mm2/s vs (0.86 ± 0.04) × 10-3 mm2/s, P = 0.000). The pathological scores of the cell transplantation group and transplantation control group gradually decreased. However, their mean ADC values gradually increased to near that of the normal control. At the end of the 1st wk, the mean ADC values of the cell transplantation group and transplantation control group were significantly lower

  18. An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells

    PubMed Central

    Cebula, Marcin; Ochel, Aaron; Hillebrand, Upneet; Pils, Marina C.; Schirmbeck, Reinhold; Hauser, Hansjörg; Wirth, Dagmar

    2013-01-01

    The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreERT2 mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred Kb/OVA257-264-specific OT-I T cells to OVA_X_CreERT2 mice or generated triple transgenic OVA_X CreERT2_X_OT-I mice. OT-I T cells become activated in OVA_X_CreERT2 mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreERT2_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreERT2_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance. PMID:23869228

  19. An inducible transgenic mouse model for immune mediated hepatitis showing clearance of antigen expressing hepatocytes by CD8+ T cells.

    PubMed

    Cebula, Marcin; Ochel, Aaron; Hillebrand, Upneet; Pils, Marina C; Schirmbeck, Reinhold; Hauser, Hansjörg; Wirth, Dagmar

    2013-01-01

    The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreER(T2) mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred K(b)/OVA257-264-specific OT-I T cells to OVA_X_CreER(T2) mice or generated triple transgenic OVA_X CreER(T2)_X_OT-I mice. OT-I T cells become activated in OVA_X_CreER(T2) mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreER(T2)_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreER(T2)_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance.

  20. Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model

    SciTech Connect

    Rong, Libin; Guedj, Jeremie; Dahari, Harel; Coffield, Daniel J.; Levi, Micha; Smith, Patrick; Perelson, Alan S.

    2013-03-14

    The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). In this paper, we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion, the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). Finally, the multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.

  1. Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model

    DOE PAGES

    Rong, Libin; Guedj, Jeremie; Dahari, Harel; ...

    2013-03-14

    The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). In this paper, we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion,more » the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). Finally, the multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.« less

  2. [Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure].

    PubMed

    Yamanishi, A; Ishibashi, Y; Kuriyama, K; Tachiiri, T; Kusajima, H; Kojima, E; Momo, K

    1999-01-01

    To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction.

  3. Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus

    USDA-ARS?s Scientific Manuscript database

    Equine hepacivirus (EHCV; non-primate hepacivirus) is a hepatotropic member of the Flaviviridae family that infects horses. Although EHCV is the closest known relative to hepatitis C virus (HCV), its complete replication kinetics in vivo have not been described, and direct evidence that it causes he...

  4. OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION

    EPA Science Inventory

    Evaluating the Effects of Methapyrilene and Clofibrate on Hepatic Gene Expression: A Collaboration Between Laboratories and a Comparison of Platform and Analytical Approaches

    Roger G. Ulrich1, John C. Rockett2, G. Gordon Gibson3 and Syril Pettit4

    1 Rosetta Inpharmat...

  5. OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION

    EPA Science Inventory

    Evaluating the Effects of Methapyrilene and Clofibrate on Hepatic Gene Expression: A Collaboration Between Laboratories and a Comparison of Platform and Analytical Approaches

    Roger G. Ulrich1, John C. Rockett2, G. Gordon Gibson3 and Syril Pettit4

    1 Rosetta Inpharmat...

  6. Quantitative Analyses of the Influence of Parameters Governing Rate-Determining Process of Hepatic Elimination of Drugs on the Magnitudes of Drug-Drug Interactions via Hepatic OATPs and CYP3A Using Physiologically Based Pharmacokinetic Models.

    PubMed

    Yoshikado, Takashi; Maeda, Kazuya; Kusuhara, Hiroyuki; Furihata, Ken-Ichi; Sugiyama, Yuichi

    2017-09-01

    Physiologically based pharmacokinetic models were constructed for hepatic organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), although the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study. Parameters optimized from clinical PK data were confirmed to reproduce their blood concentrations in control phase. DDIs with rifampicin and itraconazole were simulated using in vivo Rdif (ratio of diffusional uptake to active uptake) and β (the fraction of the sum of intrinsic clearances for metabolism and biliary excretion in all possible itineraries of intracellular drugs including basolateral efflux) estimated by static analyses based on the extended clearance concept, in vivo inhibition constant (Ki) for hepatic OATPs reported previously, and in vivo Ki for CYP3A determined from DDI data with midazolam and itraconazole. Sensitivity analyses showed the magnitudes of DDIs largely depended on Rdif and β. In conclusion, our approach using physiologically based pharmacokinetic modeling showed that the rational estimation of parameters governing rate-determining process of hepatic elimination is critical to accurately predict DDI magnitudes involving OATPs/CYP3A inhibition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  7. Impact of calcineurin inhibitors with or without interferon on hepatitis C virus titers in a chimeric mouse model of hepatitis C virus infection.

    PubMed

    Kneteman, Norman M; Asthana, Sonal; Lewis, Jamie; Dibben, Chelcey; Douglas, Donna; Nourbakhsh, Mahra; Tyrrell, Lorne J; Lund, Garry

    2012-01-01

    Cyclosporine A (CSA) has potent effects against hepatitis C virus (HCV) in vitro, but its clinical efficacy after liver transplantation (LT) is uncertain. We evaluated the impact of CSA and tacrolimus (TAC) with or without concomitant interferon (IFN) therapy on serum HCV titers in a chimeric mouse model of HCV infection. Six groups of HCV-infected mice received only the vehicle, IFN, CSA, CSA and IFN, TAC, or TAC and IFN for 4 weeks. The quantitative HCV polymerase chain reaction levels were determined after 1, 2, and 4 weeks of drug administration. There were no significant differences in the HCV titers after 4 weeks of treatment between the non-IFN-treated groups (log HCV titers: 3.5 ± 0.3 for the vehicle group, 4.4 ± 0.6 for the CSA group, and 4.3 ± 0.4 for the TAC group, P = 0.3). Although IFN had a consistent effect of reducing HCV titers across the groups, there was no significant impact of CSA on HCV levels when it was used alone or in combination with IFN at any time point. The 4-week HCV titers were as follows: 3.2 ± 0.3 for the IFN group, 4.7 ± 0.4 for the CSA/IFN group, and 4.0 ± 0.5 for the TAC/IFN group (P = 0.07). The CSA/IFN and TAC/IFN groups did not differ significantly (P = 0.6). Six of the 7 animals in the IFN group (85.7%) had an HCV titer decline ≥ 1 log, whereas in the test groups (CSA/IFN and TAC/IFN), 6 of 9 animals (66.7%) achieved a 1-log decline in the HCV titer (P = 1). Using this animal model, we could find no evidence supporting the routine use of CSA after LT in HCV-infected patients.

  8. Reversal learning impairment and alterations in the prefrontal cortex and the hippocampus in a model of portosystemic hepatic encephalopathy.

    PubMed

    Méndez, Marta; Méndez-López, Magdalena; López, Laudino; Begega, Azucena; Aller, María Angeles; Arias, Jaime; Arias, Jorge L

    2010-09-01

    Patients with liver dysfunction often suffer from hepatic encephalopathy (HE), a neurological complication that affects attention and memory. Various experimental animal models have been used to study HE, the most frequently used being the portocaval shunt (PCS). In order to determine brain substrates of cognitive impairment in this model, we assessed reversal learning and c-Fos expression in a rat model of portosystemic derivation. PCS and sham-operated rats (SHAM) were tested for reversal learning. Brains were processed for c-Fos immunocytochemistry. The total number of c-Fos positive nuclei was quantified in the prefrontal cortex and hippocampus. The spatial reference memory task showed no differences between groups in escape latencies. The no-platform probe test showed that both the PCS and the SHAM learned the location of platform. However, the PCS group perseverated in the old target during reversal. The PCS group presented less c-Fos- positive cells in prelimbic cortex, CA1 and dentate gyrus of the dorsal hippocampus than SHAM. Overall, these results suggest that this specific model of portosystemic hepatic encephalopathy produces reversal learning impairment that could be linked to dysfunction in neuronal activity in the prefrontal cortex and hippocampus.

  9. [Use the Markov-decision tree model to optimize vaccination strategies of hepatitis E among women aged 15 to 49].

    PubMed

    Chen, Z M; Ji, S B; Shi, X L; Zhao, Y Y; Zhang, X F; Jin, H

    2017-02-10

    Objective: To evaluate the cost-utility of different hepatitis E vaccination strategies in women aged 15 to 49. Methods: The Markov-decision tree model was constructed to evaluate the cost-utility of three hepatitis E virus vaccination strategies. Parameters of the models were estimated on the basis of published studies and experience of experts. Both methods on sensitivity and threshold analysis were used to evaluate the uncertainties of the model. Results: Compared with non-vaccination group, strategy on post-screening vaccination with rate as 100%, could save 0.10 quality-adjusted life years per capital in the women from the societal perspectives. After implementation of screening program and with the vaccination rate reaching 100%, the incremental cost utility ratio (ICUR) of vaccination appeared as 5 651.89 and 6 385.33 Yuan/QALY, respectively. Vaccination post to the implementation of a screening program, the result showed better benefit than the vaccination rate of 100%. Results from the sensitivity analysis showed that both the cost of hepatitis E vaccine and the inoculation compliance rate presented significant effects. If the cost were lower than 191.56 Yuan (RMB) or the inoculation compliance rate lower than 0.23, the vaccination rate of 100% strategy was better than the post-screening vaccination strategy, otherwise the post-screening vaccination strategy appeared the optimal strategy. Conclusion: Post-screening vaccination for women aged 15 to 49 from social perspectives seemed the optimal one but it had to depend on the change of vaccine cost and the rate of inoculation compliance.

  10. Application of a Combined Model with Autoregressive Integrated Moving Average (ARIMA) and Generalized Regression Neural Network (GRNN) in Forecasting Hepatitis Incidence in Heng County, China

    PubMed Central

    Liang, Hao; Gao, Lian; Liang, Bingyu; Huang, Jiegang; Zang, Ning; Liao, Yanyan; Yu, Jun; Lai, Jingzhen; Qin, Fengxiang; Su, Jinming; Ye, Li; Chen, Hui

    2016-01-01

    Background Hepatitis is a serious public health problem with increasing cases and property damage in Heng County. It is necessary to develop a model to predict the hepatitis epidemic that could be useful for preventing this disease. Methods The autoregressive integrated moving average (ARIMA) model and the generalized regression neural network (GRNN) model were used to fit the incidence data from the Heng County CDC (Center for Disease Control and Prevention) from January 2005 to December 2012. Then, the ARIMA-GRNN hybrid model was developed. The incidence data from January 2013 to December 2013 were used to validate the models. Several parameters, including mean absolute error (MAE), root mean square error (RMSE), mean absolute percentage error (MAPE) and mean square error (MSE), were used to compare the performance among the three models. Results The morbidity of hepatitis from Jan 2005 to Dec 2012 has seasonal variation and slightly rising trend. The ARIMA(0,1,2)(1,1,1)12 model was the most appropriate one with the residual test showing a white noise sequence. The smoothing factor of the basic GRNN model and the combined model was 1.8 and 0.07, respectively. The four parameters of the hybrid model were lower than those of the two single models in the validation. The parameters values of the GRNN model were the lowest in the fitting of the three models. Conclusions The hybrid ARIMA-GRNN model showed better hepatitis incidence forecasting in Heng County than the single ARIMA model and the basic GRNN model. It is a potential decision-supportive tool for controlling hepatitis in Heng County. PMID:27258555

  11. Impact of input parameters on the prediction of hepatic plasma clearance using the well-stirred model.

    PubMed

    Wan, Hong; Bold, Peter; Larsson, Lars-Olof; Ulander, Johan; Peters, Sheila; Löfberg, Boel; Ungell, Anna-Lena; Någård, Mats; Llinàs, Antonio

    2010-09-01

    The in vitro metabolic stability assays are indispensable for screening the metabolic liability of new chemical entities (NCEs) in drug discovery. Intrinsic clearance (CL(int)) values from liver microsomes and/or hepatocytes are frequently used to assess metabolic stability as well as to quantitatively predict in vivo hepatic plasma clearance (CL(H)). An often used approximation is the so called well-stirred model which has gained widespread use. The applications of the well-stirred model are typically dependent on several measured parameters and hence with potential for error-propagation. Despite widespread use, it was recently suggested that the well-stirred model in some circumstances has been misused for in vitro in vivo extrapolation (IVIVE). In this work, we follow up that discussion and present a retrospective analysis of IVIVE for hepatic clearance prediction from in vitro metabolic stability data. We focus on the impact of input parameters on the well stirred model; in particular comparing "reference model" (with all experimentally determined values as input parameters) versus simplified models (with incomplete input parameters in the models). Based on a systematic comparative analysis and model comparison using datasets of diverse drug-like compounds and NCEs from rat and human, we conclude that simplified models, disregarding binding data, may be sufficiently good for IVIVE evaluation and compound ranking at early stage for cost-effective screening. Factors that can influence prediction accuracy are discussed, including in vitro intrinsic clearance (CL(int)) and in vivo CL(int) scaling factor used, non-specific binding to microsomes (fu(m)), blood to plasma ratio (C(B)/C(P)) and in particular fraction unbound in plasma (fu). In particular, the fu discrepancies between literature data and in-house values and between two different compound concentrations 1 and 10 µM are exemplified and its potential impact on prediction performance is demonstrated using a

  12. Hepatic arterial administration of sorafenib and iodized oil effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX2 hepatocellular carcinoma model

    PubMed Central

    Zhang, Lin; Liu, Feng-Yong; Fu, Jin-Xin; Duan, Feng; Fan, Qing-Sheng; Wang, Mao-Qiang

    2014-01-01

    Aim: To investigate the therapeutic effect of the hepatic arterial administration of sorafenib in rabbit VX-2 hepatocellular carcinoma (HCC) model. Methods: Rabbit VX-2 HCC models were established via implanting VX-2 tumors into the livers, and randomly divided into four groups, respectively treated with (1) The hepatic arterial administration of iodized oil alone (TACE-i), (2) The hepatic arterial administration of iodized oil and pharmorubicin (TACE-ip), (3) The hepatic arterial administration of iodized and cis-DDP (TACE-ic), (4) The hepatic arterial administration of iodized and sorafenib (TACE-is). The growth rate and intrahepatic metastasis of implanted VX-2 tumor in each rabbit were measured. Microvessel density (MVD) in the adjacent tissues of implanted VX-2 tumor were estimated by detecting the expression of CD34 and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. Results: Compared with other groups, TACE-is treatment group presented a better effect on inhibiting tumor growth rate and intrahepatic metastasis in rabbit VX-2 HCC model. The angiogenesis (assessed by MVD) in the adjacent tissues were suppressed more dramatically in TACE-is treated group. Moreover, TACE-is treatment did not significantly increase the levels of alanine transaminase and creatinine compared to the group with TACE-i treatment. Conclusion: The hepatic arterial administration of sorafenib and iodized oil (TACE-is) effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX-2 HCC model without obvious hepatic and renal toxicity. One of the related mechanisms may be due to the inhibition of angiogenesis in the adjacent tissues. Our data indicated that TACE-is may be a secure and effective treatment for HCC. PMID:25550815

  13. Inactivation of Viruses and Bacteriophages as Models for Swine Hepatitis E Virus in Food Matrices.

    PubMed

    Emmoth, Eva; Rovira, Jordi; Rajkovic, Andreja; Corcuera, Elena; Wilches Pérez, Diego; Dergel, Irene; Ottoson, Jakob R; Widén, Frederik

    2017-03-01

    Hepatitis E virus has been recognised as a food-borne virus hazard in pork products, due to its zoonotic properties. This risk can be reduced by adequate treatment of the food to inactivate food-borne viruses. We used a spectrum of viruses and bacteriophages to evaluate the effect of three food treatments: high pressure processing (HPP), lactic acid (LA) and intense light pulse (ILP) treatments. On swine liver at 400 MPa for 10 min, HPP gave log10 reductions of ≥4.2, ≥5.0 and 3.4 for feline calicivirus (FCV) 2280, FCV wildtype (wt) and murine norovirus 1 (MNV 1), respectively. Escherichia coli coliphage ϕX174 displayed a lower reduction of 1.1, while Escherichia coli coliphage MS2 was unaffected. For ham at 600 MPa, the corresponding reductions were 4.1, 4.4, 2.9, 1.7 and 1.3 log10. LA treatment at 2.2 M gave log10 reductions in the viral spectrum of 0.29-2.1 for swine liver and 0.87-3.1 for ham, with ϕX174 and MNV 1, respectively, as the most stable microorganisms. The ILP treatment gave log10 reductions of 1.6-2.8 for swine liver, 0.97-2.2 for ham and 1.3-2.3 for sausage, at 15-60 J cm(-2), with MS2 as the most stable microorganism. The HPP treatment gave significantly (p < 0.05) greater virus reduction on swine liver than ham for the viruses at equivalent pressure/time combinations. For ILP treatment, reductions on swine liver were significantly (p < 0.05) greater than on ham for all microorganisms. The results presented here could be used in assessments of different strategies to protect consumers against virus contamination and in advice to food producers. Conservative model indicators for the pathogenic viruses could be suggested.

  14. Hepatitis Vaccines

    PubMed Central

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  15. A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model

    PubMed Central

    Quan, Chao; Hu, Chunxiu; Xie, Bingxian; Du, Yinan; Chen, Liang; Yang, Wei; Yang, Liu; Chen, Qiaoli; Shen, Bin; Hu, Bian; Zheng, Zhihong; Zhu, Haibo; Huang, Xingxu; Xu, Guowang; Chen, Shuai

    2016-01-01

    ABSTRACT The low-density lipoprotein receptor (LDLR) plays a critical role in the liver for the clearance of plasma low-density lipoprotein (LDL). Its deficiency causes hypercholesterolemia in many models. To facilitate the usage of rats as animal models for the discovery of cholesterol-lowering drugs, we took a genetic approach to delete the LDLR in rats aiming to increase plasma LDL cholesterol (LDL-C). An LDLR knockout rat was generated via zinc-finger nuclease technology, which harbors a 19-basepair deletion in the seventh exon of the ldlr gene. As expected, deletion of the LDLR elevated total cholesterol and total triglyceride in the plasma, and caused a tenfold increase of plasma LDL-C and a fourfold increase of plasma very low-density lipoprotein (VLDL-C). A lipidomics analysis revealed that deletion of the LDLR affected hepatic lipid metabolism, particularly lysophosphatidylcholines, free fatty acids and sphingolipids in the liver. Cholesterol ester (CE) 20:4 also displayed a significant increase in the LDLR knockout rats. Taken together, the LDLR knockout rat offers a new model of hypercholesterolemia, and the lipidomics analysis reveals hepatic lipid signatures associating with deficiency of the LDL receptor. PMID:27378433

  16. PRELIMINARY RESULTS OF TOPICAL HEPATIC HYPOTHERMIA IN A MODEL OF LIVER ISCHEMIA/REPERFUSION INJURY IN RATS.

    PubMed

    Abdo, Emilio Elias; Figueira, Estela Regina Ramos; Rocha-Filho, Joel Avancini; Chaib, Eleazar; D'Albuquerque, Luiz Augusto Carneiro; Bacchella, Telesforo

    2017-01-01

    Ischemia/reperfusion causes organ damage but it is mandatory in hepatic transplantation, trauma and other complex liver surgeries, when Pringle maneuver is applied to minimize bleeding during these procedures. It is well known that liver ischemia/reperfusion leads to microcirculatory disturbance and cellular injury. In this setting hypothermia is known to reduce oxygen demand, lowering intracellular metabolism. To evaluate the effects of hypothermia in liver ischemia/reperfusion injury, using a new model of topic isolated liver hypothermia. We used male Wistar rats weighting about 250 grams, kept in ad libitum feeding regime and randomly divided into two groups of nine animals: 1) Normothermic group, rats were submitted to normothermic ischemia of the median and left hepatic lobes, with subsequent resection of right and caudate lobes during liver reperfusion; and 2) Hypothermic group, rats were submitted to liver ischemia under hypothermia at 10°C. Liver ischemia was performed for 45 minutes. The animals were euthanized 48 hours after liver reperfusion for blood and liver tissue sampling. The transaminases analyses showed a significant decrease of AST and ALT in Hypothermic group (P<0.01) compared to Normothermic group (1403±1234 x 454±213 and 730±680 x 271±211 U/L, respectively). Histology showed severe necrosis in 50% and mild necrosis in 50% of cases in Normothermic group, but severe necrosis in 10% and mild or absent necrosis 90% of the cases in hypothermic group. A simplified model of liver ischemia/reperfusion that simulates orthotopic liver autotransplantion was demonstrated. Topical hypothermia of isolated hepatic lobules showed liver protection, being a viable and practical method for any kind of in vivo liver preservation study.

  17. Comparison of trout hepatocytes and liver S9 fractions as in vitro models for predicting hepatic clearance in fish.

    PubMed

    Fay, Kellie A; Fitzsimmons, Patrick N; Hoffman, Alex D; Nichols, John W

    2017-02-01

    Isolated hepatocytes and liver S9 fractions have been used to collect in vitro biotransformation data for fish as a means of improving modeled estimates of chemical bioaccumulation. To date, however, there have been few direct comparisons of these 2 methods. In the present study, cryopreserved trout hepatocytes were used to measure in vitro intrinsic clearance rates for 6 polycyclic aromatic hydrocarbons (PAHs). These rates were extrapolated to estimates of in vivo intrinsic clearance and used as inputs to a well stirred liver model to predict hepatic clearance. Predicted rates of hepatic clearance were then evaluated by comparison with measured rates determined previously using isolated perfused livers. Hepatic clearance rates predicted using hepatocytes were in good agreement with measured values (<2.1-fold difference for 5 of 6 compounds) under 2 competing binding assumptions. These findings, which may be attributed in part to high rates of PAH metabolism, are similar to those obtained previously using data from liver S9 fractions. For 1 compound (benzo[a]pyrene), the in vivo intrinsic clearance rate calculated using S9 data was 10-fold higher than that determined using hepatocytes, possibly due to a diffusion limitation on cellular uptake. Generally, however, there was good agreement between calculated in vivo intrinsic clearance rates obtained using either in vitro test system. These results suggest that both systems can be used to improve bioaccumulation assessments for fish, particularly when vitro rates of activity are relatively high, although additional work is needed to determine if the chemical domain of applicability for each system differs. Environ Toxicol Chem 2017;36:463-471. Published 2016 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

  18. Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review.

    PubMed

    Owiti, John A; Greenhalgh, Trisha; Sweeney, Lorna; Foster, Graham R; Bhui, Kamaldeep S

    2015-02-15

    Hepatitis B and C (HBV, HCV) infections are associated with high morbidity and mortality. Many countries with traditionally low prevalence (such as UK) are now planning interventions (screening, vaccination, and treatment) of high-risk immigrants from countries with high prevalence. This review aimed to synthesise the evidence on immigrants' knowledge of HBV and HCV that might influence the uptake of clinical interventions. The review was also used to inform the design and successful delivery of a randomised controlled trial of targeted screening and treatment. Five databases (PubMed, CINHAL, SOCIOFILE, PsycINFO & Web of Science) were systematically searched, supplemented by reference tracking, searches of selected journals, and of relevant websites. We aimed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas. Evidence, extracted according to a conceptual framework of Kleinman's explanatory model, was subjected to narrative synthesis. We adapted the PEN-3 model to categorise and analyse themes, and recommend strategies for interventions to influence help-seeking behaviour. We identified 51 publications including quantitative (n = 39), qualitative (n = 11), and mixed methods (n = 1) designs. Most of the quantitative studies included small samples and had heterogeneous methods and outcomes. The studies mainly concentrated on hepatitis B and ethnic groups of South East Asian immigrants residing in USA, Canada, and Australia. Many immigrants lacked adequate knowledge of aetiology, symptoms, transmission risk factors, prevention strategies, and treatment, of hepatitis HBV and HCV. Ethnicity, gender, better education, higher income, and English proficiency influenced variations in levels and forms of knowledge. Immigrants are vulnerable to HBV and HCV, and risk life-threatening complications from these infections because of poor knowledge and help

  19. Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B

    PubMed Central

    Fletcher, Simon P.; Chin, Daniel J.; Gruenbaum, Lore; Bitter, Hans; Rasmussen, Erik; Ravindran, Palanikumar; Swinney, David C.; Birzele, Fabian; Schmucki, Roland; Lorenz, Stefan H.; Kopetzki, Erhard; Carter, Jade; Triyatni, Miriam; Thampi, Linta M.; Yang, Junming; AlDeghaither, Dalal; Murredu, Marta G.; Cote, Paul; Menne, Stephan

    2015-01-01

    Recombinant interferon-alpha (IFN-α) is an approved therapy for chronic hepatitis B (CHB), but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV) infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with recombinant woodchuck IFN-α (wIFN-α) or placebo (n = 12/group) for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8–12/group) at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs) by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB. PMID:26352406

  20. Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia.

    PubMed

    Jamshidzadeh, Akram; Heidari, Reza; Abasvali, Mozhgan; Zarei, Mehdi; Ommati, Mohammad Mehdi; Abdoli, Narges; Khodaei, Forouzan; Yeganeh, Yasaman; Jafari, Faezeh; Zarei, Azita; Latifpour, Zahra; Mardani, Elnaz; Azarpira, Negar; Asadi, Behnam; Najibi, Asma

    2017-02-01

    Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis.

  1. Hepatic drug clearance: the effect of age using indocyanine green as a model compound.

    PubMed Central

    Wynne, H A; Goudevenos, J; Rawlins, M D; James, O F; Adams, P C; Woodhouse, K W

    1990-01-01

    The hepatic extraction ratio and clearance of indocyanine green (ICG) were determined and used to derive apparent liver blood flow in nine subjects between the ages of 22 and 83 years. There was no correlation between the hepatic extraction ratio of ICG and age (rs = -0.435, NS). There was a significant negative correlation between both ICG clearance and age (rs = -0.710, P less than 0.05) and apparent liver blood flow and age (rs = -0.750, P less than 0.05). These results validate the comparison of liver blood flow values derived from ICG clearance in humans over a wide age range and confirm that liver blood flow does fall with age. PMID:2291878

  2. Akt2 is required for hepatic lipid accumulation in models of insulin resistance

    PubMed Central

    Leavens, Karla F.; Easton, Rachael M.; Shulman, Gerald I.; Previs, Stephen F.; Birnbaum, Morris J.

    2009-01-01

    Summary Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin’s control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin-deficiency or high fat diet feeding. Lepob/ob mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to fatty acid synthesis, as mice fed high fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. These data demonstrate that Akt2 is a requisite component of the insulin-dependent regulation of lipid metabolism during insulin resistance. PMID:19883618

  3. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy

    SciTech Connect

    Basile, A.S.; Pannell, L.; Jaouni, T.; Gammal, S.H.; Fales, H.M.; Jones, E.A.; Skolnick, P. )

    1990-07-01

    Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4- to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.

  4. Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models.

    PubMed

    Markusic, David M; Nichols, Timothy C; Merricks, Elizabeth P; Palaschak, Brett; Zolotukhin, Irene; Marsic, Damien; Zolotukhin, Sergei; Srivastava, Arun; Herzog, Roland W

    2017-05-01

    Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable. We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B by hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated through molecular evolution. AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation FIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however, expression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC capsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog. Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in hepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict efficacy in other species and thus is of limited translational utility.

  5. Hepatitis B and Hepatitis C in Pregnancy

    MedlinePlus

    ... signs and symptoms of hepatitis C virus infection? Hepatitis C virus infection causes signs and symptoms similar to those of hepatitis B virus infection. It also can cause no symptoms. Unlike hepatitis B virus infection, most ...

  6. Feature Hepatitis: Hepatitis Can Strike Anyone

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis Can Strike Anyone Past Issues / Spring 2009 Table ... from all walks of life are affected by hepatitis, especially hepatitis C, the most common form of ...

  7. Treatment of hepatitis C virus infection with interferon and small molecule direct antivirals: viral kinetics and modeling

    PubMed Central

    Rong, Libin; Perelson, Alan S.

    2010-01-01

    Hepatitis C virus (HCV) infection remains a threat to global public health. Treatment with pegylated interferon (IFN) plus ribavirin leads to a sustained virologic response in about 50% of patients. New therapies using direct antiviral agents have the potential to cure patients unresponsive to IFN-based therapies. Mathematical modeling has played an important role in studying HCV kinetics. Using models one can evaluate the effectiveness of new treatment agents, estimate important parameters that govern virus-host interactions, explore possible mechanisms of drug action against HCV, investigate the development of drug resistance and study quasispecies dynamics during therapy. Here we review our current knowledge of HCV kinetics under IFN-based therapy and newly developed antiviral agents specifically targeted to attack HCV, and show how mathematical models have helped improve our understanding of HCV infection and treatment. PMID:20370626

  8. Generation and characterization of a transgenic mouse model with hepatic expression of human CYP2A6.

    PubMed

    Zhang, Qing-Yu; Gu, Jun; Su, Ting; Cui, Huadong; Zhang, Xiuling; D'Agostino, Jaime; Zhuo, Xiaoliang; Yang, Weizhu; Swiatek, Pamela J; Ding, Xinxin

    2005-12-09

    The aim of this study was to prepare and characterize a transgenic mouse model in which CYP2A6, a human P450 enzyme, is expressed specifically in the liver. CYP2A6, which is mainly expressed in human liver, is active toward many xenobiotics. Our transgene construct contained the mouse transthyretin promoter/enhancer, a full-length CYP2A6 cDNA, and a downstream neomycin-resistance gene for positive selection in embryonic stem cells. Hepatic expression of the CYP2A6 transgene was demonstrated by immunoblotting, whereas tissue specificity of CYP2A6 expression was confirmed by RNA-PCR. The transgenic mouse was further characterized after being backcrossed to the B6 strain for six generations. Hepatic microsomes from homozygous transgenic mice had activities significantly higher than those of B6 mice toward coumarin. The in vivo activity of transgenic CYP2A6 was also determined. Systemic clearance of coumarin was significantly higher in the transgenic mice than in B6 controls, consistent with the predicted role of CYP2A6 as the major coumarin hydroxylase in human liver. The CYP2A6-transgenic mouse model should be valuable for studying the in vivo function of this polymorphic human enzyme in drug metabolism and chemical toxicity.

  9. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis

    PubMed Central

    Chu, Andrew S.; Diaz, Rosalyn; Hui, Jia-Ji; Yanger, Kilangsungla; Zong, Yiwei; Alpini, Gianfranco; Stanger, Ben Z.; Wells, Rebecca G.

    2011-01-01

    Whether or not cholangiocytes or their hepatic progenitors undergo an epithelial-to-mesenchymal transition (EMT) to become matrix-producing myofibroblasts during biliary fibrosis is a significant ongoing controversy. To assess whether EMT is active during biliary fibrosis, we used Alfp-Cre x Rosa26-YFP mice, in which the epithelial cells of the liver (hepatocytes, cholangiocytes, and their bipotential progenitors) are heritably labeled at high efficiency with yellow fluorescent protein (YFP). Primary cholangiocytes isolated from our reporter strain were able to undergo EMT in vitro when treated with transforming growth factor-β1 alone or in combination with tumor necrosis factor-α, as indicated by adoption of fibroblastoid morphology, intracellular relocalization of E-cadherin, and expression of α-smooth muscle actin (α-SMA). To determine whether EMT occurs in vivo, we induced liver fibrosis in Alfp-Cre x Rosa26-YFP mice using the bile duct ligation (BDL; 2, 4, and 8 weeks), carbon tetrachloride (CCl4, 3 weeks), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 2 and 3 weeks) models. In no case did we find evidence of co-localization of YFP with the mesenchymal markers S100A4, vimentin, α-SMA, or pro-collagen 1α2, although these proteins were abundant in the peribiliary regions. Conclusion Hepatocytes and cholangiocytes do not undergo EMT in murine models of hepatic fibrosis. PMID:21520179

  10. Hepatitis C Test

    MedlinePlus

    ... Hepatitis C Antibody; Anti-HCV; HCV-PCR; HCV-RNA; Hepatitis C Viral Load Formal name: Viral Hepatitis C Antibody Screen; Viral Hepatitis C RNA by PCR; Hepatitis C Virus Genotype Related tests: ...

  11. Travelers' Health: Hepatitis B

    MedlinePlus

    ... Chapter 3 - Hepatitis A Chapter 3 - Hepatitis C Hepatitis B Francisco Averhoff INFECTIOUS AGENT Hepatitis B is ... their exposures. Map 3-04. Prevalence of chronic hepatitis B virus infection among adults PDF Version (printable) ...

  12. Analysis of hepatic gene expression profile in a spontaneous mouse model of type 2 diabetes under a high sucrose diet.

    PubMed

    Nojima, Koji; Sugimoto, Ken; Ueda, Hironori; Babaya, Naru; Ikegami, Hiroshi; Rakugi, Hiromi

    2013-01-01

    Both genetic factors and diabetogenic environmental factors, such as a high-sucrose diet (HSD), are involved in the development of type 2 diabetes. In this study, the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes and C3H mice used as controls, were fed a HSD, a high-fat diet (HFD) or a regular diet (RD) from weaning. In C3H mice, HFD significantly increased body weight gain, but maintained glucose tolerance. In contrast, in NSY mice, HSD resulted in increased body weight gain and liver steatosis and increased glucose intolerance to a greater extent than HFD. Furthermore, we performed DNA microarray analysis to detect differences in hepatic gene expression levels in both strains under HSD. We then performed RT-PCR analysis on selected genes to evaluate basal expression level under RD and changes under HSD conditions. HSD-fed NSY, but not C3H mice, exhibited increased hepatic expression levels of Pparg2, an isoform of Pparg as well as G0s2, a target of Pparg, which are known to be adipocyte-specific genes. Compared to RD-fed C3H mice, hepatic expression levels of Kat2b (transcriptional regulation), Hsd3b5 (steroid hormone metabolism) and Cyp7b1 (bile acid metabolism) were initially lower in RD-fed NSY mice, and were further decreased in HSD-fed NSY mice. Expression of Metallothionein (Mt1) and Metallothionein 2 (Mt2) was significantly lower in NSY mice compared to C3H mice, irrespective of dietary condition. These data suggest that elucidation of this heterogeneity in response to HSD might contribute to further understanding of the gene-environment interactions leading to diabetes in humans.

  13. Metformin Prevents Hepatocellular Carcinoma Development by Suppressing Hepatic Progenitor Cell Activation in a Rat Model of Cirrhosis

    PubMed Central

    DePeralta, Danielle K.; Wei, Lan; Ghoshal, Sarani; Schmidt, Benjamin; Lauwers, Gregory Y.; Lanuti, Michael; Chung, Raymond T.; Tanabe, Kenneth K.; Fuchs, Bryan C.

    2016-01-01

    Background Hepatocellular carcinoma (HCC) associated mortality is increasing at an alarming rate and there is a readily identifiable cohort of at risk patients with cirrhosis, viral hepatitis, non-alcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention since it is inexpensive, has a favorable safety profile and is well tolerated over long time periods. Methods We studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, where tumors develop in the setting of chronic inflammation and cirrhosis. We used repeated injections of diethylnitrosamine to induce sequential cirrhosis and HCC and administered metformin either at the first signs of fibrosis or cirrhosis. Results Prolonged metformin exposure was safe and associated with decreases in fibrotic and inflammatory markers especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, while tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. Interestingly, activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis and therefore only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells. Conclusions Our results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC. PMID:26914713

  14. Identification of an intrahepatic transcriptional signature associated with self-limiting infection in the woodchuck model of hepatitis B

    PubMed Central

    Fletcher, Simon P.; Chin, Daniel J.; Cheng, Donavan T.; Ravindran, Palanikumar; Bitter, Hans; Gruenbaum, Lore; Cote, Paul J.; Ma, Han; Klumpp, Klaus; Menne, Stephan

    2012-01-01

    The woodchuck model of hepatitis B virus (HBV) infection displays many characteristics of human infection and has particular value for characterizing the host immune responses during the development of chronic infection. Using the newly developed custom woodchuck microarray platform, we compared the intrahepatic transcriptional profiles of neonatal woodchucks with self-limiting woodchuck hepatitis virus (WHV) infection to those woodchucks progressing to persistent WHV infection. This revealed that WHV does not induce significant intrahepatic gene expression changes during the early-acute stage of infection (8 weeks), suggesting it is a stealth virus. At the mid-acute phase of infection (14 weeks), resolution was associated with induction of a prominent cytotoxic T cell signature. Strikingly, this was accompanied by high level expression of PD-1 and various other inhibitory T cell receptors, which likely act to minimize liver damage by cytotoxic T cells during viral clearance. In contrast to the expression of perforin and other cytotoxic effector genes, the interferon-γ (IFN-γ) signaling response in the mid-acute phase was comparable to that in chronically infected adult animals. The absence of a strong IFN-α/β transcriptional response indicated that type I IFN is not a critical mediator of self-limiting infection. Nevertheless, a number of antiviral genes, including viperin, were differentially expressed during resolving infection, suggesting that a subset of IFN-stimulated genes (ISGs) may play a role in the control of WHV replication. Conclusion We identified new immune pathways associated with the clearance of hepadnavirus infection revealing novel molecular targets with potential for the therapeutic treatment of chronic hepatitis B. PMID:22806943

  15. Modeling the fiscal costs and benefits of alternative treatment strategies in the United Kingdom for chronic Hepatitis C.

    PubMed

    Connolly, Mark P; Kotsopoulos, Nikos; Ustianowski, Andrew

    2017-09-05

    Hepatitis C (HCV) infection causes substantial direct health costs, but also impacts broader societal and governmental costs, such as tax revenue and social protection benefits. This study investigated the broader fiscal costs and benefits of curative interventions for chronic Hepatitis C (CHC) that allow individuals to avoid long-term HCV attributed health conditions. A prospective cohort model, assessing the long-term fiscal consequences of policy decisions, was developed for HCV infected individuals, following the generational accounting analytic framework that combines age-specific lifetime gross taxes paid and governmental transfers received (i.e. healthcare and social support costs). The analysis assessed the burden of a theoretical cohort of untreated HCV infected patients with the alternative of treating these patients with a highly efficacious curative intervention (ledipasvir/sofosbuvir [LDV/SOF]). It also compared treating patients at all fibrosis stages (Stages F0-F4) compared to late treatment (Stage F4). Based on projected lifetime work activity and taxes paid, the treated cohort paid an additional £5,900 per patient compared to the untreated cohort. Lifetime government disability costs of £97,555 and £125,359 per patient for treated cohort vs no treatment cohort were estimated, respectively. Lifetime direct healthcare costs in the treated cohort were £32,235, compared to non-treated cohort of £26,424, with an incremental healthcare costs increase of £5,901 per patient. The benefit cost ratio (BCR) of total government benefits and savings relative to government treatment costs (including LDV/SOF) ranged from 1.8-5.6. Treating patients early resulted in 77% less disability costs, 43% lower healthcare costs, and 33% higher tax revenue. The ability to cure Hepatitis C offers considerable fiscal benefits beyond direct medical costs and savings attributed to reduced disability costs, public allowances, and improved tax revenue. Changes in parameters

  16. Transient Receptor Potential Vanilloid 1 Gene Deficiency Ameliorates Hepatic Injury in a Mouse Model of Chronic Binge Alcohol-Induced Alcoholic Liver Disease

    PubMed Central

    Liu, Huilin; Beier, Juliane I.; Arteel, Gavin E.; Ramsden, Christopher E.; Feldstein, Ariel E.; McClain, Craig J.; Kirpich, Irina A.

    2016-01-01

    Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca2+ levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD. PMID:25447051

  17. In vivo transfer of hepatocyte growth factor gene accelerates proliferation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats.

    PubMed

    Shiota, G; Kunisada, T; Oyama, K; Udagawa, A; Nomi, T; Tanaka, K; Tsutsumi, A; Isono, M; Nakamura, T; Hamada, H; Sakatani, T; Sell, S; Sato, K; Ito, H; Kawasaki, H

    2000-03-31

    To clarify the effect of hepatocyte growth factor (HGF) on proliferation of hepatic oval cells, we transferred HGF gene into liver of the Solt-Farber rat model. Male Fisher 344 rats were infected with a recombinant adenovirus carrying the cDNA for HGF (pAxCAHGF) from tail vein. HGF mRNA showed its peak at 4 days, and diminished thereafter. The total and proliferating cell nuclear antigen-positive hepatic oval cells were significantly elevated in HGF-transferred rats, in which stem cell factor and c-kit mRNA increased at each time point. Our results suggest that in vivo transfer of the HGF gene into liver accelerates proliferation of hepatic oval cells in the Solt-Farber model in rats.

  18. A Proteomic Investigation of Hepatic Resistance to Ascaris in a Murine Model.

    PubMed

    Deslyper, Gwendoline; Colgan, Thomas J; Cooper, Andrew J R; Holland, Celia V; Carolan, James C

    2016-08-01

    The helminth Ascaris causes ascariasis in both humans and pigs. Humans, especially children, experience significant morbidity including respiratory complications, growth deficits and intestinal obstruction. Given that 800 million people worldwide are infected by Ascaris, this represents a significant global public health concern. The severity of the symptoms and associated morbidity are related to the parasite burden and not all hosts are infected equally. While the pathology of the disease has been extensively examined, our understanding of the molecular mechanisms underlying resistance and susceptibility to this nematode infection is poor. In order to investigate host differences associated with heavy and light parasite burden, an experimental murine model was developed utilising Ascaris-susceptible and -resistant mice strains, C57BL/6J and CBA/Ca, respectively, which experience differential burdens of migratory Ascaris larvae in the host lungs. Previous studies identified the liver as the site where this difference in susceptibility occurs. Using a label free quantitative proteomic approach, we analysed the hepatic proteomes of day four post infection C57BL/6J and CBA/Ca mice with and without Ascaris infection to identify proteins changes potentially linked to both resistance and susceptibility amongst the two strains, respectively. Over 3000 proteins were identified in total and clear intrinsic differences were elucidated between the two strains. These included a higher abundance of mitochondrial proteins, particularly those associated with the oxidative phosphorylation pathway and reactive oxygen species (ROS) production in the relatively resistant CBA/Ca mice. We hypothesise that the increased ROS levels associated with higher levels of mitochondrial activity results in a highly oxidative cellular environment that has a dramatic effect on the nematode's ability to successfully sustain a parasitic association with its resistant host. Under infection, both

  19. A Proteomic Investigation of Hepatic Resistance to Ascaris in a Murine Model

    PubMed Central

    Deslyper, Gwendoline; Colgan, Thomas J.; Cooper, Andrew J. R.; Holland, Celia V.; Carolan, James C.

    2016-01-01

    The helminth Ascaris causes ascariasis in both humans and pigs. Humans, especially children, experience significant morbidity including respiratory complications, growth deficits and intestinal obstruction. Given that 800 million people worldwide are infected by Ascaris, this represents a significant global public health concern. The severity of the symptoms and associated morbidity are related to the parasite burden and not all hosts are infected equally. While the pathology of the disease has been extensively examined, our understanding of the molecular mechanisms underlying resistance and susceptibility to this nematode infection is poor. In order to investigate host differences associated with heavy and light parasite burden, an experimental murine model was developed utilising Ascaris-susceptible and -resistant mice strains, C57BL/6J and CBA/Ca, respectively, which experience differential burdens of migratory Ascaris larvae in the host lungs. Previous studies identified the liver as the site where this difference in susceptibility occurs. Using a label free quantitative proteomic approach, we analysed the hepatic proteomes of day four post infection C57BL/6J and CBA/Ca mice with and without Ascaris infection to identify proteins changes potentially linked to both resistance and susceptibility amongst the two strains, respectively. Over 3000 proteins were identified in total and clear intrinsic differences were elucidated between the two strains. These included a higher abundance of mitochondrial proteins, particularly those associated with the oxidative phosphorylation pathway and reactive oxygen species (ROS) production in the relatively resistant CBA/Ca mice. We hypothesise that the increased ROS levels associated with higher levels of mitochondrial activity results in a highly oxidative cellular environment that has a dramatic effect on the nematode’s ability to successfully sustain a parasitic association with its resistant host. Under infection, both

  20. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver.

    PubMed

    Savransky, Vladimir; Bevans, Shannon; Nanayakkara, Ashika; Li, Jianguo; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

    2007-10-01

    Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

  1. Hepatic Overexpression of Hemopexin Inhibits Inflammation and Vascular Stasis in Murine Models of Sickle Cell Disease.

    PubMed

    Vercellotti, Gregory M; Zhang, Ping; Nguyen, Julia; Abdulla, Fuad; Chen, Chunsheng; Nguyen, Phong; Nowotny, Carlos; Steer, Clifford J; Smith, Ann; Belcher, John D

    2016-07-19

    Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesize that in SCD mice, hepatic overexpression of hemopexin will scavenge the proximal mediator of vascular activation, heme, and will inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx(-/-) or Hpx(+/+) C57BL/6 mice. Dorsal skin fold chambers were implanted in week 13 post-transplant and microvascular stasis (% non-flowing venules) evaluated in response to heme infusion. Hpx(-/-) sickle mice had significantly greater microvascular stasis in response to heme infusion than Hpx(+/+) sickle mice (p<0.05), demonstrating the protective effect of Hpx in SCD. We utilized Sleeping Beauty (SB) transposon-mediated gene transfer to overexpress wild-type rat Hpx (wt-Hpx) in NY1DD and Townes-SS SCD mice. Control SCD mice were treated with lactated Ringer's solution (LRS) or a luciferase (Luc) plasmid. Plasma and hepatic Hpx were significantly increased compared to LRS and Luc controls. Microvascular stasis in response to heme infusion in NY1DD and Townes-SS mice overexpressing wt-Hpx had significantly less stasis than controls (p<0.05). Wt-Hpx overexpression markedly increased hepatic nuclear Nrf2 expression, HO-1 activity and protein, the heme-Hpx binding protein and scavenger receptor, CD91/LRP1 and decreased NF-κB activation. Two missense (ms)-Hpx SB-constructs that bound neither heme nor the Hpx receptor, CD91/LRP1, did not prevent heme-induced stasis. In conclusion, increasing Hpx levels in transgenic sickle mice via gene transfer activates the Nrf2/HO-1 anti-oxidant axis and ameliorates inflammation and vaso-occlusion.

  2. Hepatic Overexpression of Hemopexin Inhibits Inflammation and Vascular Stasis in Murine Models of Sickle Cell Disease

    PubMed Central

    Vercellotti, Gregory M; Zhang, Ping; Nguyen, Julia; Abdulla, Fuad; Chen, Chunsheng; Nguyen, Phong; Nowotny, Carlos; Steer, Clifford J; Smith, Ann; Belcher, John D

    2016-01-01

    Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesized that in SCD mice, hepatic overexpression of hemopexin would scavenge the proximal mediator of vascular activation, heme, and inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx-/- or Hpx+/+ C57BL/6 mice. Dorsal skin fold chambers were implanted 13 wks post-transplant, and microvascular stasis (% nonflowing venules) was evaluated in response to heme infusion. Hpx-/- sickle mice had significantly greater microvascular stasis in response to heme infusion than Hpx+/+ sickle mice (p < 0.05), demonstrating the protective effect of Hpx in SCD. We utilized Sleeping Beauty (SB) transposon-mediated gene transfer to overexpress wild-type rat Hpx (wt-Hpx) in NY1DD and Townes-SS SCD mice. Control SCD mice were treated with lactated Ringer’s solution (LRS) or a luciferase (Luc) plasmid. Plasma and hepatic Hpx were significantly increased compared with LRS and Luc controls. Microvascular stasis in response to heme infusion in NY1DD and Townes-SS mice overexpressing wt-Hpx had significantly less stasis than controls (p < 0.05). Wt-Hpx overexpression markedly increased hepatic nuclear Nrf2 expression, HO-1 activity and protein, and the heme-Hpx binding protein and scavenger receptor CD91/LRP1, and decreased NF-κB activation. Two missense (ms)-Hpx SB constructs that bound neither heme nor the Hpx receptor CD91/LRP1 did not prevent heme-induced stasis. In conclusion, increasing Hpx levels in transgenic sickle mice via gene transfer activates the Nrf2/HO-1 antioxidant axis and ameliorates inflammation and vasoocclusion. PMID:27451971

  3. Estimating Functional Liver Reserve Following Hepatic Irradiation: Adaptive Normal Tissue Response Models

    PubMed Central

    Stenmark, Matthew H.; Cao, Yue; Wang, Hesheng; Jackson, Andrew; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

    2014-01-01

    Purpose To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. Materials and Methods From 2005–2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1−(ICG-R15pre-RT/ICG-R15post-RT)] where no toxicity was observed using a beta distribution function. Results Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of ≥78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p<0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. Conclusion The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient’s tolerance to hepatic irradiation. PMID:24813090

  4. Green tea polyphenol epigallocatechin-3-gallate inhibits oxidative damage and preventive effects on carbon tetrachloride-induced hepatic fibrosis.

    PubMed

    Zhen, Mao-Chuan; Wang, Qian; Huang, Xiao-Hui; Cao, Liang-Qi; Chen, Xi-Ling; Sun, Kai; Liu, Yun-Jian; Li, Wen; Zhang, Long-Juan

    2007-12-01

    The aim of the study was to examine the effects of epigallocatechin-3-gallate (EGCG) on hepatic fibrogenesis and on cultured hepatic stellate cells (HSCs). The rat model of carbon tetrachloride (CCl(4))-induced hepatic fibrosis was used to assess the effect of daily intraperitoneal injections of EGCG on the indexes of fibrosis. Histological and hepatic hydroxyproline examination revealed that EGCG significantly arrested progression of hepatic fibrosis. EGCG caused significant amelioration of liver injury (reduced activities of serum alanine aminotransferase and aspartate aminotransferase). The development of CCl(4)-induced hepatic fibrosis altered the redox state with a decreased hepatic glutathione and increased the formation of lipid peroxidative products, which were partially normalized by treatment with EGCG, respectively. Moreover, EGCG markedly attenuated HSC activation as well as matrix metalloproteinase (MMP)-2 activity. In cultured stellate cell, the expression of MMP-2 mRNA and protein were substantially reduced by EGCG treatment. Concanavalin A-induced activation of secreted MMP-2 was inhibited by EGCG through the influence of membrane type 1-MMP activity. These results demonstrate that administration of EGCG may be useful in the treatment and prevention of hepatic fibrosis.

  5. Protective Effect of Baccharis trimera Extract on Acute Hepatic Injury in a Model of Inflammation Induced by Acetaminophen

    PubMed Central

    Pádua, Bruno da Cruz; Rossoni Júnior, Joamyr Victor; de Brito Magalhães, Cíntia Lopes; Chaves, Míriam Martins; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia; de Souza, Gustavo Henrique Bianco; Brandão, Geraldo Célio; Rodrigues, Ivanildes Vasconcelos; Lima, Wanderson Geraldo; Costa, Daniela Caldeira

    2014-01-01

    Background. Acetaminophen (APAP) is a commonly used analgesic and antipyretic. When administered in high doses, APAP is a clinical problem in the US and Europe, often resulting in severe liver injury and potentially acute liver failure. Studies have demonstrated that antioxidants and anti-inflammatory agents effectively protect against the acute hepatotoxicity induced by APAP overdose. Methods. The present study attempted to investigate the protective effect of B. trimera against APAP-induced hepatic damage in rats. The liver-function markers ALT and AST, biomarkers of oxidative stress, antioxidant parameters, and histopathological changes were examined. Results. The pretreatment with B. trimera attenuated serum activities of ALT and AST that were enhanced by administration of APAP. Furthermore, pretreatment with the extract decreases the activity of the enzyme SOD and increases the activity of catalase and the concentration of total glutathione. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by APAP. Conclusions. The hepatoprotective action of B. trimera extract may rely on its effect on reducing the oxidative stress caused by APAP-induced hepatic damage in a rat model. General Significance. These results make the extract of B. trimera a potential candidate drug capable of protecting the liver against damage caused by APAP overdose. PMID:25435714

  6. Transplacental Transfer of Hepatitis B Neutralizing Antibody during Pregnancy in an Animal Model: Implications for Newborn and Maternal Health

    PubMed Central

    Ma, Li; Norton, Malgorzata G.; Mahmood, Iftekhar; Zhao, Zhong; Zhong, Lilin; Zhang, Pei; Struble, Evi B.

    2014-01-01

    Despite the success of postexposure prophylaxis (PEP) of the newborn in preventing mother-to-child transmission of hepatitis B virus), in non-US clinical trials, administering hepatitis B immune globulin (HBIG) to mothers at the end of pregnancy (in addition to passive-active PEP of the newborn) only partially improved outcomes. That is, a significant percentage of newborns became infected during their first year of life. We used a relevant animal model for human IgG transplacental transfer to study dose, time and subclass dependence of HBV neutralizing antibody (nAb) maternal, and fetal levels at the end of pregnancy. Pregnant guinea pigs received 50 or 100 IU/kg HBIGIV 2–5 days before delivery. Human total IgG, IgG subclasses, and nAb in mothers and their litters were measured. In vitro analyses of guinea pig Fc neonatal receptor binding to HBIGIV, as well as to all human IgG subclasses, were also performed. Our study showed that nAb transferred transplacentally from the pregnant guinea pigs to their litters; no transfer occurred during parturition. The amount of the transferred nAb was dose and time dependent. Thus, selection of an efficacious dose in the clinic is important: microdosing may be underdosing, particularly in cases of high viraemia. PMID:24800066

  7. Oral administered particulate yeast-derived glucan promotes hepatitis B virus clearance in a hydrodynamic injection mouse model.

    PubMed

    Yu, Xiaoyu; Zhang, Dandan; Shi, Bisheng; Ren, Guangxu; Peng, Xiuhua; Fang, Zhong; Kozlowski, Maya; Zhou, Xiaohui; Zhang, Xiaonan; Wu, Min; Wang, Cong; Yuan, Zhenghong

    2015-01-01

    Hepatitis B virus (HBV) persistent infection is associated with ineffective immune response for the clearance of virus. Immunomodulators represent an important class of therapeutics, which potentially could be beneficial for the treatment of HBV infection. The particulate yeast-derived glucan (PYDG) has been shown to enhance the innate and adaptive immune responses. We therefore, assessed the efficacy of PYDG in enhancing HBV specific immune responses by employing the hydrodynamic injection-based (HDI) HBV transfection mouse model. Mice were intragatric administered PYDG daily for 9 weeks post pAAV/HBV1.2 hydrodynamic injection. PYDG treatment significantly promoted HBV DNA clearance and production of HBsAb compared to control mice. PYDG treatment resulted in recruitment of macrophages, dendritic cells (DCs) and effector T cells to the liver microenvironment, accompanied by a significantly augmented DCs maturation and HBV-specific IFN-γ and TNF-α production by T cell. In addition, enhanced production of Th1 cytokines in liver tissue interstitial fluid (TIF) was associated with PYDG administration. Live imaging showed the accumulation of PYDG in the mouse liver. Our results demonstrate that PYDG treatment significantly enhances HBV-specific Th1 immune responses, accompanied by clearance of HBV DNA, and therefore holds promise for further development of therapeutics against chronic hepatitis B.

  8. Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

    PubMed Central

    Wang, Jizhou; Lu, Zhaoyang; Xu, Zhilin; Tian, Pei; Miao, Hui; Pan, Shangha; Song, Ruipeng; Sun, Xueying; Zhao, Baolei; Wang, Dawei; Ma, Yong; Song, Xuan; Zhang, Shugeng; Liu, Lianxin; Jiang, Hongchi

    2017-01-01

    Hypoxia-inducible factor (HIF)-1α and HIF-2α play an important role in liver fibrosis. von Hippel–Lindau protein (VHL), a key mediator of HIF-α, regulates fibrosis in an organ- and cell-specific way. In this study, human liver samples were collected from hepatitis C-, alcoholic-, and cholestatic-associated fibrotic and healthy individuals. Two mouse models of liver fibrosis were established: bile duct ligation and carbon tetrachloride injection. We constructed adenovirus vectors to overexpress VHL, normoxia-active HIF-α, and lentiviral vectors to silence HIF-α. The results showed that liver sections from fibrosis patients had a lower level of VHL and higher levels of HIF-1α and HIF-2α compared with healthy sections, a finding which was confirmed in mice. Overexpression of VHL attenuated liver fibrosis, downregulated fibrogenic genes, and inhibited liver inflammation, apoptosis, and angiogenesis. Overexpression of VHL was more successful at inhibiting fibrosis compared with silencing HIF-1α plus HIF-2α. Normoxia-active HIF-1α or HIF-2α prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1α- and HIF-2α-dependent to some extent. In addition, overexpression of VHL inhibited mouse hepatic stellate cells activation and proliferation and promoted apoptosis. Taken together, VHL may be considered a new target to inhibit liver fibrosis. PMID:28112200

  9. Shear Wave Elastography for Assessment of Steatohepatitis and Hepatic Fibrosis in Rat Models of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Kang, Bo-Kyeong; Lee, Seung Soo; Cheong, Hyunhee; Hong, Seung Mo; Jang, Kiseok; Lee, Moon-Gyu

    2015-12-01

    The purpose of this study was to evaluate shear wave elastography (SWE) as a method for determining the severity of non-alcoholic fatty liver disease (NAFLD) and the stage of hepatic fibrosis, as well as the major determinants of liver elasticity among the various histologic and biomolecular changes associated with NAFLD. Rat NAFLD models with various degrees of NAFLD severity were created and imaged using SWE. The explanted livers were subjected to histopathologic evaluation and RNA expression analysis. Among the histologic and biomolecular findings, the fibrosis stage and the collagen RNA level were significant independent factors associated with liver elasticity (p < 0.001). Liver elasticity was effective in detecting non-alcoholic steatohepatitis (NASH) and in determining fibrosis stage, and the corresponding areas under the receiver operating characteristic curves were 0.963 and 0.927-0.997, respectively. In conclusion, SWE is a potential non-invasive method for the detection of NASH and staging of hepatic fibrosis in patients with NAFLD.

  10. Hepatitis A

    MedlinePlus

    ... inflammation of the liver.” This inflammation can be caused by a wide variety of toxins, drugs, and metabolic diseases, as well as infection. There are at least 5 hepatitis viruses. Hepatitis A is contracted when a child eats food or drinks water that is contaminated with the virus or has ...

  11. Hepatitis A

    MedlinePlus

    ... MW, Sheffield JS. Prevention and management of viral hepatitis in pregnancy. Obstetrics and Gynecology Clinics of North America . 2014;41(4):573–592. [4] Centers for Disease Control and Prevention. Chapter 9: Hepatitis A. In Hamborsky J, Kroger A, Wolfe S, eds. ...

  12. Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B

    PubMed Central

    Cheng, Jieyao; Hou, Jinlin; Ding, Huiguo; Chen, Guofeng; Xie, Qing; Wang, Yuming; Zeng, Minde; Ou, Xiaojuan; Ma, Hong; Jia, Jidong

    2015-01-01

    Background and Aims Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients. Methods The diagnostic performance of ten noninvasive models (HALF index, FibroScan, S index, Zeng model, Youyi model, Hui model, APAG, APRI, FIB-4 and FibroTest) was assessed against the liver histology by ROC curve analysis in CHB patients. The reproducibility of the ten models were evaluated by recalculating the diagnostic values at the given cut-off values defined by the original studies. Results Six models (HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest) had AUROCs higher than 0.70 in predicting any fibrosis stage and 2 of them had best diagnostic performance with AUROCs to predict F≥2, F≥3 and F4 being 0.83, 0.89 and 0.89 for HALF index, 0.82, 0.87 and 0.87 for FibroScan, respectively. Four models (HALF index, FibroScan, Zeng model and Youyi model) showed good diagnostic values at given cut-offs. Conclusions HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest show a good diagnostic performance and all of them, except S index and FibroTest, have good reproducibility for evaluating liver fibrosis in CHB patients. Registration Number ChiCTR-DCS-07000039. PMID:26709706

  13. Validation of ⁹⁹mTechnetium-labeled mebrofenin hepatic extraction method to quantify meal-induced splanchnic blood flow responses using a porcine model.

    PubMed

    Zacho, Helle Damgaard; Kristensen, Niels Bastian; Henriksen, Jens Henrik; Abrahamsen, Jan

    2012-03-01

    The aim of this study was to evaluate the measurement of the total splanchnic blood flow (SBF) using a clinical diagnostic method based on Fick's principle and hepatic extraction of 99mTc-mebrofenin (99mTc-MBF) compared with a paraaminohippuric acid (pAH) dilution method in a porcine model. Another aim was to investigate whether enterohepatic cycling of 99mTc-MBF affected the SBF measurement. Five indwelling catheters were placed in each pig (n = 15) in the portal, mesenteric, and hepatic veins, as well as in the aorta and the vena cava. The SBF was measured using both methods. The portal blood flow; the intestinal and hepatic oxygen uptake; the net fluxes of oxygen, lactate, and glucose; and the extraction fraction (EF) of 99mTc-MBF were measured before and for 70 min after feeding. The mean baseline SBF was 2,961 ml/min vs. 2,762 ml/min measured by pAH and 99mTc-MBF, respectively, and increased significantly to 3,977 ml/min and 3,981 ml/min postprandially. The hepatic EF of 99mTc-MBF decreased from 40% at the start of the investigation to 16% 70 min after feeding. The arterial-portal difference in 99mTc-MBF concentration was 0.21% (P = 0.48), indicating no intestinal extraction or metabolism. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is robust compared with the indicator dilution method, despite the decrease seen in hepatic extraction of 99mTc-MBF. Because there was no difference in the content of 99mTc-MBF between the arterial and portal vein plasma, the SBF can be calculated from an arterial and a hepatic vein sample.

  14. Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma.

    PubMed

    Al-Harbi, Naif O; Nadeem, Ahmed; Al-Harbi, Mohammed M; Ansari, Mushtaq A; AlSharari, Shakir D; Bahashwan, Saleh A; Attia, Sabry M; Al-Hosaini, Khaled A; Al Hoshani, Ali R; Ahmad, Sheikh F

    2016-05-01

    Oxidants are generated in asthmatic airways due to infiltration of inflammatory leukocytes and resident cells in the lung. Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide radical may leak into systemic circulation when generated in uncontrolled manner and may impact vasculature. Our previous studies have shown an association between airway inflammation and systemic inflammation; however so far none has investigated the impact of airway oxidative inflammation on hepatic oxidative stress and Th1/Th2/Th17 cytokine markers in liver/vasculature in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of systemic/hepatic Th1/Th2/Th17 cytokines balance and hepatic oxidative stress. Mice were sensitized intraperitoneally with cockroach extract (CE) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with CE. Mice were then assessed for systemic/hepatic inflammation through assessment of Th1/Th2/Th17 cytokines and oxidative stress (iNOS, protein nitrotyrosine, lipid peroxides and myeloperoxidase activity). Challenge with CE led to increased Th2/Th17 cytokines in blood/liver and hepatic oxidative stress. However, only Th17 related pro-inflammatory markers were upregulated by hydrogen peroxide (H2O2) inhalation in vasculature and liver, whereas antioxidant treatment, N-acetyl cysteine (NAC) downregulated them. Hepatic oxidative stress was also upregulated by H2O2 inhalation, whereas NAC attenuated it. Therefore, our study shows that airway oxidative inflammation may contribute to systemic inflammation through upregulation of Th17 immune responses in blood/liver and hepatic oxidative stress. This might predispose these patients to increased risk for the development of cardiovascular disorders.

  15. A model of interaction: aflatoxins and hepatitis viruses in liver cancer aetiology and prevention.

    PubMed

    Wild, Christopher P; Montesano, Ruggero

    2009-12-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Saharan Africa where the major risk factors are chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins. Aflatoxin B1, the most commonly occurring and potent of the aflatoxins is associated with a specific AGG to AGT transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease. Prospective epidemiological studies have shown a more than multiplicative interaction between HBV and aflatoxins in terms of HCC risk. However, the biology underlying this statistical interaction is not fully understood. There are a number of potential mechanisms including, among others: the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection; the predisposition of HBV-infected hepatocytes to aflatoxin-induced DNA damage; an increase in susceptibility to chronic HBV infection in aflatoxin-exposed individuals; and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection. Priorities for prevention are global HBV vaccination, primary and secondary prevention strategies against aflatoxin and the avoidance of transmission of HCV through good hygiene practices.

  16. Chunggan extract, a traditional herbal formula, ameliorated alcohol-induced hepatic injury in rat model

    PubMed Central

    Kim, Hyeong-Geug; Kim, Jung-Min; Han, Jong-Min; Lee, Jin-Seok; Choi, Min-Kyung; Lee, Dong-Soo; Park, Yeon-Hwa; Son, Chang-Gue

    2014-01-01

    AIM: To evaluate protective effects of Chunggan extract (CGX), a traditional herbal formula, under 4 wk of alcohol consumption-induced liver injury. METHODS: Male Sprague-Dawley Rats were orally administered 30% ethanol daily for 4 wk with or without CGX. The pharmaceutical properties were assessed through liver enzymes, histopathology, fibrogenic cytokines, and alcohol metabolism in hepatic tissues as well as by in vitro experiment using HSC-T6 cells. RESULTS: Four weeks of alcohol consumption notably increased liver enzymes and malondialdehyde levels in serum and hepatic tissue. CGX not only prevented the collagen deposition determined by histopathology and hydroxyproline content, but also normalized transforming growth factor-beta, platelet-derived growth factor-beta and connective tissue growth factor at the gene expression and protein levels in liver tissue. Moreover, CGX treatment also significantly normalized the abnormal changes in gene expression profiles of extracellular matrix proteins, matrix metalloproteinase and their inhibitors, alcohol metabolism, and inflammatory reactions. In the acetaldehyde-stimulated HSC-T6 cells, CGX considerably inhibited collagen production and normalized fibrogenic cytokines in both gene expression and protein levels. CONCLUSION: The present study evidenced that CGX has hepatoprotective properties via modulation of fibrogenic cytokines and alcohol metabolism in alcoholic liver injury. PMID:25400454

  17. Polymyxin B protects against hepatic ischemia/reperfusion injury in a rat model of obstructive jaundice.

    PubMed

    Xu, Feng; Dai, Chao-Liu; Peng, Song-Lin; Zhao, Yang; Jia, Chang-Jun; Xu, Yong-Qing; Zhao, Chuang

    2014-08-01

    This study was conducted in order to investigate the effects of polymyxin B (PMB) against hepatic ischemia/reperfusion (I/R) injury in rats with obstructive jaundice. Thirty-six Wistar rats (eighteen each) with induced hepatic I/R injury by biliary tract ligation and recanalization were assigned to a control group (reperfused with normal saline) and a PMB group (reperfused with PMB). Indicators involving liver function, oxidation resistance, pro-inflammatory state, and anti-apoptosis effect were determined following the instructions. Compared with normal saline, PMB reperfusion resulted in a significant improvement of liver function (increase of glutathione and reduction of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), oxidation resistance (decreased malondialdehyde and myeloperoxidase activity), alleviation of pro-inflammatory state (less tumor necrosis factor (TNF)-α, interleukin-1 beta (IL-1β), nuclear factor kappa B (NF-κB) mRNA, and intercellular adhesion molecule (ICAM)-1), and anti-apoptosis effect (more Bcl-2 and less Bax). PMB protects the liver from I/R injury mainly through reducing cellular oncosis and apoptosis and regulating the expression of NF-κB, TNF-α, IL-1β, and ICAM-1.

  18. Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy*

    PubMed Central

    König, Matthias; Holzhütter, Hermann-Georg

    2012-01-01

    A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM. PMID:22977253

  19. Predicting carrier-mediated hepatic disposition of rosuvastatin in man by scaling from individual transfected cell-lines in vitro using absolute transporter protein quantification and PBPK modeling.

    PubMed

    Bosgra, Sieto; van de Steeg, Evita; Vlaming, Maria L; Verhoeckx, Kitty C; Huisman, Maarten T; Verwei, Miriam; Wortelboer, Heleen M

    2014-12-18

    In contrast to primary hepatocytes, estimating carrier-mediated hepatic disposition by using a panel of single transfected cell-lines provides direct information on the contribution of the individual transporters to the net disposition. The most direct way to correct for differences in transporter abundance between cell-lines and tissue is by using absolute protein quantification. In the present study, the performance of this strategy to predict human hepatic uptake transport was investigated and compared with traditional scaling from primary human hepatocytes. Rosuvastatin was used as a model compound. The uptake activity was measured in HEK293 cell-lines stably overexpressing OATP1B1(∗)1a, OATP1B3 or OATP2B1, the major transporters involved in human hepatic uptake of rosuvastatin, or expressing OATP1B1(∗)15, associated with reduced hepatic uptake of rosuvastatin. The abundance of these transporter proteins in the outer membranes of HEK293-cells, in human primary hepatocytes and in human liver tissue was determined by LC-MS/MS. The measured activity, corrected for protein abundance and scaled to the whole liver, gave a very accurate prediction of the hepatic intrinsic clearance observed in vivo. Embedded in a PBPK model describing the hepatic disposition and enterohepatic circulation, the collective in vitro data resulted in a good explanation of the observed oral and intravenous pharmacokinetic profiles of rosuvastatin. The model allowed simulation of the effect of polymorphic variants of OATP1B1 on rosuvastatin pharmacokinetics. These results encourage a larger scale validation. This approach may facilitate prediction of drug-drug interactions, scaling of transporter processes across subpopulations (children, diseased patients), and may be extended to tissues for which primary cells may be more difficult to obtain. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model.

    PubMed

    Tzeng, Horng-Tay; Tsai, Hwei-Fang; Chyuan, I-Tsu; Liao, Hsiu-Jung; Chen, Chun-Jen; Chen, Pei-Jer; Hsu, Ping-Ning

    2014-01-01

    Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.

  1. Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.

    PubMed

    Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M; Wiltrout, Robert H; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A; Manns, Michael P; Wang, Ena; Marincola, Francesco M; Korangy, Firouzeh; Greten, Tim F

    2015-04-01

    Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b(+) Gr-1(+) cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b(+) Gr-1(+) cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+) Gr-1(+) MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.

  2. Establishing a new animal model for hepadnaviral infection: susceptibility of Chinese Marmota-species to woodchuck hepatitis virus infection.

    PubMed

    Wang, Bao-Ju; Tian, Yong-Jun; Meng, Zhong-Ji; Jiang, Min; Wei, Bo-Qing; Tao, Yuan-Qing; Fan, Wei; Li, An-Yi; Bao, Jun-Jie; Li, Xin-Yu; Zhang, Zheng-Mao; Wang, Zhong-Dong; Wang, Hu; Roggendorf, Michael; Lu, Meng-Ji; Yang, Dong-Liang

    2011-03-01

    Hepatitis B virus infection (HBV) is a major medical problem in China. The lack of a suitable infection model in China is recognized as an obstacle for research on HBV in China. Chinese Marmota-species is phylogenetically closely related to Marmota monax, thus, it might be suitable to serve as an animal model for HBV infection. Therefore, we attempted to prove the claim about the existence of woodchuck hepatitis virus (WHV)-like viruses in Chinese Marmota-species and to determine the susceptibility of these species to experimental WHV infection. In the present study, 653 sera from three Chinese Marmota-species, Marmota himalayana, Marmota baibacina and Marmota bobak, were screened for WHV-like viruses by serological and molecular assays. The susceptibility to WHV of three species was investigated by experimental infection and monitored by testing of anti-WHc and WHsAg by ELISA, detection of WHV DNA by PCR, and detection of WHV replication intermediates and antigens in liver samples. No evidence for the existence of a genetically closely related virus to WHV in three Chinese Marmota-species was found by serological assays and PCR. M. himalayana was susceptible to WHV infection as inoculated animals became positive for anti-WHc, WHsAg and WHV DNA. Further, WHV replication intermediates and proteins were detected in liver samples. In contrast, M. baibacina remained negative for tested virological parameters. M. bobak species showed a limited susceptibility to WHV. Our data do not support early reports about WHV-like viruses in China. M. himalayana is suitable for the establishment of a model for hepadnaviral infection.

  3. Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation.

    PubMed

    Allweiss, Lena; Gass, Sofia; Giersch, Katja; Groth, Anne; Kah, Janine; Volz, Tassilo; Rapp, Gianna; Schöbel, Anja; Lohse, Ansgar W; Polywka, Susanne; Pischke, Sven; Herker, Eva; Dandri, Maura; Lütgehetmann, Marc

    2016-05-01

    Hepatitis E virus (HEV) is a major cause of acute hepatitis as well as chronic infection in immunocompromised individuals; however, in vivo infection models are limited. The aim of this study was to establish a small animal model to improve our understanding of HEV replication mechanisms and permit the development of effective therapeutics. UPA/SCID/beige mice repopulated with primary human hepatocytes were used for infection experiments with HEV genotype (GT) 1 and 3. Virological parameters were determined at the serological and intrahepatic level by real time PCR, immunohistochemistry and RNA in situ hybridization. Establishment of HEV infection was achieved after intravenous injection of stool-derived virions and following co-housing with HEV-infected animals but not via inoculation of serum-derived HEV. GT 1 infection resulted in a rapid rise of viremia and high stable titres in serum, liver, bile and faeces of infected mice for more than 25 weeks. In contrast, viremia in GT 3 infected mice developed more slowly and displayed lower titres in all analysed tissues as compared to GT 1. HEV-infected human hepatocytes could be visualized using HEV ORF2 and ORF3 specific antibodies and HEV RNA in situ hybridization probes. Finally, six-week administration of ribavirin led to a strong reduction of viral replication in the serum and liver of GT 1 infected mice. We established an efficient model of HEV infection to test the efficacy of antiviral agents and to exploit mechanisms of HEV replication and interaction with human hepatocytes in vivo. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  4. Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago

    SciTech Connect

    Echevarria, Desarae; Gutfraind, Alexander; Boodram, Basmattee; Major, Marian; Del Valle, Sara; Cotler, Scott J.; Dahari, Harel

    2015-08-21

    New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). In our paper, we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago.

  5. The Efficacy of Social Role Models to Increase Motivation to Obtain Vaccination against Hepatitis B among Men Who Have Sex with Men

    ERIC Educational Resources Information Center

    Vet, R.; de Wit, J. B. F.; Das, E.

    2011-01-01

    This study assessed the effects of role models in persuasive messages about risk and social norms to increase motivation to obtain hepatitis B virus (HBV) vaccination in men who have sex with men (MSM). MSM at risk for HBV in The Netherlands (N = 168) were recruited online via a range of websites and were randomly assigned to one of four…

  6. Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago

    DOE PAGES

    Echevarria, Desarae; Gutfraind, Alexander; Boodram, Basmattee; ...

    2015-08-21

    New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago.

  7. Application of a Physiologically Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation: Utility of In Vitro and In Vivo Data

    PubMed Central

    Gill, Katherine L.; Gertz, Michael; Houston, J. Brian

    2013-01-01

    A physiologically based pharmacokinetic (PBPK) modeling approach was used to assess the prediction accuracy of propofol hepatic and extrahepatic metabolic clearance and to address previously reported underprediction of in vivo clearance based on static in vitro–in vivo extrapolation methods. The predictive capacity of propofol intrinsic clearance data (CLint) obtained in human hepatocytes and liver and kidney microsomes was assessed using the PBPK model developed in MATLAB software. Microsomal data obtained by both substrate depletion and metabolite formation methods and in the presence of 2% bovine serum albumin were considered in the analysis. Incorporation of hepatic and renal in vitro metabolic clearance in the PBPK model resulted in underprediction of propofol clearance regardless of the source of in vitro data; the predicted value did not exceed 35% of the observed clearance. Subsequently, propofol clinical data from three dose levels in intact patients and anhepatic subjects were used for the optimization of hepatic and renal CLint in a simultaneous fitting routine. Optimization process highlighted that renal glucuronidation clearance was underpredicted to a greater extent than liver clearance, requiring empirical scaling factors of 17 and 9, respectively. The use of optimized clearance parameters predicted hepatic and renal extraction ratios within 20% of the observed values, reported in an additional independent clinical study. This study highlights the complexity involved in assessing the contribution of extrahepatic clearance mechanisms and illustrates the application of PBPK modeling, in conjunction with clinical data, to assess prediction of clearance from in vitro data for each tissue individually. PMID:23303442

  8. Antitumor effects of FP3 in combination with capecitabine on PDTT xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases.

    PubMed

    Jin, Ketao; Lan, Huanrong; Xie, Bojian; He, Kuifeng; Xu, Zhenzhen; Li, Guangliang; Han, Na; Teng, Lisong; Cao, Feilin

    2012-07-01

    FP3 is an engineered protein which contains the extracellular domain 2 of VEGF receptor 1 (Flt-1) and extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G 1. Previous studies demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with capecitabine. Xenografts were treated with FP3, capecitabine, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, and PCNA in the tumor were examined by immunohistonchamical staining, level of thymidine phosphorylase (TP) was examined by ELISA, and levels of related cell signaling pathways proteins expression were examined by western blotting. FP3 in combination with capecitabine showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with capecitabine was lower than that of the control. Antitumor activity of FP3 in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). This study indicated that addition of FP3 to capecitabine significantly improved tumor growth inhibition in the PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.

  9. The Efficacy of Social Role Models to Increase Motivation to Obtain Vaccination against Hepatitis B among Men Who Have Sex with Men

    ERIC Educational Resources Information Center

    Vet, R.; de Wit, J. B. F.; Das, E.

    2011-01-01

    This study assessed the effects of role models in persuasive messages about risk and social norms to increase motivation to obtain hepatitis B virus (HBV) vaccination in men who have sex with men (MSM). MSM at risk for HBV in The Netherlands (N = 168) were recruited online via a range of websites and were randomly assigned to one of four…

  10. [Joint application of mathematic models in assessing the residual risk of hepatitis C virus transmitted through blood transfusion].

    PubMed

    Wang, Xun; Jia, Yao; Xie, Yun-zheng; Li, Xiu-mei; Liu, Xiao-ying; Wu, Xiao-fei

    2011-09-01

    The practicable and effective methods for residual risk assessment on transfusion-transmitted disease was to establish the mathematic models. Based on the characteristics of the repeat donors which donated their blood on a regular base, a model of sero-conversion during the interval of donations was established to assess the incidence of the repeat donors. Based on the characteristics of the prevalence in the population, a model of 'prevalence increased with the age of the donor' was established to assess the incidence of those first-time donors. And based on the impact of the windows period through blood screening program, a model of residual risk associated with the incidence and the length of the windows period was established to assess the residual risk of blood transfusion. In this paper, above said 3 kinds of mathematic models were jointly applied to assess the residual risk of hepatitis C virus (HCV) which was transmitted through blood transfusion in Shanghai, based on data from the routine blood collection and screening program. All the anti-HCV unqualified blood donations were confirmed before assessment. Results showed that the residual risk of HCV transmitted through blood transfusion during Jan. 1(st), 2007 to Dec. 31(st), 2008 in Shanghai was 1:101 000. Data showed that the results of residual risk assessment with mathematic models was valuable. The residual risk of transfusion-transmitted HCV in Shanghai was at a safe level, according to the results in this paper.

  11. A mathematical model for HIV and hepatitis C co-infection and its assessment from a statistical perspective.

    PubMed

    Castro Sanchez, Amparo Yovanna; Aerts, Marc; Shkedy, Ziv; Vickerman, Peter; Faggiano, Fabrizio; Salamina, Guiseppe; Hens, Niel

    2013-03-01

    The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are a clear threat for public health, with high prevalences especially in high risk groups such as injecting drug users. People with HIV infection who are also infected by HCV suffer from a more rapid progression to HCV-related liver disease and have an increased risk for cirrhosis and liver cancer. Quantifying the impact of HIV and HCV co-infection is therefore of great importance. We propose a new joint mathematical model accounting for co-infection with the two viruses in the context of injecting drug users (IDUs). Statistical concepts and methods are used to assess the model from a statistical perspective, in order to get further insights in: (i) the comparison and selection of optional model components, (ii) the unknown values of the numerous model parameters, (iii) the parameters to which the model is most 'sensitive' and (iv) the combinations or patterns of values in the high-dimensional parameter space which are most supported by the data. Data from a longitudinal study of heroin users in Italy are used to illustrate the application of the proposed joint model and its statistical assessment. The parameters associated with contact rates (sharing syringes) and the transmission rates per syringe-sharing event are shown to play a major role.

  12. Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment.

    PubMed

    Chaudhari, Pooja; Tian, Lipeng; Deshmukh, Abhijeet; Jang, Yoon-Young

    2016-09-01

    Due to the limitations of research using human embryos and the lack of a biological model of human liver development, the roles of the various markers associated with liver stem or progenitor cell potential in humans are largely speculative, and based on studies utilizing animal models and certain patient tissues. Human pluripotent stem cell-based in vitro multistage hepatic differentiation systems may serve as good surrogate models for mimicking normal human liver development, pathogenesis and injury/regeneration studies. Here, we describe the implications of various liver stem or progenitor cell markers and their bipotency (i.e. hepatocytic- and biliary-epithelial cell differentiation), based on the pluripotent stem cell-derived model of human liver development. Future studies using the human cellular model(s) of liver and biliary development will provide more human relevant biological and/or pathological roles of distinct markers expressed in heterogeneous liver stem/progenitor cell populations. © 2016 by the Society for Experimental Biology and Medicine.

  13. Safety limit of large-volume hepatic radiofrequency ablation in a rat model.

    PubMed

    Ng, Kelvin K; Lam, Chi Ming; Poon, Ronnie T; Shek, Tony W; Ho, David W; Fan, Sheung Tat

    2006-03-01

    Large-volume hepatic radiofrequency ablation (RFA) has been used to treat large liver tumors, but its safety limit is unknown. This study aimed to investigate the possible systemic responses of large-volume hepatic RFA and to estimate its safety limit in normal and cirrhotic rats. Large-volume hepatic RFA causes a significant systemic inflammatory reaction. Experimental study. University teaching hospital. Using the Cool-tip RF System (Radionics, Burlington, Mass), RFA was performed for different percentages of the liver volume by weight in normal and cirrhotic Sprague-Dawley rats. Changes in concentrations of serum inflammatory markers (tumor necrosis factor alpha [TNF-alpha] and interleukin [IL] 6), functions of various end organs, and survival rates were assessed. In the normal liver groups, the concentrations of TNF-alpha and IL-6 were significantly elevated in the early postoperative period when 50% (mean +/- SD TNF-alpha concentration, 130.3 +/- 15.6 pg/mL; mean +/- SD IL-6 concentration, 163.2 +/- 12.2 pg/mL) and 60% (mean +/- SD TNF-alpha concentration, 145.7 +/- 13.0 pg/mL; mean +/- SD IL-6 concentration, 180.8 +/- 11.0 pg/mL) of the liver volume were ablated compared with the control group (mean +/- SD TNF-alpha concentration, 30.4 +/- 9.9 pg/mL, P<.001; mean +/- SD IL-6 concentration, 28.4 +/- 6.7 pg/mL, P<.001). The concentrations of TNF-alpha and IL-6 in other groups remained similar to those in the control group. Thrombocytopenia, prolonged clotting time, and interstitial pneumonitis occurred when 50% and 60% of the liver volume were ablated. The 4-week survival rates were 100%, 60%, and 0% when 40%, 50%, and 60%, respectively, of the liver volume were ablated. Similar systemic inflammatory responses and poor survival rates were observed among the cirrhotic liver groups when 30% and 40% of the liver volume were ablated. The normal rats can tolerate RFA of 40% of the liver volume with minimal morbidity and no mortality whereas the cirrhotic rats can

  14. Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling.

    PubMed

    Kratochwil, Nicole A; Meille, Christophe; Fowler, Stephen; Klammers, Florian; Ekiciler, Aynur; Molitor, Birgit; Simon, Sandrine; Walter, Isabelle; McGinnis, Claudia; Walther, Johanna; Leonard, Brian; Triyatni, Miriam; Javanbakht, Hassan; Funk, Christoph; Schuler, Franz; Lavé, Thierry; Parrott, Neil J

    2017-03-01

    Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HμREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. For in vitro to in vivo extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the in vivo situation in these long-term culture models.

  15. Hepatic excretory function in sepsis: implications from biophotonic analysis of transcellular xenobiotic transport in a rodent model

    PubMed Central

    2013-01-01

    Introduction Hepatobiliary elimination of endo- and xenobiotics is affected by different variables including hepatic perfusion, hepatocellular energy state and functional integrity of transporter proteins, all of which are altered during sepsis. A particular impairment of hepatocellular transport at the canalicular pole resulting in an accumulation of potentially hepatotoxic compounds would have major implications for critical care pharmacology and diagnostics. Methods Hepatic transcellular transport, that is, uptake and hepatobiliary excretion, was studied in a rodent model of severe polymicrobial sepsis by two different biophotonic techniques to obtain insights into the handling of potentially toxic endo- and xenobiotics in sepsis. Direct and indirect in vivo imaging of the liver was performed by intravital multifluorescence microscopy and non-invasive whole-body near-infrared (NIRF) imaging after administration of two different, primarily hepatobiliary excreted xenobiotics, the organic anionic dyes indocyanine green (ICG) and DY635. Subsequent quantitative data analysis enabled assessment of hepatic uptake and fate of these model substrates under conditions of sepsis. Results Fifteen hours after sepsis induction, animals displayed clinical and laboratory signs of multiple organ dysfunction, including moderate liver injury, cholestasis and an impairment of sinusoidal perfusion. With respect to hepatocellular transport of both dyes, excretion into bile was significantly delayed for both dyes and resulted in net accumulation of potentially cytotoxic xenobiotics in the liver parenchyma (for example, specific dye fluorescence in liver at 30 minutes in sham versus sepsis: ICG: 75% versus 89%; DY635 20% versus 40% of maximum fluorescence; P < 0.05). Transcutaneous assessment of ICG fluorescence by whole body NIRF imaging revealed a significant increase of ICG fluorescence from the 30th minute on in the bowel region of the abdomen in sham but not in septic animals

  16. Differential effect of corn oil-based low trans structured fat on the plasma and hepatic lipid profile in an atherogenic mouse model: comparison to hydrogenated trans fat

    PubMed Central

    2011-01-01

    Background Trans fat are not desirable in many aspects on health maintenance. Low trans structured fats have been reported to be relatively more safe than trans fats. Methods We examined the effects of low trans structured fat from corn oil (LC), compared with high trans fat shortening, on cholesterol and fatty acid metabolism in apo E deficient mice which is an atherogenic animal model. The animals were fed a high trans fat (10% fat: commercial shortening (CS)) or a low trans fat (LC) diet for 12 weeks. Results LC decreased apo B and hepatic cholesterol and triglyceride concentration compared to the CS group but significantly increased plasma total cholesterol and triglyceride concentration and fecal lipids with a simultaneous increase in HDL-cholesterol level, apo A-I, and the ratio of HDL-cholesterol to total cholesterol (HTR). Reduction of hepatic lipid levels by inclusion of LC intake was observed alongside modulation of hepatic enzyme activities related to cholesterol esterification, fatty acid metabolism and fecal lipids level compared to the CS group. The differential effects of LC intake on the plasma and hepatic lipid profile seemed to be partly due to the fatty acid composition of LC which contains higher MUFA, PUFA and SFA content as well as lower content of trans fatty acids compared to CS. Conclusions We suggest that LC may exert a dual effect on plasma and hepatic lipid metabolism in an atherogenic animal model. Accordingly, LC, supplemented at 10% in diet, had an anti-atherogenic effect on these apo E-/- mice, and increased fecal lipids, decreased hepatic steatosis, but elevated plasma lipids. Further studies are needed to verify the exact mode of action regarding the complex physiological changes and alteration in lipid metabolism caused by LC. PMID:21247503

  17. Efficient Delivery of DOX to Nuclei of Hepatic Carcinoma Cells in the Subcutaneous Tumor Model Using pH-Sensitive Pullulan-DOX Conjugates.

    PubMed

    Li, Huanan; Cui, Yani; Sui, Junhui; Bian, Shaoquan; Sun, Yong; Liang, Jie; Fan, Yujiang; Zhang, Xingdong

    2015-07-29

    A series of pullulan-doxorubicin conjugates (Pu-DOXs) were investigated for effectively delivering DOX to nuclei of hepatic carcinoma cells in subcutaneous tumor model. These Pu-DOXs were prepared by conjugating DOX onto pullulan molecule via pH-responsive hydrazone bond using spacers with different alkane chain length. The highest drug loading content of Pu-DOXs went up to nearly 50%, and the diameter of Pu-DOX nanoparticles ranged from 50 to 170 nm, as measured by DLS and TEM. These Pu-DOX nanoparticles could rapidly release DOX in the acidic environment at pH = 5.0 while being kept relatively stable in neural conditions. The in vitro cell coculture experiments revealed that these Pu-DOX nanoparticles were selectively internalized by hepatic carcinoma cells through receptor-mediated endocytosis via asialoglycoprotein receptor on the hepatic carcinoma cell surface. DOX was rapidly released from Pu-DOX nanoparticles in acidic endosome/lysosome, diffused into cell nuclei due to its strong affinity to nucleic acid, inhibited the cell proliferation, and accelerated the cell apoptosis. In the nude mice subcutaneous hepatic carcinoma model, Pu-DOX nanoparticles efficiently accumulated in the tumor site through the enhanced permeation and retention effect. Then DOX was specifically internalized by hepatic carcinoma cells and rapidly diffused into the nuclei of cells. Compared with the control group in in vivo experiments, these Pu-DOX nanoparticles effectively inhibited solid tumor growth, prolonging the lifetime of the experimental animal. These pH sensitive nanoparticles might provide an important clinical implication for targeted hepatic carcinoma therapy with high efficiency and low systematic toxicity.

  18. Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model.

    PubMed

    Anderson, Gail D; Peterson, Todd C; Vonder Haar, Cole; Farin, Fred M; Bammler, Theo K; MacDonald, James W; Kantor, Eric D; Hoane, Michael R

    2015-09-01

    In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.

  19. Cutthroat Trout Virus—Towards a Virus Model to Support Hepatitis E Research

    PubMed Central

    von Nordheim, Marcus; Boinay, Michel; Leisi, Remo; Kempf, Christoph; Ros, Carlos

    2016-01-01

    Cutthroat trout virus (CTV) is a non-pathogenic fish virus belonging to the Hepeviridae family, and it is distantly related to hepatitis E virus (HEV). Here, we report the development of an efficient cell culture system where CTV can consistently replicate to titers never observed before with a hepevirus. By using the rainbow trout gill (RTGill-W1) cell line, CTV reaches 1010 geq/mL intracellularly and 109 geq/mL extracellularly within 5–6 days in culture. We additionally established a qPCR system to investigate CTV infectivity, and developed a specific antibody directed against the viral capsid protein encoded by ORF2. With these methods, we were able to follow the progressive accumulation of viral RNA and the capsid protein, and their intracellular distribution during virus replication. Virus progeny purified through iodixanol density gradients indicated—that similar to HEV—CTV produced in cell culture is also lipid-associated. The lack of an efficient cell culture system has greatly impeded studies with HEV, a major human pathogen that causes hepatitis worldwide. Although several cell culture systems have recently been established, the replication efficiency of HEV is not robust enough to allow studies on different aspects of the virus replication cycle. Therefore, a surrogate virus that can replicate easily and efficiently in cultured cells would be helpful to boost research studies with hepeviruses. Due to its similarities, but also its key differences to HEV, CTV represents a promising tool to elucidate aspects of the replication cycle of Hepeviridae in general, and HEV in particular. PMID:27775612

  20. Weight loss enhances hepatic antioxidant status in a NAFLD model induced by high fat diet.

    PubMed

    Mendes, Iara Karise Santos; Matsuura, Cristiane; Aguila, Marcia Barbosa; Daleprane, Julio Beltrame; Martins, Marcela Anjos; Mury, Wanda Vianna; Brunini, Tatiana Marlowe Cunha

    2017-08-23

    Nonalcoholic fatty liver disease (NAFLD) is a benign condition that can progress to more severe liver damage in a process mediated, in part, by disturbances in redox balance. Additionally, some argue that it is set to become the main cause of end-stage liver disease in the near future. Here, we investigated whether a diet-induced weight loss is able to reverse hepatic lipid accumulation and to reduce oxidative stress in liver from C57BL/6 mice fed a high-fat (HF) diet. Male C57BL/6 mice were divided into four groups: SC (standard chow, 10% energy from fat, 16 wk); HF (high fat diet, 50% energy from fat, 16 wk); SC-HF (SC 8 wk followed by HF 8 wk); and HF-SC (HF 8 wk followed by SC 8 wk). The HF diet during 8 (SC-HF) and 16 weeks (HF) downregulated mRNA levels and protein expression of Nrf2 and endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) in the liver, caused liver steatosis, affected liver function markers, increased intra-abdominal and subcutaneous adipose tissue, and induced glucose intolerance and hypercholesterolemia compared to controls (SC). Diet-induced weight loss significantly reduced the intrahepatic lipid accumulation, improved glucose tolerance, and restored both gene and protein expression of the antioxidant enzymes. Our findings suggest that a dietary intervention aimed to induce weight loss may exert protective effects in NAFLD as it can reduce hepatic oxidative stress and intrahepatic lipid accumulation, which can hinder the progression of this condition to more severe states.

  1. Cutthroat Trout Virus-Towards a Virus Model to Support Hepatitis E Research.

    PubMed

    von Nordheim, Marcus; Boinay, Michel; Leisi, Remo; Kempf, Christoph; Ros, Carlos

    2016-10-20

    Cutthroat trout virus (CTV) is a non-pathogenic fish virus belonging to the Hepeviridae family, and it is distantly related to hepatitis E virus (HEV). Here, we report the development of an efficient cell culture system where CTV can consistently replicate to titers never observed before with a hepevirus. By using the rainbow trout gill (RTGill-W1) cell line, CTV reaches 10(10) geq/mL intracellularly and 10⁸ geq/mL extracellularly within 5-6 days in culture. We additionally established a qPCR system to investigate CTV infectivity, and developed a specific antibody directed against the viral capsid protein encoded by ORF2. With these methods, we were able to follow the progressive accumulation of viral RNA and the capsid protein, and their intracellular distribution during virus replication. Virus progeny purified through iodixanol density gradients indicated-that similar to HEV-CTV produced in cell culture is also lipid-associated. The lack of an efficient cell culture system has greatly impeded studies with HEV, a major human pathogen that causes hepatitis worldwide. Although several cell culture systems have recently been established, the replication efficiency of HEV is not robust enough to allow studies on different aspects of the virus replication cycle. Therefore, a surrogate virus that can replicate easily and efficiently in cultured cells would be helpful to boost research studies with hepeviruses. Due to its similarities, but also its key differences to HEV, CTV represents a promising tool to elucidate aspects of the replication cycle of Hepeviridae in general, and HEV in particular.

  2. Fucoidan reduces inflammatory response in a rat model of hepatic ischemia-reperfusion injury.

    PubMed

    Li, Xiao-Jing; Ye, Qi-Fa

    2015-11-01

    Ischemia-reperfusion (I/R) injury after a liver transplant is a major cause of severe complications that lead to graft dysfunction. Fucoidan, a complex of sulfated polysaccharides derived from marine brown algae, demonstrated antiapoptotic as well as potential anti-inflammatory properties in previous studies. Fucoidan has also shown protective effects on I/R-injured kidney and heart. However, whether fucoidan can attenuate hepatic I/R injury has not been examined. To clarify the role of fucoidan in hepatic I/R injury, Sprague-Dawley rats were subjected to sham operation or ischemia followed by reperfusion with treatment of saline or fucoidan (50, 100, or 200 mg·(kg body mass)(-1)·d(-1)). The fucoidan-treated group showed decreased levels of alanine aminotransferase and aspartate aminotransferase compared with the control group. Myeloperoxidase and malondialdehyde activities and mRNA levels of CD11b in the fucoidan-treated group were significantly decreased. Hepatocellular swelling/necrosis, sinusoidal/vascular congestion, and inflammatory cell infiltration were also attenuated in the fucoidan group. The expression of TNF-α, IL-6, IL-1β, CXCL-10, VCAM-1, and ICAM-1 were markedly decreased in the samples from the fucoidan-treated group. Fucoidan largely prevented activation of the inflammatory signaling pathway, compared with the control group. In summary, fucoidan can protect the liver from I/R injury through suppressing activation of the inflammatory signaling pathway, as well as the expression of inflammatory mediators, and inflammatory cell infiltration.

  3. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis.

    PubMed

    Klein, Thomas; Fujii, Masato; Sandel, Jan; Shibazaki, Yuichiro; Wakamatsu, Kyoko; Mark, Michael; Yoneyama, Hiroyuki

    2014-09-01

    Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Dipeptidyl peptidase (DPP)-4 inhibitors are established therapies for type 2 diabetes and although DPP-4 inhibitors can reduce hepatic steatosis, their impact on local inflammation and fibrosis in NASH remains unknown. Using two different experimental treatment regimens (4- and 2-week treatments) in streptozotocin-treated neonatal mice on a high-fat diet, we show that the DPP-4 inhibitor linagliptin (10 and 30 mg/kg) significantly attenuated the NAS score from 4.9 ± 0.6 to 3.7 ± 0.4 and 3.6 ± 0.3, respectively, in the 4-week study. In the 2-week study, linagliptin 10 mg/kg significantly reduced NAS score from 4.1 ± 0.4 to 2.4 ± 0.4. Telmisartan was used as a positive control in both studies and lowered NAS score to 1.9 ± 0.7 and 1.4 ± 0.3, respectively. Due to streptozotocin treatment, elevated glucose levels were unchanged by either drug treatment. Further, linagliptin 10 mg/kg significantly reduced mRNA levels of SOCS-3 (from 1.68 ± 0.2 to 0.83 ± 0.08), IFN-γ (from 4.0 ± 0.5 to 2.3 ± 0.3), and TNF-α (from 5.7 ± 0.5 to 2.13 ± 0.3). The latter observation was confirmed by immunohistochemistry of TNF-α in liver specimens. In addition, using microautoradiography, we showed that the distribution of radiolabeled linagliptin was heterogeneous with the highest density associated with interlobular bile ducts and portal tracts (acini). In conclusion, these studies confirm that linagliptin has high exposure in hepatic tissue and has both anti-inflammatory and anti-steatotic activity in NASH.

  4. Hepatic ischemia

    MedlinePlus

    ... blood or oxygen, causing injury to liver cells. Causes Low blood pressure from any condition can lead to hepatic ischemia. ... liver's blood vessels Treatment Treatment depends on the cause. Low blood pressure and blood clots must be treated right away. ...

  5. Hepatitis C

    MedlinePlus

    ... a mother who had hepatitis C Received a tattoo or acupuncture with needles that were not disinfected ... is very low with practitioners who have a tattoo license or permit or an acupuncture license) Received ...

  6. Autoimmune hepatitis.

    PubMed

    Heneghan, Michael A; Yeoman, Andrew D; Verma, Sumita; Smith, Alastair D; Longhi, Maria Serena

    2013-10-26

    Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.

  7. Autoimmune Hepatitis

    MedlinePlus

    ... the same symptoms as those of other liver diseases or metabolic disorders. Blood tests. A blood test involves drawing ... the same symptoms as those of other liver diseases or metabolic disorders. Treatment for autoimmune hepatitis includes medication to ...

  8. Hepatic Encephalopathy

    MedlinePlus Videos and Cool Tools

    ... is a condition that causes temporary worsening of brain function in people with advanced liver disease. When ... travel through your body until they reach your brain, causing mental and physical symptoms of HE. Hepatic ...

  9. Hepatitis B

    MedlinePlus

    ... My Health e Vet Prescriptions Refills Crisis Prevention Mental Health PTSD Public Health Veterans Access, Choice & Accountability Act ... and Complementary Therapies Diet and Nutrition Managing Pain Mental Health Sex and Sexuality (for Hepatitis C) Success Stories ...

  10. Alcoholic Hepatitis

    MedlinePlus

    ... alcoholic hepatitis include: Fluid accumulation in your abdomen (ascites) Confusion and behavior changes due to a buildup ... is life-threatening and requires immediate medical care. Ascites. Fluid that accumulates in the abdomen might become ...

  11. Hepatitis A

    MedlinePlus

    ... bowel movements Loss of appetite Low-grade fever Dark urine Joint pain Yellowing of the skin and ... person ingests even tiny amounts of contaminated fecal matter. The hepatitis A virus infects liver cells and ...

  12. Developmental changes in hepatic glucose metabolism in a newborn piglet model: A comparative analysis for suckling period and early weaning period.

    PubMed

    Xie, Chunyan; Wang, Qinhua; Wang, Jing; Tan, Bie; Fan, Zhiyong; Deng, Ze-yuan; Wu, Xin; Yin, Yulong

    2016-02-19

    The liver glucose metabolism, supplying sufficient energy for glucose-dependent tissues, is important in suckling or weaned animals, although there are few studies with piglet model. To better understand the development of glucose metabolism in the piglets during suckling period and early weaning period, we determined the hepatic glycogen content, and investigated the relative protein expression of key enzymes of glucogenesis (GNG) and mRNA levels of some glucose metabolism-related genes. During suckling period, the protein level of G6Pase in the liver of suckling piglets progressively declined with day of age compared with that of newborn piglets (at 1 day of age), whereas the PEPCK level stabilized until day 21 of age, indicating that hepatic GNG capacity gradually weakened in suckling piglets. The synthesis of hepatic glycogen, which was consistent with the fluctuation of glycolytic key genes PFKL and PKLR that gradually decreased after birth and was more or less steady during latter suckling period, although both the mRNA levels of GCK and key glucose transporter GLUT2 presented uptrend in suckling piglets. However, early weaning significantly suppressed the hepatic GNG in the weaned piglets, especially at d 3-5 of weaning period, then gradually recovered at d 7 of weaning period. Meanwhile, PFKL, PKLR and GLUT2 showed the similar trend during weaning period. On the contrast, the hepatic glycogen reached the maximum value when the G6Pase and PEPCK protein expression were at the lowest level, although the GCK level maintained increasing through 7 days of weaning period. Altogether, our study provides evidence that hepatic GNG and glycolysis in newborn piglets were more active than other days during suckling period, and early weaning could significantly suppressed glucose metabolism in liver, but this inhibition would progressively recover at day 7 after weaning.

  13. Validation of the Model for End-Stage Liver Disease Score Criteria in Urgent Liver Transplantation for Acute Flare Up of Hepatitis B

    PubMed Central

    Lee, Wei-Chen; Lee, Ching-Song; Wang, Yu-Chao; Cheng, Chih-Hsien; Wu, Tsung-Han; Lee, Chen-Fang; Soong, Ruey-Shyang; Chang, Ming-Ling; Wu, Ting-Jung; Chou, Hong-Shiue; Chan, Kun-Ming

    2016-01-01

    Abstract Acute flare up of hepatitis B in noncirrhotic liver with rapid liver function deterioration is a critical condition. This flare up of hepatitis B may be subsided under medical treatments, otherwise urgent liver transplantation is needed. However, the necessity of urgent liver transplantation is hard to decide. In this institute, the indications of urgent liver transplantation for acute flare up of hepatitis B in noncirrhotic liver were settled according to the model for end-stage liver disease (MELD) scores: once upon MELD scores ≥35 (criterion 1) or MELD score < 35 at beginning and increased in the subsequent 1 to 2 weeks (criterion 2). This study was to examine whether MELD score criteria for liver transplantation were valid in such an urgent condition. Eighty-three patients having acute flare up of hepatitis B virus with total bilirubin ≥17.5 mg/dL were included in this study. Among 83 patients, 20 patients met criterion 1. Five patients were transplanted and 15 patients died of liver failure with a median survival of 17 days. Fifty-one patients met criterion 2. Nineteen were transplanted, 30 patients died of liver failure with a median survival of 23.5 days, and 2 patients recovered from this critical condition. The other 12 patients did not meet criteria 1 and 2, and urgent liver transplantation was spared although 5 patients needed liver transplantation in subsequent 2 to 3 months. Therefore, the sensitivity of MELD score criteria for urgent liver transplantation was 100% and specificity was 85.7%. In conclusion, determination of urgent liver transplantation for hepatitis B with acute liver failure is crucial. MELD score criteria are valid to make a decision of urgent liver transplantation for hepatitis B patients with acute flare up and liver failure. PMID:27258492

  14. Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

    PubMed Central

    Alexandropoulos, Konstantina; Bonito, Anthony J.; Weinstein, Erica G.; Herbin, Olivier

    2015-01-01

    Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease. PMID:25603179

  15. The transmission dynamics of hepatitis B in the UK: a mathematical model for evaluating costs and effectiveness of immunization programmes.

    PubMed Central

    Williams, J. R.; Nokes, D. J.; Medley, G. F.; Anderson, R. M.

    1996-01-01

    Complex hepatitis B (HBV) epidemiology makes it difficult to evaluate and compare effectiveness of different immunization policies. A method for doing so is presented using a mathematical model of HBV transmission dynamics which can represent universal infant and adolescent vaccination strategies and those targeted at genito-urinary (GU) clinic attenders and infants born to infectious mothers. Model structure, epidemiological underpinning, and parameterization, are described. Data from the UK National Survey of Sexual Attitudes and Lifestyles is used to define patterns of sexual activity and GU clinic attendance; data deficiencies are discussed, in particular that of UK seroprevalence of HBV markers stratified by age, sex, and risk factors. General model predictions of endemic HBV marker prevalence in homosexual and heterosexual populations seem consistent with published UK data. The simulations exhibit non-linearities in the impact of different vaccination strategies. Estimated number of carriers prevented per vaccine dose for each strategy provides a measure of costs and benefits, varying temporally over the course of a programme, and with level of vaccine coverage. Screening before vaccination markedly increases payback per dose in homosexuals but not in heterosexuals; mass infant vaccination gives the poorest effectiveness ratio and vaccination of infants after antenatal screening the best; in general, increasing vaccine coverage yields lower pay-back per dose. The model provides a useful framework for evaluating costs and benefits of immunization programmes, but for precise quantitative comparison more UK epidemiological data is urgently needed. PMID:8626006

  16. A model-based meta-analysis of sofosbuvir-based treatments in chronic hepatitis C patients.

    PubMed

    Pérez-Pitarch, Alejandro; Guglieri-López, Beatriz; Ferriols-Lisart, Rafael; Merino-Sanjuán, Matilde

    2016-03-01

    The objective of this study was to compare the efficacy of sofosbuvir-based treatments in patients with chronic hepatitis C virus (HCV) infection using a model-based meta-analysis (MBMA). A bibliographic search was performed to identify clinical trials involving sofosbuvir as a unique direct-acting antiviral (DAA) agent or together with daclatasvir, ledipasvir or simeprevir for the treatment of diagnosed HCV infection. The time course of the virological response (VR) was modelled to estimate the effect of treatment and the influence of population characteristics on the longitudinal efficacy profile. The model was validated and simulations of 10 different treatment schedules were performed. Data from 19 clinical trials were included in the analysis. According to the developed model, therapy with sofosbuvir+ledipasvir is the most effective therapy in all scenarios, but it does not differ greatly in terms of sustained VR with respect to other combinations of DAA treatments. In conclusion, this MBMA generates knowledge regarding hypothetical head-to-head trials that have not been conducted previously. Therapies with sofosbuvir+ledipasvir are probably the most effective sofosbuvir-based treatments.

  17. A predictive model for carcinogenesis in patients with chronic hepatitis B undergoing entecavir therapy and its validation.

    PubMed

    Nishikawa, Hiroki; Nishijima, Norihiro; Enomoto, Hirayuki; Sakamoto, Azusa; Nasu, Akihiro; Komekado, Hideyuki; Nishimura, Takashi; Kita, Ryuichi; Kimura, Toru; Iijima, Hiroko; Nishiguchi, Shuhei; Osaki, Yukio

    2016-09-01

    We created a model to predict the development of liver carcinogenesis in patients with chronic hepatitis B (CHB) undergoing entecavir (ETV) therapy and to validate the accuracy using an independent dataset.A total of 328 CHB subjects were analyzed. Subjects were randomly assigned into 2 groups: the training group (n = 164) and the validation group (n = 164). Using data from the training group, we built a predictive model for liver carcinogenesis by performing univariate and multivariate analyses using variables associated with liver carcinogenesis. We subsequently assessed the applicability of the constructed model in the validation group.The median (range) follow-up periods in the training and the validation groups were 5.03 years (1.03-9.98) and 4.84 years (1.10-9.97), respectively. The proportion of hepatitis B virus-DNA at 24 weeks <1.9 log IU/mL in the training group was 70.7% (116/164), while that in the validation group was 71.3% (117/164). For the entire cohort (n = 328), the median alpha-fetoprotein (AFP) value at 24 weeks (3.45 ng/mL; range, 0.9-102.7 ng/mL) significantly decreased compared to the baseline values (5.55 ng/mL; range, 0.9-1039.5 ng/mL), while the median alanine aminotransferase (ALT) value at 24 weeks (24 IU/mL; range, 6-251 IU/mL) also significantly decreased compared to baseline values (57 IU/mL; range, 7-1450 IU/mL). During the observation period, hepatocellular carcinoma (HCC) developed in 15 (9.1%) patients in the training group and in 17 (10.4%) patients in the validation group. The 3- and 5-year cumulative HCC incidence rates in the entire cohort were 4.48% and 9.52%, respectively. In the multivariate analysis of the training group, age ≥54 years (P = 0.0273), ALT level at 24 weeks (P = 0.0456), and AFP at 24 weeks (P = 0.0485) were found to be significant predictors linked to HCC. Using these independent predictors, the risk for HCC development was well stratified in the validation group (overall significance

  18. Diagnostic potential of serum direct markers and non-invasive fibrosis models in patients with chronic hepatitis B.

    PubMed

    Gümüşay, Ozge; Ozenirler, Seren; Atak, Ayşegül; Sönmez, Cemile; Ozkan, Seçil; Tuncel, Ayşe Fıtnat; Yılmaz, Güldal; Akyol, Gülen

    2013-03-01

      Liver biopsy is recommended in the majority of patients with chronic viral hepatitis for fibrosis evaluation. Because of the disadvantages of liver biopsy, many studies related to non-invasive biomarkers and scores have been performed. In this study, we aimed to assess the diagnostic value of serum direct markers and non-invasive fibrosis models to predict liver fibrosis in the treatment-naive chronic hepatitis B (CHB) patients and to compare their diagnostic performance.   This study included 58 patients with a diagnosis of CHB virus infection and 30 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase 1 and amino-terminal propeptide of type III procollagen were measured by enzyme-linked immunosorbent assay; and the Original European Liver Fibrosis panel, the Enhanced Liver Fibrosis (ELF) panel, PP score, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 indexes were calculated using the formulas taken from previous publications. Fibrosis stage was determined using Ishak's scoring system.   The fibrosis stages identified upon liver biopsy was F0 in 12 patients (20.7%), F1-2 in 36 (62.1%) and F3-5 in 10 (17.2%). The diagnostic value of all the non-invasive indices was low to detect mild fibrosis. We demonstrated that the diagnostic accuracy of HA is the best for predicting fibrosis of F3 or more (area under the receiver-operator curve, 0.902). In our study, the results from a combination of tests showed that ELF and APRI had the highest diagnostic value sensitivity of 90%, specificity of 100%, positive predictive value of 100% and negative predictive value of 96.4% for detection of fibrosis of F3 or more.   In CHB patients, combination of ELF and APRI has a better diagnostic value in predicting fibrosis of F3 or more. © 2012 The Japan Society of Hepatology.

  19. Establishment of an in-use testing method for evaluating disinfection of surgical instruments using the duck hepatitis B model.

    PubMed

    Deva, A K; Vickery, K; Zou, J; West, R H; Harris, J P; Cossart, Y E

    1996-06-01

    Nosocomial transmission of hepatitis B virus (HBV), associated with interventional procedures, has been attributed to its survival on improperly decontaminated instruments. To date, guidelines for chemical disinfection of potentially contaminated heat-sensitive instruments have been based largely on extrapolation of data from in-vitro disinfectant testing. Direct infectivity testing has not been possible for HBV because of the lack of a practical culture assay or susceptible experimental animal model. In this study the related duck hepadnavirus was used to simulate in-vivo transmission of a HBV during surgery, and to evaluate the effectiveness of 2% glutaraldehyde disinfection of surgical laparoscopes. Multiple laparoscopic liver biopsies were performed on 'biohazardous' duck hepatitis B (DHBV) positive ducks. Laparoscopes were then subjected to different disinfection regimes using 2% glutaraldehyde, and residual infectivity tested by placing their tips into the peritoneal cavities of uninfected four-day-old ducklings. Direct transmission of DHBV occurred in all ducks when laparoscopes were not washed. Rinsing with water lowered the transmission rate to 64% and no infection transmission occurred after 5 min of contact time with the disinfectant. In contrast, previous in-vitro studies had shown complete viral inactivation after a shorter period of disinfection. It is postulated that the longer inactivation time observed in our study may be a result of surface interactions of virus and instrument, interfering with disinfectant access or activity. Tests of instrument surface samples for viral DNA by the polymerase chain reaction (PCR) did not correlate with transmission of virus infection in vivo. PCR is an inappropriate test for evaluating the efficacy of disinfectant action despite its sensitivity. This in use method will allow testing of other decontamination procedures and their effectiveness on more complex surgical instruments.

  20. Antifibrotic effects of Artemisia capillaris and Artemisia iwayomogi in a carbon tetrachloride-induced chronic hepatic fibrosis animal model.

    PubMed

    Wang, Jing-Hua; Choi, Min-Kyung; Shin, Jang-Woo; Hwang, Seock-Yeon; Son, Chang-Gue

    2012-03-06

    Artemisia capillaris and Artemisia iwayomogi, both members of the Compositae family, have been indiscriminately used for various liver disorders as traditional hepatotherapeutic medicines in Korea for many years. In this study, the anti-hepatofibrotic effects of Artemisia capillaris and Artemisia iwayomogi were comparatively analyzed using a carbon tetrachloride (CCl(4))-induced liver fibrosis rat model. Hepatic fibrosis was induced via a 10-week course of intraperitoneal CCl(4) injections (50% dissolved in olive oil, 2mL/kg, twice per week). Water extract of Artemisia capillaris (AC) or Artemisia iwayomogi (AI) was orally administered six times per week from the 5th to the 10th week. AI (50mg/kg) significantly attenuated the CCl(4)-induced excessive release of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in serum (p<0.05), and hydroxyproline and malondialdehyde (MDA) contents in liver tissue (p<0.05). Further, AI markedly ameliorated the depletion of total antioxidant capacity (TAC), glutathione (GSH), and superoxide dismutase (SOD) in liver tissue (p<0.01). Unexpectedly, AC did not exert any effects on the above parameters. Histopathological and immunohistochemical analyses revealed that AI drastically reduced inflammation, necrosis, fatty infiltration, collagen accumulation, and activation of hepatic satellite cells in liver tissue. These changes were not observed with AC treatment. Several critical genes of fibrosis-related cytokines including transforming growth factor beta (TGF-β), platelet-derived growth factor beta (PDGF-β), and alpha smooth muscle actin (α-SMA) were more prominently downregulated by AI compared to AC treatment. Our results show that AI exerts greater hepatoprotective and anti-fibrotic effects as compared with AC via enhancing antioxidant capacity and downregulating fibrogentic cytokines. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. Hepatitis (For Parents)

    MedlinePlus

    ... people at risk for contracting hepatitis. But frequent hand washing and good hygiene practices can reduce this risk. ... After Having Hepatitis B? Hepatitis B (HBV) Hepatitis Hand Washing Blood Transfusions Body Piercing Tattoos Contact Us Print ...

  2. Hepatitis A Test

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Hepatitis A Testing Share this page: Was this page ... HAV-Ab total; Anti-HAV Formal name: Viral Hepatitis A Antibody Related tests: Hepatitis B Testing ; Hepatitis ...

  3. Hepatitis B Foundation

    MedlinePlus

    ... worldwide 2 Billion People have been infected with Hepatitis B Worldwide The Hepatitis B Foundation is working ... of people living with hepatitis B. Learn About Hepatitis B in 11 Other Languages . Resource Video See ...

  4. Hepatitis A - Multiple Languages

    MedlinePlus

    ... Hepatitis A Vaccine: What You Need to Know - English Vaccine Information Statement (VIS) -- Hepatitis A Vaccine: What ... Hepatitis A Vaccine: What You Need to Know - English Vaccine Information Statement (VIS) -- Hepatitis A Vaccine: What ...

  5. Metabolomic analysis reveals hepatic metabolite perturbations in citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice, a model of human citrin deficiency.

    PubMed

    Saheki, Takeyori; Inoue, Kanako; Ono, Hiromi; Tushima, Anmi; Katsura, Natsumi; Yokogawa, Mana; Yoshidumi, Yukari; Kuhara, Tomiko; Ohse, Morimasa; Eto, Kazuhiro; Kadowaki, Takashi; Sinasac, David S; Kobayashi, Keiko

    2011-12-01

    The citrin/mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis and adult-onset type II citrullinemia, making it a suitable model of human citrin deficiency. In the present study, we investigated metabolic disturbances in the livers of wild-type, citrin (Ctrn) knockout, mGPD knockout, and Ctrn/mGPD double-knockout mice following oral sucrose versus saline administration using metabolomic approaches. By using gas chromatography/mass spectrometry and capillary electrophoresis/mass spectrometry, we found three general groupings of metabolite changes in the livers of the double-knockout mice following sucrose administration that were subsequently confirmed using liquid chromatography/mass spectrometry or enzymatic methods: a marked increase of hepatic glycerol 3-phosphate, a generalized decrease of hepatic tricarboxylic acid cycle intermediates, and alterations of hepatic amino acid levels related to the urea cycle or lysine catabolism including marked increases in citrulline and lysine. Furthermore, concurrent oral administration of sodium pyruvate with sucrose ameliorated the hyperammonemia induced by sucrose, as had been shown previously, as well as almost completely normalizing the hepatic metabolite perturbations found. Overall, we have identified additional metabolic disturbances in double-KO mice following oral sucrose administration, and provided further evidence for the therapeutic use of sodium pyruvate in our mouse model of citrin deficiency. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Simplified technique for 75% and 90% hepatic resection with hemodynamic monitoring in a large white swine model.

    PubMed

    Bucur, Petru; Bekheit, Mohamed; Audebert, Chloe; Vignon-Clementel, Irene; Vibert, Eric

    2017-03-01

    Accurate measuring of the hepatic hemodynamic parameters in humans is inconvenient. Swine has been a favorite surgical model for the study of liver conditions due to many similarities with human livers. However, pigs cannot tolerate pedicle clamping and to reduce bleeding during resection a simplified technique is required. The aim of this study is to present a simplified technique for different percentages of hepatic resection in a porcine model. Twenty-two consecutive large white pigs were operated with 75% and 90% liver resection. Computarized tomography liver volumetry is performed before and after surgery. In both types of surgery, hemodynamic monitoring was performed using a specialized apparatus. Resections were performed in both groups successfully. The residual volume in the planned 75% was 235 ± 77 mL and 118 ± 119 mL in the planned 90% resection. For 75% resection, the portal flow was reduced after resection by 8.13 ± 28%, which might be part of systemic circulatory depression. However, the portal pressure increased by 20.1 ± 51%. The hepatic artery flow decreased by 63.86 ± 26.3% as well as the pressure by 5 ± 28%. The central venous pressure at the start of surgery was 3.34 ± 1.9 mm Hg and 2.8 ± 2.2 mm Hg at the end of surgery. The portacaval pressure gradient was 4.4 ± 2.9 mm Hg at the beginning of surgery and was 5.9 ± 2.8 mm Hg at the end of surgery. For 90% resection, the portal flow decreased by 33.6 ± 12.6% and the pressure increased by 104 ± 58%. The hepatic artery flow decreased by 88 ± 7%, and the pressure decreased by 5 ± 14.8%. The central venous pressure was 3.5 ± 1.7 mm Hg before resection and 3 ± 2.5 mm Hg after resection. The portacaval pressure gradient was 3.8 ± 1.1 mm Hg before resection and 8 ± 3.7 mm Hg after resection. The mean anesthesia time was 6.6 ± 1.05 h and 6.9 ± 0.5 h for 75% and 90% resection, respectively. The mean operative time was 4.6 ± 0.9

  7. [Compartmental model of the adsorption of a dye by proteins. The possible role of adsorption in the hepatic excretion of bromosulphophthalein].

    PubMed

    Nguyen-Phong-Chau; Brocas, J

    1976-07-01

    A compartmental model was suggested for the study of the hepatic excretion of bromosulphophthalein (BSP). By using a hypothesis concerning the adsorption of the BSP compound by proteins, one derives from the equations of the model several known experimental results, viz. form of concentration curves that vary in accordance with the strength of the injection, existence of a limiting Tm value, etc. An explicit formula is given for calculating Tm.

  8. Hepatitis A through E (Viral Hepatitis)

    MedlinePlus

    ... the treatment of chronic hepatitis B include alpha interferon and peginterferon, which slow the replication of the ... Chronic hepatitis D is usually treated with pegylated interferon, although other potential treatments are under study. Hepatitis ...

  9. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 ... No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will test your blood. You ...

  10. The herbal compound Songyou Yin (SYY) inhibits hepatocellular carcinoma growth and improves survival in models of chronic fibrosis via paracrine inhibition of activated hepatic stellate cells

    PubMed Central

    Xue, Tong-Chun; Zhang, Quan-Bao; Zhang, Ke-Zhi; Zhang, Qiang-Bo; You, Yang; Tian, Hui; Qin, Lun-Xiu; Tang, Zhao-You

    2015-01-01

    Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down-regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells. PMID:26517671

  11. Cost-Effectiveness Modelling of Sofosbuvir-Containing Regimens for Chronic Genotype 5 Hepatitis C Virus Infection in South Africa.

    PubMed

    Fraser, Ilanca; Burger, Johanita; Lubbe, Martie; Dranitsaris, George; Sonderup, Mark; Stander, Tienie

    2016-04-01

    The recently launched nucleotide polymerase inhibitor sofosbuvir represents a significant turn in the treatment paradigm of chronic hepatitis C. While effective, sofosbuvir is also associated with a considerable cost. The objective of this study was to evaluate the cost effectiveness of sofosbuvir-containing regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 5 (HCV-G5) mono-infection in South Africa (SA). We constructed a lifetime horizon decision-analytic Markov model of the natural history of HCV infection to evaluate the cost effectiveness of sofosbuvir-ledipasvir (SOF/LDV) monotherapy against sofosbuvir triple therapy (SOF-TT) (sofosbuvir + pegylated interferon and ribavirin [peg-INF/RBV]) and the current standard of care (SOC) (peg-INF/RBV) for patients with chronic HCV-G5 in the South African context. The model was populated with data from published literature, expert opinion and South African private sector cost data. The price modelled for sofosbuvir was the predicted South African private sector price of 82,129.32 South African rand (R) (US$7000) for 12 weeks. The analysis was conducted from a third-party payer perspective. The outcome measures were discounted and undiscounted costs (in 2015 South African rand and US dollars) and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Outcomes from the cost-effectiveness model show that SOF/LDV yields the most favourable future health economic outcomes compared with SOF-TT and the current SOC in SA. Findings relating to the lifetime incremental cost per QALY gained for patients infected with HCV-G5 indicate that SOF/LDV dominated both SOF-TT and SOC, i.e. SOF/LDV is less costly and more effective. Outcomes from this analysis suggest that at a price of R123,190 ($US10,500) for 12 weeks of SOF/LDV might be cost effective for South African patients infected with HCV-G5.

  12. Hepatitis E Virus (HEV) Genotype 3 Infection of Human Liver Chimeric Mice as a Model for Chronic HEV Infection

    PubMed Central

    Pas, Suzan D.; van der Net, Guido; de Man, Robert A.; Osterhaus, Albert D. M. E.; Haagmans, Bart L.; Boonstra, Andre

    2016-01-01

    ABSTRACT Genotype 3 (gt3) hepatitis E virus (HEV) infections are emerging in Western countries. Immunosuppressed patients are at risk of chronic HEV infection and progressive liver damage, but no adequate model system currently mimics this disease course. Here we explore the possibilities of in vivo HEV studies in a human liver chimeric mouse model (uPA+/+Nod-SCID-IL2Rγ−/−) next to the A549 cell culture system, using HEV RNA-positive EDTA-plasma, feces, or liver biopsy specimens from 8 immunocompromised patients with chronic gt3 HEV. HEV from feces- or liver-derived inocula showed clear virus propagation within 2 weeks after inoculation onto A549 cells, compared to slow or no HEV propagation of HEV RNA-positive, EDTA-plasma samples. These in vitro HEV infectivity differences were mirrored in human-liver chimeric mice after intravenous (i.v.) inoculation of selected samples. HEV RNA levels of up to 8 log IU HEV RNA/gram were consistently present in 100% of chimeric mouse livers from week 2 to week 14 after inoculation with human feces- or liver-derived HEV. Feces and bile of infected mice contained moderate to large amounts of HEV RNA, while HEV viremia was low and inconsistently detected. Mouse-passaged HEV could subsequently be propagated for up to 100 days in vitro. In contrast, cell culture-derived or seronegative EDTA-plasma-derived HEV was not infectious in inoculated animals. In conclusion, the infectivity of feces-derived human HEV is higher than that of EDTA-plasma-derived HEV both in vitro and in vivo. Persistent HEV gt3 infections in chimeric mice show preferential viral shedding toward mouse bile and feces, paralleling the course of infection in humans. IMPORTANCE Hepatitis E virus (HEV) genotype 3 infections are emerging in Western countries and are of great concern for immunosuppressed patients at risk for developing chronic HEV infection. Lack of adequate model systems for chronic HEV infection hampers studies on HEV infectivity and transmission

  13. Prevention of Hepatic Fibrosis in a Murine Model of Metabolic Syndrome with Nonalcoholic Steatohepatitis

    PubMed Central

    DeLeve, Laurie D.; Wang, Xiangdong; Kanel, Gary C.; Atkinson, Roscoe D.; McCuskey, Robert S.

    2008-01-01

    The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-4F. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyperleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-4F prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit. PMID:18772330

  14. Model based estimates of long-term persistence of inactivated hepatitis A vaccine-induced antibodies in adults.

    PubMed

    Hens, Niel; Habteab Ghebretinsae, Aklilu; Hardt, Karin; Van Damme, Pierre; Van Herck, Koen

    2014-03-14

    In this paper, we review the results of existing statistical models of the long-term persistence of hepatitis A vaccine-induced antibodies in light of recently available immunogenicity data from 2 clinical trials (up to 17 years of follow-up). Healthy adult volunteers monitored annually for 17 years after the administration of the first vaccine dose in 2 double-blind, randomized clinical trials were included in this analysis. Vaccination in these studies was administered according to a 2-dose vaccination schedule: 0, 12 months in study A and 0, 6 months in study B (NCT00289757/NCT00291876). Antibodies were measured using an in-house ELISA during the first 11 years of follow-up; a commercially available ELISA was then used up to Year 17 of follow-up. Long-term antibody persistence from studies A and B was estimated using statistical models for longitudinal data. Data from studies A and B were modeled separately. A total of 173 participants in study A and 108 participants in study B were included in the analysis. A linear mixed model with 2 changepoints allowed all available results to be accounted for. Predictions based on this model indicated that 98% (95%CI: 94-100%) of participants in study A and 97% (95%CI: 94-100%) of participants in study B will remain seropositive 25 years after receiving the first vaccine dose. Other models using part of the data provided consistent results: ≥95% of the participants was projected to remain seropositive for ≥25 years. This analysis, using previously used and newly selected model structures, was consistent with former estimates of seropositivity rates ≥95% for at least 25 years. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Modelling the prevalence of hepatitis C virus amongst blood donors in Libya: An investigation of providing a preventive strategy.

    PubMed

    Daw, Mohamed A; Shabash, Amira; El-Bouzedi, Abdallah; Dau, Aghnya A; Habas, Moktar

    2016-02-12

    To determine hepatitis C virus (HCV) seroprevalence among the Libyan population using blood donors and applying the autoregressive integrated moving average (ARIMA) model to predict future trends and formulate plans to minimize the burden of HCV infection. HCV positive cases were collected from 1008214 healthy blood donors over a 6-year period from 2008 to 2013. Data were used to construct the ARIMA model to forecast HCV seroprevalence among blood donors. The validity of the model was assessed using the mean absolute percentage error between the observed and fitted seroprevalence. The fitted ARIMA model was used to forecast the incidence of HCV beyond the observed period for the year 2014 and further to 2055. The overall prevalence of HCV among blood donors was 1.8%, varying over the study period from 1.7% to 2.5%, though no significant variation was found within each calendar year. The ARIMA model showed a non-significant auto-correlation of the residuals, and the prevalence was steady within the last 3 years as expressed by the goodness-of-fit test. The forecast incidence showed an increase in HCV seropositivity in 2014, ranging from 500 to 700 per 10000 population, with an overall prevalence of 2.3%-2.7%. This may be extended to 2055 with minimal periodical variation within each 6-year period. The applied model was found to be valuable in evaluating the seroprevalence of HCV among blood donors, and highlighted the growing burden of such infection on the Libyan health care system. The model may help in formulating national policies to prevent increases in HCV infection and plan future strategies that target the consequences of the infection.

  16. Modelling the prevalence of hepatitis C virus amongst blood donors in Libya: An investigation of providing a preventive strategy

    PubMed Central

    Daw, Mohamed A; Shabash, Amira; El-Bouzedi, Abdallah; Dau, Aghnya A; Habas, Moktar; Libyan Study Group of Hepatitis and HIV

    2016-01-01

    AIM: To determine hepatitis C virus (HCV) seroprevalence among the Libyan population using blood donors and applying the autoregressive integrated moving average (ARIMA) model to predict future trends and formulate plans to minimize the burden of HCV infection. METHODS: HCV positive cases were collected from 1008214 healthy blood donors over a 6-year period from 2008 to 2013. Data were used to construct the ARIMA model to forecast HCV seroprevalence among blood donors. The validity of the model was assessed using the mean absolute percentage error between the observed and fitted seroprevalence. The fitted ARIMA model was used to forecast the incidence of HCV beyond the observed period for the year 2014 and further to 2055. RESULTS: The overall prevalence of HCV among blood donors was 1.8%, varying over the study period from 1.7% to 2.5%, though no significant variation was found within each calendar year. The ARIMA model showed a non-significant auto-correlation of the residuals, and the prevalence was steady within the last 3 years as expressed by the goodness-of-fit test. The forecast incidence showed an increase in HCV seropositivity in 2014, ranging from 500 to 700 per 10000 population, with an overall prevalence of 2.3%-2.7%. This may be extended to 2055 with minimal periodical variation within each 6-year period. CONCLUSION: The applied model was found to be valuable in evaluating the seroprevalence of HCV among blood donors, and highlighted the growing burden of such infection on the Libyan health care system. The model may help in formulating national policies to prevent increases in HCV infection and plan future strategies that target the consequences of the infection. PMID:26870670

  17. Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis.

    PubMed

    Fan, Hui-Ning; Chen, Ni-Wei; Shen, Wei-Lin; Zhao, Xiang-Yun; Zhang, Jing

    2015-09-01

    The present study aimed to investigate the effects of endogenous hydrogen sulfide (H2S) on the expression levels of angiotensin II type 1 receptor (AGTR1) in a rat model of carbon tetrachloride (CCl4)‑induced hepatic fibrosis. A total of 56 Wistar rats were randomly divided into four groups: Normal control group, model group, sodium hydrosulfide (NaHS) group, and DL‑propargylglycine (PAG) group. Hepatic fibrosis was induced by CCl4. The rats in the PAG group were intraperitoneally injected with PAG, an inhibitor of cystathionine‑γ‑lyase (CSE). The rats in the NaHS group were intraperitoneally injected with NaHS. An equal volume of saline solution was intraperitoneally injected into both the control and model groups. All rats were sacrificed at week three or four following treatment. The serum levels of hyaluronidase (HA), laminin protein (LN), procollagen III (PcIII), and collagen IV (cIV) were detected using ELISA. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin (ALB) were detected using an automatic biochemical analyzer. The liver mRNA expression levels of CSE were detected by reverse transcription‑quantitative polymerase chain reaction. The liver expression levels of AGTR1 and the plasma expression levels of H2S were detected using western blot analyses. The results indicated that the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly higher in the PAG group, as compared with the model group (P<0.05). Conversely, the expression levels of ALB were significantly lower in the PAG group, as compared with the model group. In addition, the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly lower in the NaHS group, as

  18. Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis

    PubMed Central

    FAN, HUI-NING; CHEN, NI-WEI; SHEN, WEI-LIN; ZHAO, XIANG-YUN; ZHANG, JING

    2015-01-01

    The present study aimed to investigate the effects of endogenous hydrogen sulfide (H2S) on the expression levels of angiotensin II type 1 receptor (AGTR1) in a rat model of carbon tetrachloride (CCl4)-induced hepatic fibrosis. A total of 56 Wistar rats were randomly divided into four groups: Normal control group, model group, sodium hydrosulfide (NaHS) group, and DL-propargylglycine (PAG) group. Hepatic fibrosis was induced by CCl4. The rats in the PAG group were intraperitoneally injected with PAG, an inhibitor of cystathionine-γ-lyase (CSE). The rats in the NaHS group were intraperitoneally injected with NaHS. An equal volume of saline solution was intraperitoneally injected into both the control and model groups. All rats were sacrificed at week three or four following treatment. The serum levels of hyaluronidase (HA), laminin protein (LN), procollagen III (PcIII), and collagen IV (cIV) were detected using ELISA. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin (ALB) were detected using an automatic biochemical analyzer. The liver mRNA expression levels of CSE were detected by reverse transcription-quantitative polymerase chain reaction. The liver expression levels of AGTR1 and the plasma expression levels of H2S were detected using western blot analyses. The results indicated that the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly higher in the PAG group, as compared with the model group (P<0.05). Conversely, the expression levels of ALB were significantly lower in the PAG group, as compared with the model group. In addition, the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly lower in the NaHS group, as compared with

  19. Understanding early serum hepatitis D virus and HBsAg kinetics during pegylated interferon-alfa therapy via mathematical modeling

    PubMed Central

    Guedj, Jeremie; Rotman, Yaron; Cotler, Scott J.; Koh, Christopher; Schmid, Peter; Albrecht, Jeff; Haynes-Williams, Vanessa; Liang, Jake T.; Hoofnagle, Jay H.; Heller, Theo; Dahari, Harel

    2014-01-01

    There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy a median delay of 9 days (interquartile range IQR:[5;15]) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first-phase lasting for 25 days (IQR:[23;58]) was followed by a slower or plateau second-phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR:[93;99.8]). Median serum HDV half-life (t1/2) was estimated to 2.9 days (IQR:[1.5;5.3]) with pretreatment production and clearance of about 1010 (IQR:[109.8-1010.8]) virions/day. None of the patients with flat 2nd phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second-phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR:[20-460]. The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. Conclusions Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients. PMID:25098971

  20. Liver Cancer and Hepatitis B

    MedlinePlus

    ... Our Accomplishments Annual Reports Our Videos What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  1. Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease

    PubMed Central

    Le, Anh; Shibata, Noreene M.; French, Samuel W.; Kim, Kyoungmi; Kharbanda, Kusum K.; Islam, Mohammad S.; LaSalle, Janine M.; Halsted, Charles H.; Keen, Carl L.; Medici, Valentina

    2014-01-01

    Background Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation. PMID:24810691

  2. Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease.

    PubMed

    Le, Anh; Shibata, Noreene M; French, Samuel W; Kim, Kyoungmi; Kharbanda, Kusum K; Islam, Mohammad S; LaSalle, Janine M; Halsted, Charles H; Keen, Carl L; Medici, Valentina

    2014-05-07

    Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.

  3. The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice.

    PubMed

    Ideta, Takayasu; Shirakami, Yohei; Miyazaki, Tsuneyuki; Kochi, Takahiro; Sakai, Hiroyasu; Moriwaki, Hisataka; Shimizu, Masahito

    2015-12-08

    Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a novel NAFLD model mouse using monosodium glutamate (MSG) and a high-fat diet (HFD) and investigated the effects of a DPP-4 inhibitor, teneligliptin, on the progression of NAFLD. Male MSG/HFD-treated mice were divided into two groups, one of which received teneligliptin in drinking water. Administration of MSG and HFD caused mice to develop severe fatty changes in the liver, but teneligliptin treatment improved hepatic steatosis and inflammation, as evaluated by the NAFLD activity score. Serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased in teneligliptin-treated mice (p < 0.05). Hepatic mRNA levels of the genes involved in de novo lipogenesis were significantly downregulated by teneligliptin (p < 0.05). Moreover, teneligliptin increased hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein. These findings suggest that teneligliptin attenuates lipogenesis in the liver by activating AMPK and downregulating the expression of genes involved in lipogenesis. DPP-4 inhibitors may be effective for the treatment of NAFLD and may be able to prevent its progression to non-alcoholic steatohepatitis.

  4. Functional hepatic recovery after xenotransplantation of cryopreserved fetal liver cells or soluble cell-factor administration in a cirrhotic rat model: are viable cells necessary?

    PubMed

    Ochenashko, Olga V; Nikitchenko, Yurii V; Volkova, Nataliya A; Mazur, Svetlana P; Somov, Alexander Y; Fuller, Barry J; Petrenko, Alexander Y

    2008-07-01

    Chronic liver failure results in the decrease of the number of functioning hepatocytes. It dictates the necessity of using exogenous viable cells or/and agents that can stimulate hepatic regenerative processes. Fetal liver contains both hepatic and hematopoietic stem cells with high proliferative potential, which may replace damaged cells. Also, immature cells produce fetal-specific factors which may support the injured liver. Our aim was to test the ability of human fetal liver cells and cell-free fetal-specific factors of non-hepatic origin to stimulate recovery processes in an experimental model of carbon tetrachloride-induced cirrhosis in rats. Cirrhotic rats were intrasplenically injected with fetal liver cells (1 x 10(7) cells/0.3 mL medium) or cell-free fetal-specific factors (0.3 mL/1 mg protein). Control groups received medium alone. Serum indexes, hepatic functions, and morphology were evaluated for 15 days. Human fetal liver cell transplantation was shown to abrogate the mortality of cirrhotic animals, to improve serum markers, and to restore liver mitochondrial function and detoxification. Morphological patterns of liver recovery were observed by histology. In comparison, an injection of fetal-specific factors produced similar functional recovery, whilst a more limited liver regeneration was observed by histology. The positive effects of fetal liver cell and cell-free fetal-specific factors in experimental cirrhosis may result from the presence of stage-specific factors activating hepatocellular repair.

  5. COMPARISON OF THE EFFECTS OF AGING AND IL-6 ON THE HEPATIC INFLAMMATORY RESPONSE IN TWO MODELS OF SYSTEMIC INJURY: SCALD INJURY VERSUS I.P. LPS ADMINISTRATION

    PubMed Central

    Gomez, Christian R.; Nomellini, Vanessa; Baila, Horea; Oshima, Kiyoko; Kovacs, Elizabeth J.

    2011-01-01

    Regardless of age, a marked elevation in circulating IL-6 levels correlates with increased mortality after injury or an inflammatory challenge. We previously reported that aged IL-6 knockout mice given LPS have improved survival and reduced inflammatory response than LPS-treated aged wild type (WT) mice. Herein, we analyzed the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: dorsal scald (burn) injury versus intraperitoneal LPS administration. At 24 h after burn injury, circulating alanine aminotransferase and hepatic neutrophil accumulation were comparable regardless of age or IL-6 deficiency. However, at this same time point, these indicators of liver damage, in addition to hepatic levels of KC, a neutrophil chemoattractant, were increased in aged WT mice given LPS relative to young WT mice given LPS. The hepatic injury was drastically reduced in aged IL-6 knockout mice given LPS as compared with LPS-exposed aged WT mice. Our results suggest that the nature of the insult will determine the degree of remote injury in aged animals. In addition, the role of IL-6 as a contributing factor of tissue injury may be insult specific. PMID:18636046

  6. Comparison of the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: scald injury versus i.p. LPS administration.

    PubMed

    Gomez, Christian R; Nomellini, Vanessa; Baila, Horea; Oshima, Kiyoko; Kovacs, Elizabeth J

    2009-02-01

    Regardless of age, a marked elevation in circulating IL-6 levels correlates with increased mortality after injury or an inflammatory challenge. We previously reported that aged IL-6 knockout mice given LPS have improved survival and reduced inflammatory response than LPS-treated aged wild type (WT) mice. Herein, we analyzed the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: dorsal scald (burn) injury versus intraperitoneal LPS administration. At 24 h after burn injury, circulating alanine aminotransferase and hepatic neutrophil accumulation were comparable regardless of age or IL-6 deficiency. However, at this same time point, these indicators of liver damage, in addition to hepatic levels of KC, a neutrophil chemoattractant, were increased in aged WT mice given LPS relative to young WT mice given LPS. The hepatic injury was drastically reduced in aged IL-6 knockout mice given LPS as compared with LPS-exposed aged WT mice. Our results suggest that the nature of the insult will determine the degree of remote injury in aged animals. In addition, the role of IL-6 as a contributing factor of tissue injury may be insult specific.

  7. [Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure].

    PubMed

    Foerster, F; Wörns, M A; Galle, P R; Schattenberg, J M

    2015-12-01

    Direct acting antivirals (DAAs) have increased cure rates for chronic hepatitis C infection up to nearly 100 %. At the same time treatment costs have risen significantly. Treating all HCV infected patients in Germany with DAAs would generate medication costs ranging between 19 and 37 billion EUR depending on the drug regimen used. Expenses in patients who fail to respond to treatment would amount to approximately 0.9 to 2.15 billion EUR. In difficult to treat patient populations that are characterized by prior failure to treatment or advanced liver disease, lost drug expenses are particularly high due to lower cure rates and longer treatment duration. Outcome-based reimbursement schemes are used to improve the quality of care and to reduce costs in the health care system. In Germany, disease management programs have been implemented for defined chronic diseases. However, drug reimbursement is still based on packages sold (pay for pill). In this context, it would be appealing to link reimbursement and treatment success (pay for cure) in order to reward successful treatment, limit lost drug spending and develop a shared risk environment that would involve all concerned parties. Under the assumption that 20,000 patients with HCV are treated each year in Germany and that cure rates are 95.4 %, the saved treatment costs would amount up to 45 and 107 million EUR per year. By this approach, economic incentives to withhold therapy from difficult to treat patients could be avoided. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Viral evolution and interferon resistance of hepatitis C virus RNA replication in a cell culture model.

    PubMed

    Sumpter, Rhea; Wang, Chunfu; Foy, Eileen; Loo, Yueh-Ming; Gale, Michael

    2004-11-01

    Hepatitis C virus (HCV) replicates through an error-prone process that may support the evolution of genetic variants resistant to the host cell antiviral response and interferon (IFN)-based therapy. We evaluated HCV-IFN interactions within a long-term culture system of Huh7 cell lines harboring different variants of an HCV type 1b subgenomic RNA replicon that differed at only two sites within the NS5A-encoding region. A replicon with a K insertion at HCV codon 2040 replicated efficiently and exhibited sequence stability in the absence of host antiviral pressure. In contrast, a replicon with an L2198S point mutation replicated poorly and triggered a cellular response characterized by IFN-beta production and low-level IFN-stimulated gene (ISG) expression. When maintained in long term-culture, the L2198S RNA evolved into a stable high-passage (HP) variant with six additional point mutations throughout the HCV protein-encoding region that enhanced viral replication. The HP RNA transduced Huh7 cells with more than 1,000-fold greater efficiency than its L2198S progenitor or the K2040 sequence. Replication of the HP RNA resisted suppression by IFN-alpha treatment and was associated with virus-directed reduction in host cell expression of ISG56, an antagonist of HCV RNA translation. Accordingly, the HP RNA was retained within polyribosome complexes in vivo that were refractory to IFN-induced disassembly. These results identify ISG56 as a translational control effector of the host response to HCV and provide direct evidence to link this response to viral sequence evolution, ISG regulation, and selection of the IFN-resistant viral phenotype.

  9. Noninvasive serum models to predict significant liver related events in chronic hepatitis C.

    PubMed

    Thandassery, Ragesh Babu; Kaabi, Saad Al; Soofi, Madiha E; Tharian, Benjamin; Singh, Rajvir

    2017-07-01

    We aim to compare 20 noninvasive fibrosis scores (NIFS), derived from routine blood tests, for predicting significant liver-related adverse events (SLRE) in patients with chronic hepatitis C (CHC) after anti-viral treatment (AVT) with the goal to identify independent predictors for these outcomes. From 1605 patients who received AVT (pegylated interferon and ribavirin) from January 2002 to June 2014, 20 NIFS were calculated from routine blood tests prior to AVT. Areas under the receiver-operating characteristic curve (AUROC) were calculated for each of these NIFS for predicting non-response to AVT and development of SLRE on follow-up. Mean age was 41.9 ± 9.7 years, and patients were predominantly genotype 4 (65%). After AVT, there were 1089 (67.8%) responders, 482 (30%) non-responders and 34 (2.1%) relapsers. After median follow-up of 6580.5 patient-years, 60 (3.8%) had SLRE, 52 (3.2%) had decompensation, and 11 (0.7%) had hepatocellular carcinoma (HCC). The predictive accuracy of NIFS and liver biopsy (LB) for non-response to AVT was low. FIB-4, FibroQ and King score showed high accuracy for predicting adverse events. For predicting decompensation, HCC and SLRE, FibroQ (0.881), King score (0.905) and FibroQ (0.877) had the highest AUROC, respectively. On multivariate analysis, independent predictors for treatment non-response (age, ALT, GGT, platelet count), HCC (albumin, GGT) and SLRE (albumin, GGT, platelet count) were identified. Some simple pretreatment blood parameters and NIFS showed high accuracy for predicting development of SLRE post treatment. Application of these simple scores can improve assessment of long-term liver prognosis for CHC.

  10. Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model

    PubMed Central

    Wei, Jishu; Wu, Junli; Gao, Wentao; Li, Qiang; Jiang, Kuirong

    2016-01-01

    Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury. PMID:27872855

  11. Relaxivity-iron calibration in hepatic iron overload: Probing underlying biophysical mechanisms using a Monte Carlo model

    PubMed Central

    Ghugre, Nilesh R.; Wood, John C.

    2010-01-01

    Iron overload is a serious condition for patients with β-thalassemia, transfusion-dependent sickle cell anemia and inherited disorders of iron metabolism. MRI is becoming increasingly important in non-invasive quantification of tissue iron, overcoming the drawbacks of traditional techniques (liver biopsy). R2*(1/T2*) rises linearly with iron while R2(1/T2) has a curvilinear relationship in human liver. Although recent work has demonstrated clinically-valid estimates of human liver iron, the calibration varies with MRI sequence, field strength, iron chelation therapy and organ imaged, forcing recalibration in patients. To understand and correct these limitations, a thorough understanding of the underlying biophysics is of critical importance. Toward this end, a Monte Carlo based approach, using human liver as a ‘model’ tissue system, was employed to determine the contribution of particle size and distribution on MRI signal relaxation. Relaxivities were determined for hepatic iron concentrations (HIC) ranging from 0.5–40 mg iron/ g dry tissue weight. Model predictions captured the linear and curvilinear relationship of R2* and R2 with HIC respectively and were within in vivo confidence bounds; contact or chemical exchange mechanisms were not necessary. A validated and optimized model will aid understanding and quantification of iron-mediated relaxivity in tissues where biopsy is not feasible (heart, spleen). PMID:21337413

  12. Cost-effectiveness model for hepatitis C screening and treatment: Implications for Egypt and other countries with high prevalence

    PubMed Central

    Kim, David D.; Hutton, David W.; Raouf, Ahmed A.; Salama, Mohsen; Hablas, Ahmed; Seifeldin, Ibrahim A.; Soliman, Amr S.

    2014-01-01

    Hepatitis C Virus (HCV) infection is a major cause of cirrhosis and liver cancer, and many developing countries report intermediate-to-high prevalence. However, the economic impact of screening and treatment for HCV in high prevalence countries has not been well studied. Thus, we examined the cost-effectiveness of screening and treatment for HCV infection for asymptomatic, average-risk adults using a Markov decision analytic model. In our model, we collected age-specific prevalence, disease progression rates for Egyptians, and local cost estimates in Egypt, which has the highest prevalence of HCV infection (~15%) in the world. We estimated the incremental cost-effectiveness ratio (ICER) and conducted sensitivity analyses to determine how cost-effective HCV screening and treatment might be in other developing countries with high and intermediate prevalence. In Egypt, implementing a screening program using triple-therapy treatment (sofosbuvir with pegylated interferon and ribavirin) was dominant compared to no screening because it would have lower total costs and improve health outcomes. HCV screening and treatment would also be cost-effective in global settings with intermediate costs of drug treatment (~$8,000) and a higher sustained viral response rate (70–80%). PMID:25469976

  13. Cost-effectiveness model for hepatitis C screening and treatment: Implications for Egypt and other countries with high prevalence.

    PubMed

    Kim, David D; Hutton, David W; Raouf, Ahmed A; Salama, Mohsen; Hablas, Ahmed; Seifeldin, Ibrahim A; Soliman, Amr S

    2015-01-01

    Hepatitis C virus (HCV) infection is a major cause of cirrhosis and liver cancer, and many developing countries report intermediate-to-high prevalence. However, the economic impact of screening and treatment for HCV in high prevalence countries has not been well studied. Thus, we examined the cost-effectiveness of screening and treatment for HCV infection for asymptomatic, average-risk adults using a Markov decision analytic model. In our model, we collected age-specific prevalence, disease progression rates for Egyptians and local cost estimates in Egypt, which has the highest prevalence of HCV infection (~15%) in the world. We estimated the incremental cost-effectiveness ratio and conducted sensitivity analyses to determine how cost-effective HCV screening and treatment might be in other developing countries with high and intermediate prevalence. In Egypt, implementing a screening programme using triple-therapy treatment (sofosbuvir with pegylated interferon and ribavirin) was dominant compared with no screening because it would have lower total costs and improve health outcomes. HCV screening and treatment would also be cost-effective in global settings with intermediate costs of drug treatment (~$8000) and a higher sustained viral response rate (70-80%).

  14. Hepatitis E.

    PubMed

    Kamar, Nassim; Bendall, Richard; Legrand-Abravanel, Florence; Xia, Ning-Shao; Ijaz, Samreen; Izopet, Jacques; Dalton, Harry R

    2012-06-30

    Hepatitis E virus (HEV) was discovered during the Soviet occupation of Afghanistan in the 1980s, after an outbreak of unexplained hepatitis at a military camp. A pooled faecal extract from affected soldiers was ingested by a member of the research team. He became sick, and the new virus (named HEV), was detected in his stool by electron microscopy. Subsequently, endemic HEV has been identified in many resource-poor countries. Globally, HEV is the most common cause of acute viral hepatitis. The virus was not initially thought to occur in developed countries, but recent reports have shown this notion to be mistaken. The aim of this Seminar is to describe recent discoveries regarding HEV, and how they have changed our understanding of its effect on human health worldwide. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. A novel “humanized mouse” model for autoimmune hepatitis and the association of gut microbiota with liver inflammation

    PubMed Central

    Yuksel, Muhammed; Wang, Yipeng; Tai, Ningwen; Peng, Jian; Guo, Junhua; Beland, Kathie; Lapierre, Pascal; David, Chella; Alvarez, Fernando; Colle, Isabelle; Yan, Huiping; Mieli-Vergani, Giorgina; Vergani, Diego; Ma, Yun; Wen, Li

    2016-01-01

    Background Autoimmune hepatitis (AIH) in humans is a severe inflammatory liver disease, characterized by interface hepatitis, the presence of circulating autoantibodies and hyper-gammaglobulinemia. There are two types of AIH, type-1 (AIH-1) and type-2 (AIH-2) characterized by distinct autoimmune serology. Patients with AIH-1 are positive for anti-smooth muscle and/or anti-nuclear (SMA/ANA) autoantibodies whereas patients with AIH-2 have anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. Cytochrome P4502D6 (CYP2D6) is the antigenic target of anti-LKM1 and formiminotransferase cyclodeaminase (FTCD) is the antigenic target of anti-LC1. It is known that AIH, both type-1 and type-2, is strongly linked to the Human Leukocyte Antigen (HLA) alleles -DR3, -DR4 and -DR7. However, the direct evidence of the association of HLA with AIH is lacking. Methods We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the non-obese diabetic (NOD) background (HLA-DR3 NOD) by immunization of HLA-DR3− and HLA-DR3+ NOD mice with a DNA plasmid, coding for human CYP2D6/FTCD fusion protein. Results Immunization with CYP2D6/FTCD leads to a sustained elevation of alanine aminotransferase (ALT), development of ANA and anti-LKM1/anti-LC1 autoantibodies, chronic immune cell infiltration and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced Th1 immune response and paucity of the frequency of regulatory T-cell (Treg) in the liver. Moreover, HLA-DR3+ mice with exacerbated AIH showed reduced diversity and total load of gut bacteria. Conclusion Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions in vivo. PMID:26185095

  16. Modeling and analysis of innate immune responses induced by the host cells against hepatitis C virus infection.

    PubMed

    Obaid, Ayesha; Ahmad, Jamil; Naz, Anam; Awan, Faryal Mehwish; Paracha, Rehan Zafar; Tareen, Samar Hayat Khan; Anjum, Sadia; Raza, Abida; Baumbach, Jan; Ali, Amjad

    2015-05-01

    An in-depth understanding of complex systems such as hepatitis C virus (HCV) infection and host immunomodulatory response is an open challenge for biologists. In order to understand the mechanisms involved in immune evasion by HCV, we present a simplified formalization of the highly dynamic system consisting of HCV, its replication cycle and host immune responses at the cellular level using hybrid Petri net (HPN). The approach followed in this study comprises of step wise simulation, model validation and analysis of host immune response. This study was performed with an objective of making correlations among viral RNA levels, interferon (IFN) production and interferon stimulated genes (ISGs) induction. The results correlate with the biological data verifying that the model is very useful in predicting the dynamic behavior of the signaling proteins in response to a stimulus. This study implicates that HCV infection is dependent upon several key factors of the host immune response. The effect of host proteins on limiting viral infection is effectively overruled by the viral pathogen. This study also analyzes activity levels of RNase L, miR-122, IFN, ISGs and PKR induction and inhibition of TLR3/RIG1 mediated pathways in response to targeted manipulation in the presence of HCV. The results are in complete agreement at the time of writing with the published expression studies and western blot experiments. Our model also provides some biological insights regarding the role of PKR in the acute infection of HCV. It might help to explain why many patients fail to clear acute HCV infection while others, with low ISG basal levels, clear HCV spontaneously. The described methodology can easily be reproduced, which suitably supports the study of other viral infections in a formal, automated and expressive manner. The Petri net-based modeling approach applied here may provide valuable insights for study design and analyses to evaluate other disease associated integrated pathways

  17. Fish Oil Feeding Modulates the Expression of Hepatic MicroRNAs in a Western-Style Diet-Induced Nonalcoholic Fatty Liver Disease Rat Model

    PubMed Central

    Shao, Yang; Feng, Han; Li, Na; Zhang, Hongyu

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide. Recent studies have indicated that fish oil supplementation has benefits against NAFLD. Our previous transcriptomic study has validated the effect of fish oil supplementation on altering hepatic gene expression in a NAFLD rat model. In the current study, we examined the effects of fish oil on the expression of hepatic microRNAs. Male Sprague–Dawley rats were fed with a lab chow (CON), high-fat high-cholesterol diet (WD), or WD supplemented with fish oil (FOH), respectively. Small RNAs were extracted from livers for RNA-sequencing. A total of 79 miRNAs were identified as differentially expressed miRNAs (DEMs) between FOH and WD groups, exemplified by rno-miR-29c-3p, rno-miR-30d-5p, rno-miR-33-5p, rno-miR-34a, and rno-miR-328a-3p. Functional annotation of DEMs predicted target genes suggested that the altered hepatic miRNAs contributed to fish oil modification of hepatic lipid metabolism and signaling transduction. Integrative analysis of DEMs and differentially expressed genes suggested that the expression difference of Pcsk9, Insig2, Per3, and Socs1/3 between FOH and WD groups may be due to miRNA modification. Our study reveals that fish oil supplementation alters hepatic expression of miRNAs, which may contribute to fish oil amelioration of NAFLD in rats. PMID:28691019

  18. Fish Oil Feeding Modulates the Expression of Hepatic MicroRNAs in a Western-Style Diet-Induced Nonalcoholic Fatty Liver Disease Rat Model.

    PubMed

    Wang, Hualin; Shao, Yang; Yuan, Fahu; Feng, Han; Li, Na; Zhang, Hongyu; Wu, Chaodong; Liu, Zhiguo

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide. Recent studies have indicated that fish oil supplementation has benefits against NAFLD. Our previous transcriptomic study has validated the effect of fish oil supplementation on altering hepatic gene expression in a NAFLD rat model. In the current study, we examined the effects of fish oil on the expression of hepatic microRNAs. Male Sprague-Dawley rats were fed with a lab chow (CON), high-fat high-cholesterol diet (WD), or WD supplemented with fish oil (FOH), respectively. Small RNAs were extracted from livers for RNA-sequencing. A total of 79 miRNAs were identified as differentially expressed miRNAs (DEMs) between FOH and WD groups, exemplified by rno-miR-29c-3p, rno-miR-30d-5p, rno-miR-33-5p, rno-miR-34a, and rno-miR-328a-3p. Functional annotation of DEMs predicted target genes suggested that the altered hepatic miRNAs contributed to fish oil modification of hepatic lipid metabolism and signaling transduction. Integrative analysis of DEMs and differentially expressed genes suggested that the expression difference of Pcsk9, Insig2, Per3, and Socs1/3 between FOH and WD groups may be due to miRNA modification. Our study reveals that fish oil supplementation alters hepatic expression of miRNAs, which may contribute to fish oil amelioration of NAFLD in rats.

  19. Natural orifice transluminal endoscopic wedge hepatic resection with a water-jet hybrid knife in a non-survival porcine model

    PubMed Central

    Shi, Hong; Jiang, Sheng-Jun; Li, Bin; Fu, Deng-Ke; Xin, Pei; Wang, Yong-Guang

    2011-01-01

    AIM: To explore the feasibility of a water-jet hybrid knife to facilitate wedge hepatic resection using a natural orifice transluminal endoscopic surgery (NOTES) approach in a non-survival porcine model. METHODS: The Erbe Jet2 water-jet system allows a needleless, tissue-selective hydro-dissection with a pre-selected pressure. Using this system, wedge hepatic resection was performed through three natural routes (trans-anal, trans-vaginal and trans-umbilical) in three female pigs weighing 35 kg under general anesthesia. Entry into the peritoneal cavity was via a 15-mm incision using a hook knife. The targeted liver segment was marked by an APC probe, followed by wedge hepatic resection performed using a water-jet hybrid knife with the aid of a 4-mm transparent distance soft cap mounted onto the tip of the endoscope for holding up the desired plane. The exposed vascular and ductal structures were clipped with Endoclips. Hemostasis was applied to the bleeding cut edges of the liver parenchyma by electrocautery. After the procedure, the incision site was left open, and the animal was euthanized followed by necropsy. RESULTS: Using the Erbe Jet2 water-jet system, trans-anal and trans-vaginal wedge hepatic resection was successfully performed in two pigs without laparoscopic assistance. Trans-umbilical attempt failed due to an unstable operating platform. The incision for peritoneal entry took 1 min, and about 2 h was spent on excision of the liver tissue. The intra-operative blood loss ranged from 100 to 250 mL. Microscopically, the hydro-dissections were relatively precise and gentle, preserving most vessels. CONCLUSION: The Erbe Jet2 water-jet system can safely accomplish non-anatomic wedge hepatic resection in NOTES, which deserves further studies to shorten the dissection time. PMID:21412502

  20. Natural orifice transluminal endoscopic wedge hepatic resection with a water-jet hybrid knife in a non-survival porcine model.

    PubMed

    Shi, Hong; Jiang, Sheng-Jun; Li, Bin; Fu, Deng-Ke; Xin, Pei; Wang, Yong-Guang

    2011-02-21

    To explore the feasibility of a water-jet hybrid knife to facilitate wedge hepatic resection using a natural orifice transluminal endoscopic surgery (NOTES) approach in a non-survival porcine model. The Erbe Jet2 water-jet system allows a needleless, tissue-selective hydro-dissection with a pre-selected pressure. Using this system, wedge hepatic resection was performed through three natural routes (trans-anal, trans-vaginal and trans-umbilical) in three female pigs weighing 35 kg under general anesthesia. Entry into the peritoneal cavity was via a 15-mm incision using a hook knife. The targeted liver segment was marked by an APC probe, followed by wedge hepatic resection performed using a water-jet hybrid knife with the aid of a 4-mm transparent distance soft cap mounted onto the tip of the endoscope for holding up the desired plane. The exposed vascular and ductal structures were clipped with Endoclips. Hemostasis was applied to the bleeding cut edges of the liver parenchyma by electrocautery. After the procedure, the incision site was left open, and the animal was euthanized followed by necropsy. Using the Erbe Jet2 water-jet system, trans-anal and trans-vaginal wedge hepatic resection was successfully performed in two pigs without laparoscopic assistance. Trans-umbilical attempt failed due to an unstable operating platform. The incision for peritoneal entry took 1 min, and about 2 h was spent on excision of the liver tissue. The intra-operative blood loss ranged from 100 to 250 mL. Microscopically, the hydro-dissections were relatively precise and gentle, preserving most vessels. The Erbe Jet2 water-jet system can safely accomplish non-anatomic wedge hepatic resection in NOTES, which deserves further studies to shorten the dissection time.

  1. Performance of several simple, noninvasive models for assessing significant liver fibrosis in patients with chronic hepatitis B

    PubMed Central

    Zeng, Xianghua; Xu, Cheng; He, Dengming; Li, Maoshi; Zhang, Huiyan; Wu, Quanxin; Xiang, Dedong; Wang, Yuming

    2015-01-01

    Aim To compare the performance of several simple, noninvasive models comprising various serum markers in diagnosing significant liver fibrosis in the same sample of patients with chronic hepatitis B (CHB) with the same judgment standard. Methods A total of 308 patients with CHB who had undergone liver biopsy, laboratory tests, and liver stiffness measurement (LSM) at the Southwest Hospital, Chongqing, China between March 2010 and April 2014 were retrospectively studied. Receiver operating characteristic (ROC) curves and area under ROC curves (AUROCs) were used to analyze the results of the models, which incorporated age-platelet (PLT) index (API model), aspartate transaminase (AST) to alanine aminotransferase (ALT) ratio (AAR model), AST to PLT ratio index (APRI model), γ-glutamyl transpeptidase (GGT) to PLT ratio index (GPRI model), GGT-PLT-albumin index (S index model), age-AST-PLT-ALT index (FIB-4 model), and age-AST-PLT-ALT-international normalized ratio index (Fibro-Q model). Results The AUROCs of the S index, GPRI, FIB-4, APRI, API, Fibro-Q, AAR, and LSM for predicting significant liver fibrosis were 0.726 (P < 0.001), 0.726 (P < 0.001), 0.621 (P = 0.001), 0.619 (P = 0.001), 0.580 (P = 0.033), 0.569 (P = 0.066), 0.495 (P = 0.886), and 0.757 (P < 0.001), respectively. The S index and GPRI had the highest correlation with histopathological scores (r = 0.373, P < 0.001; r = 0.372, P < 0.001, respectively) and LSM values (r = 0.516, P < 0.001; r = 0.513, P < 0.001, respectively). When LSM was combined with S index and GPRI, the AUROCs were 0.753 (P < 0.001) and 0.746 (P < 0.001), respectively. Conclusion S index and GPRI had the best diagnostic performance for significant liver fibrosis and were robust predictors of significant liver fibrosis in patients with CHB for whom transient elastography was unavailable. PMID:26088852

  2. Phenethyl amides as novel noncovalent inhibitors of hepatitis C virus NS3/4A protease: discovery, initial SAR, and molecular modeling.

    PubMed

    Colarusso, Stefania; Koch, Uwe; Gerlach, Benjamin; Steinkühler, Christian; De Francesco, Raffaele; Altamura, Sergio; Matassa, Victor G; Narjes, Frank

    2003-01-30

    The discovery of novel, reversible and competitive tripeptide inhibitors of the Hepatitis C virus NS3/4A serine protease is described. These inhibitors are characterized by the presence of a C-terminal phenethyl amide group, which extends into the prime side of the enzyme. Initial SAR together with molecular modeling and data from site-directed mutagenesis suggest an interaction of the phenethyl amide group with Lys-136.

  3. Modeling the impact of early antiretroviral therapy for adults coinfected with HIV and hepatitis B or C in South Africa.

    PubMed

    Martin, Natasha K; Devine, Angela; Eaton, Jeffrey W; Miners, Alec; Hallett, Timothy B; Foster, Graham R; Dore, Gregory J; Easterbrook, Philippa J; Legood, Rosa; Vickerman, Peter

    2014-01-01

    There has been discussion about whether individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) (∼30% of all people living with HIV) should be prioritized for early HIV antiretroviral therapy (ART). We assess the relative benefits of providing ART at CD4 count below 500  cells/μl or immediate ART to HCV/HIV or HBV/HIV-coinfected adults compared with HIV-monoinfected adults. We evaluate individual outcomes (HIV/liver disease progression) and preventive benefits in a generalized HIV epidemic setting. We modeled disease progression for HIV-monoinfected, HBV/HIV-coinfected, and HCV/HIV-coinfected adults for differing ART eligibility thresholds (CD4 <350  cells/μl, CD4 <500  cells/μl, immediate ART eligibility upon infection). We report disability-adjusted life-years averted per 100 person-years on ART (DALYaverted/100PYonART) as a measure of the health benefits generated from incremental changes in ART eligibility. Sensitivity analyses explored impact on sexual HIV and vertical HIV, HCV, and HBV transmission. For HBV/HIV-coinfected adults, a switch to ART initiation at CD4 count below 500  cells/μl from CD4 below 350  cells/μl generates 9% greater health benefits per year on ART (48 DALYaverted/100PYonART) than for HIV-monoinfected adults (44 DALYaverted/100PYonART). Additionally, ART at CD4 below 500  cells/μl could prevent 25% and 32% of vertical transmissions of HIV and HBV, respectively. For HCV/HIV-coinfected adults, AR